Joseph Garner

All Publications

• Making bloodwork work: the impact of sample collection, processing, and storage on plasma glutathione measurement, and implications for translation. Translational psychiatry Coden, K. M., Nguyen, D. K., Moorhead, R., Stix-Brunell, B. E., Baker, J. N., Parker, K. J., Garner, J. P. 2024; 14 (1): 385

  Abstract

  Psychiatry has traditionally focused on the study of neurons and neurotransmitter physiology in the pathophysiology and treatment of psychiatric disorders. A growing literature highlights REDOX imbalance (a state in which demand for antioxidants surpasses their bioavailability) as a common pathophysiology for a diverse array of brain conditions (e.g., trichotillomania, schizophrenia, autism, Parkinson's disease). REDOX imbalance is typically measured via plasma glutathione, as glutathione is critical to the adaptive antioxidant response in the brain. Accordingly, glutathione, its precursors, and/or metabolites serve as biomarkers of disease risk, therapeutic targets, and measures of treatment response. However, as with any emerging field, there are currently several different methods for collection, processing, storage, and calculation of summary measures of plasma glutathione metabolism, within and between preclinical and clinical research. The lack of evidence-based best-practice methodology hampers reproducibility (preclinical or clinical), and translation (between preclinical and clinical work). To address this methodological need, here we used a repeated measures within-subject design to investigate how sample preparation (type of anticoagulant used during blood collection, deproteinization status, and storage temperature) affects plasma glutathione levels. Accordingly, we collected whole blood from mice (N = 13), and then, using a commercially available kit, quantified glutathione in plasma stored in four different ways. Presuming that these preparation conditions and post-processing calculations are unimportant, we would expect to see no difference in glutathione levels and summary measures from the same sample. However, we found each of these variables to significantly alter quantified glutathione levels. Accordingly, we propose a vital, gold-standard methodology for both sample collection, processing, and storage of plasma used for glutathione quantification and for summary calculations of glutathione that can be used preclinically and clinically, thus yielding more streamlined translation.

  View details for DOI 10.1038/s41398-024-03086-5

  View details for PubMedID 39313523

  View details for PubMedCentralID PMC11420238

• Pebble to the Metal: A Boulder Approach to Enrichment for Danio rerio. PloS one Byrd, K. A., Theil, J. H., Geronimo, J. T., Ahloy-Dallaire, J., Gutierrez, M. F., Hui, E. I., Felt, T. K., Coden, K. M., Ratuski, A. S., Felt, S. A., Chu, D. K., Garner, J. P. 2024; 19 (5): e0298657

  Abstract

  Zebrafish are an established and widely used animal model, yet there is limited understanding of their welfare needs. Despite an increasing number of studies on zebrafish enrichment, in-tank environmental enrichment remains unpopular among researchers. This is due to perceived concerns over health/hygiene when it comes to introducing enrichment into the tank, although actual evidence for this is sparse. To accommodate this belief, regardless of veracity, we tested the potential benefits of enrichments presented outside the tank. Thus, we investigated the preferences and physiological stress of zebrafish with pictures of pebbles placed underneath the tank. We hypothesized that zebrafish would show a preference for enriched environments and have lower stress levels than barren housed zebrafish. In our first experiment, we housed zebrafish in a standard rack system and recorded their preference for visual access to a pebble picture, with two positive controls: visual access to conspecifics, and group housing. Using a crossover repeated-measures factorial design, we tested if the preference for visual access to pebbles was as strong as the preference for social contact. Zebrafish showed a strong preference for visual access to pebbles, equivalent to that for conspecifics. Then, in a second experiment, tank water cortisol was measured to assess chronic stress levels of zebrafish housed with or without a pebble picture under their tank, with group housing as a positive control. Cortisol levels were significantly reduced in zebrafish housed with pebble pictures, as were cortisol levels in group housed zebrafish. In fact, single housed zebrafish with pebble pictures showed the same cortisol levels as group housed zebrafish without pebble pictures. Thus, the use of an under-tank pebble picture was as beneficial as being group housed, effectively compensating for the stress of single housing. Pebble picture enrichment had an additive effect with group housing, where group housed zebrafish with pebble pictures had the lowest cortisol levels of any treatment group.

  View details for DOI 10.1371/journal.pone.0298657

  View details for PubMedID 38713725

  View details for PubMedCentralID PMC11075867

• Rhesus macaque social functioning is paternally, but not maternally, inherited by sons: potential implications for autism. Molecular autism Garner, J. P., Talbot, C. F., Del Rosso, L. A., McCowan, B., Kanthaswamy, S., Haig, D., Capitanio, J. P., Parker, K. J. 2023; 14 (1): 25

  Abstract

  BACKGROUND: Quantitative autistic traits are common, heritable, and continuously distributed across the general human population. Patterns of autistic traits within families suggest that more complex mechanisms than simple Mendelian inheritance-in particular, parent of origin effects-may be involved. The ideal strategy for ascertaining parent of origin effects is by half-sibling analysis, where half-siblings share one, but not both, parents and each individual belongs to a unique combination of paternal and maternal half-siblings. While this family structure is rare in humans, many of our primate relatives, including rhesus macaques, have promiscuous breeding systems that consistently produce paternal and maternal half-siblings for a given index animal. Rhesus macaques, like humans, also exhibit pronounced variation in social functioning.METHODS: Here we assessed differential paternal versus maternal inheritance of social functioning in male rhesus macaque offspring (N=407) using ethological observations and ratings on a reverse-translated quantitative autistic trait measurement scale. Restricted Maximum Likelihood mixed models with unbounded variance estimates were used to estimate the variance components needed to calculate the genetic contribution of parents as the proportion of phenotypic variance (sigma2P) between sons that could uniquely be attributed to their shared genetics (sigma2g), expressed as sigma2g/sigma2P (or the proportion of phenotypic variance attributable to genetic variance), as well as narrow sense heritability (h2).RESULTS: Genetic contributions and heritability estimates were strong and highly significant for sons who shared a father but weak and non-significant for sons who shared a mother. Importantly, these findings were detected using the same scores from the same sons in the same analysis, confirmed when paternal and maternal half-siblings were analyzed separately, and observed with two methodologically distinct behavioral measures. Finally, genetic contributions were similar for full-siblings versus half-siblings that shared only a father, further supporting a selective paternal inheritance effect.LIMITATIONS: These data are correlational by nature. A larger sample that includes female subjects, enables deeper pedigree assessments, and supports molecular genetic analyses is warranted.CONCLUSIONS: Rhesus macaque social functioning may be paternally, but not maternally, inherited by sons. With continued investigation, this approach may yield important insights into sex differences in autism's genetic liability.

  View details for DOI 10.1186/s13229-023-00556-3

  View details for PubMedID 37480043

• Oxytocin and the social facilitation of placebo effects. Molecular psychiatry Itskovich, E., Bowling, D. L., Garner, J. P., Parker, K. J. 2022

  Abstract

  Significant clinical improvement is often observed in patients who receive placebo treatment in randomized double-blind placebo-controlled trials. While a proportion of this "improvement" reflects experimental design limitations (e.g., reliance on subjective outcomes, unbalanced groups, reporting biases), some of it reflects genuine improvement corroborated by physiological change. Converging evidence across diverse medical conditions suggests that clinically-relevant benefits from placebo treatment are associated with the activation of brain reward circuits. In parallel, evidence has accumulated showing that such benefits are facilitated by clinicians that demonstrate warmth and proficiency during interactions with patients. Here, we integrate research on these neural and social aspects of placebo effects with evidence linking oxytocin and social reward to advance a neurobiological account for the social facilitation of placebo effects. This account frames oxytocin as a key mediator of treatment success across a wide-spectrum of interventions that increase social connectedness, therebyproviding a biological basis for assessing this fundamental non-specific element of medical care.

  View details for DOI 10.1038/s41380-022-01515-9

  View details for PubMedID 35338314

• The Mouse in the Room: The Critical Distinction Between Regulations and Ethics Principles of Animal Research Ethics Garner, J. P. OUP. 2020: 79–98
• Power to the People: Power, Negative Results and Sample Size JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE Gaskill, B. N., Garner, J. P. 2020; 59 (1): 9–16

  Abstract

  The practical application of statistical power is becoming an increasingly important part of experimental design, data analysis, and reporting. Power is essential to estimating sample size as part of planning studies and obtaining ethical approval for them. Furthermore, power is essential for publishing and interpreting negative results. In this manuscript, we review what power is, how it can be calculated, and reporting recommendations if a null result is found. Power can be thought of as reflecting the signal to noise ratio of an experiment. The conventional wisdom that statistical power is driven by sample size (which increases the signal in the data), while true, is a misleading oversimplification. Relatively little discussion covers the use of experimental designs which control and reduce noise. Even small improvements in experimental design can achieve high power at much lower sample sizes than (for instance) a simple t test. Failure to report experimental design or the proposed statistical test on animal care and use protocols creates a dilemma for IACUCs, because it is unknown whether sample size has been correctly calculated. Traditional power calculations, which are primarily provided for animal number justifications, are only available for simple, yet low powered, experimental designs, such as paired t tests. Thus, in most controlled experimental studies, the only analyses for which power can be calculated are those that inheriently have low statistical power; these analyses should not be used because they require more animals than necessary. We provide suggestions for more powerful experimental designs (such as randomized block and factorial designs) that increase power, and we describe methods to easily calculate sample size for these designs that are suitable for IACUC number justifications. Finally we also provide recommendations for reporting negative results, so that readers and reviewers can determine whether an experiment had sufficient power. The use of more sophisticated designs in animal experiments will inevitably improve power, reproducibility, and reduce animal use.

  View details for DOI 10.30802/AALAS-JAALAS-19-000042

  View details for Web of Science ID 000510023700002

  View details for PubMedID 31852563

  View details for PubMedCentralID PMC6978577

• A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism. Science translational medicine Parker, K. J., Oztan, O. n., Libove, R. A., Mohsin, N. n., Karhson, D. S., Sumiyoshi, R. D., Summers, J. E., Hinman, K. E., Motonaga, K. S., Phillips, J. M., Carson, D. S., Fung, L. K., Garner, J. P., Hardan, A. Y. 2019

  Abstract

  The social impairments of autism spectrum disorder (ASD) have a major impact on quality of life, yet there are no medications that effectively treat these core social behavior deficits. Preclinical research suggests that arginine vasopressin (AVP), a neuropeptide involved in promoting mammalian social behaviors, may be a possible treatment for ASD. Using a double-blind, randomized, placebo-controlled, parallel study design, we tested the efficacy and tolerability of a 4-week intranasal AVP daily treatment in 30 children with ASD. AVP-treated participants aged 6 to 9.5 years received the maximum daily target dose of 24 International Units (IU); participants aged 9.6 to 12.9 years received the maximum daily target dose of 32 IU. Intranasal AVP treatment compared to placebo enhanced social abilities as assessed by change from baseline in this phase 2 trial's primary outcome measure, the Social Responsiveness Scale, 2nd Edition total score (SRS-2 T score; F1,20 = 9.853; P = 0.0052; ηp2 = 33.0%; Cohen's d = 1.40). AVP treatment also diminished anxiety symptoms and some repetitive behaviors. Most of these findings were more pronounced when we accounted for pretreatment AVP concentrations in blood. AVP was well tolerated with minimal side effects. No AVP-treated participants dropped out of the trial, and there were no differences in the rate of adverse events reported between treatment conditions. Last, no changes from baseline were observed in vital signs, electrocardiogram tracings, height and body weight, or clinical chemistry measurements after 4 weeks of AVP treatment. These preliminary findings suggest that AVP has potential for treating social impairments in children with ASD.

  View details for PubMedID 31043522

• Preventing, treating, and predicting barbering: A fundamental role for biomarkers of oxidative stress in a mouse model of Trichotillomania PLOS ONE Vieira, G. d., Lossie, A. C., Lay, D. C., Radcliffe, J. S., Garner, J. P. 2017; 12 (4)

  Abstract

  Barbering, where a "barber" mouse plucks hair from its cagemates or itself, is both a spontaneously occurring abnormal behavior in mice and a well validated model of Trichotillomania (TTM). N-Acetylcysteine, (NAC) a cysteine derived food additive, is remarkably effective in treating TTM patients, but its mechanism of action is unknown. Reactive Oxygen Species (ROS), also known as free radicals, form as a natural byproduct of the normal metabolism of oxygen. Under normal circumstances, cells are able to defend themselves against ROS damage with antioxidant pathways. NAC is the precursor to the main antioxidant produced to defend the brain. Therefore, we hypothesized that barbering is a disease of oxidative stress, whereby ROS and/or a failure of antioxidant defenses leads to neuronal damage that induces barbering in susceptible animals. We tested this hypothesis in 32 female C57BL/6J mice by treating half with 1g/kg BW/day of NAC in their diet, and testing for protection against developing barbering behavior and curing of barbering behavior, and simultaneously testing for a panel of biomarkers of oxidative stress. NAC reduced the chance that mice would be barbers, and this effect did not differ between healthy (i.e. prevention) and affected animals (i.e. cure). Barbering animals had elevated urinary antioxidant capacity, indicative of oxidative stress, at all timepoints. Additionally, after treatment the risk of barbering increased with decreasing hydroxy-2'-deoxyguanosine (8-OHdG) levels, and with increasing glutathione (GSH) and oxidized glutathione (GSSG) levels, further indicating that barbering mice were under oxidative stress regardless of treatment with NAC. We did not find compelling evidence that urinary total antioxidant capacity, or urinary 8-OHdG, could predict response to NAC treatment. We conclude that NAC is effective in preventing and/or curing barbering at least in part by promoting GSH synthesis, thereby preventing oxidative damage.

  View details for DOI 10.1371/journal.pone.0175222

  View details for Web of Science ID 000399875900023

  View details for PubMedID 28426681

• Introducing Therioepistemology: the study of how knowledge is gained from animal research LAB ANIMAL Garner, J. P., Gaskill, B. N., Webers, E. M., Ahloy-Dallaire, J., Pritchett-Corning, K. R. 2017; 46 (4): 103-113

  Abstract

  This focus issue of Lab Animal coincides with a tipping point in biomedical research. For the first time, the scale of the reproducibility and translatability crisis is widely understood beyond the small cadre of researchers who have been studying it and the pharmaceutical and biotech companies who have been living it. Here we argue that an emerging literature, including the papers in this focus issue, has begun to congeal around a set of recurring themes, which themselves represent a paradigm shift. This paradigm shift can be characterized at the micro level as a shift from asking "what have we controlled for in this model?" to asking "what have we chosen to ignore in this model, and at what cost?" At the macro level, it is a shift from viewing animals as tools (the furry test tube), to viewing them as patients in an equivalent human medical study. We feel that we are witnessing the birth of a new discipline, which we term Therioepistemology, or the study of how knowledge is gained from animal research. In this paper, we outline six questions that serve as a heuristic for critically evaluating animal-based biomedical research from a therioepistemological perspective. These six questions sketch out the broad reaches of this new discipline, though they may change or be added to as this field evolves. Ultimately, by formalizing therioepistemology as a discipline, we can begin to discuss best practices that will improve the reproducibility and translatability of animal-based research, with concomitant benefits in terms of human health and animal well-being.

  View details for Web of Science ID 000398431900020

  View details for PubMedID 28328885

• Systematic variation improves reproducibility of animal experiments NATURE METHODS Richter, S. H., Garner, J. P., Auer, C., Kunert, J., Wuerbel, H. 2010; 7 (3): 167-168

  View details for DOI 10.1038/nmeth0310-167

  View details for Web of Science ID 000275058200003

  View details for PubMedID 20195246

• Letter to the Editor Regarding "Assessing Methods for Replacement of Soiled Bedding Sentinels in Cage-level Exhaust IVC Racks" by Eichner and Smith. Journal of the American Association for Laboratory Animal Science : JAALAS Manuel, C., Luchins, K., Peterson, N. C., Dodelet-Devillers, A., Pettan-Brewer, C., Phaneuf, L., Garner, J. P., Lafollette, M. 2024; 63 (2): 103-104

  View details for PubMedID 38693638

• Naturally occurring low sociality in female rhesus monkeys: A tractable model for autism or not? Molecular autism Oztan, O., Del Rosso, L. A., Simmons, S. M., Nguyen, D. K., Talbot, C. F., Capitanio, J. P., Garner, J. P., Parker, K. J. 2024; 15 (1): 8

  Abstract

  Autism spectrum disorder (ASD) is characterized by persistent social interaction impairments and is male-biased in prevalence. We have established naturally occurring low sociality in male rhesus monkeys as a model for the social features of ASD. Low-social male monkeys exhibit reduced social interactions and increased autistic-like trait burden, with both measures highly correlated and strongly linked to low cerebrospinal fluid (CSF) arginine vasopressin (AVP) concentration. Little is known, however, about the behavioral and neurochemical profiles of female rhesus monkeys, and whether low sociality in females is a tractable model for ASD.Social behavior assessments (ethological observations; a reverse-translated autistic trait measurement scale, the macaque Social Responsiveness Scale-Revised [mSRS-R]) were completed on N = 88 outdoor-housed female rhesus monkeys during the non-breeding season. CSF and blood samples were collected from a subset of N = 16 monkeys across the frequency distribution of non-social behavior, and AVP and oxytocin (OXT) concentrations were quantified. Data were analyzed using general linear models.Non-social behavior frequency and mSRS-R scores were continuously distributed across the general female monkey population, as previously found for male monkeys. However, dominance rank significantly predicted mSRS-R scores in females, with higher-ranking individuals showing fewer autistic-like traits, a relationship not previously observed in males from this colony. Females differed from males in several other respects: Social behavior frequencies were unrelated to mSRS-R scores, and AVP concentration was unrelated to any social behavior measure. Blood and CSF concentrations of AVP were positively correlated in females; no significant relationship involving any OXT measure was found.This study sample was small, and did not consider genetic, environmental, or other neurochemical measures that may be related to female mSRS-R scores.Dominance rank is the most significant predictor of autistic-like traits in female rhesus monkeys, and CSF neuropeptide concentrations are unrelated to measures of female social functioning (in contrast to prior CSF AVP findings in male rhesus monkeys and male and female autistic children). Although preliminary, this evidence suggests that the strong matrilineal organization of this species may limit the usefulness of low sociality in female rhesus monkeys as a tractable model for ASD.

  View details for DOI 10.1186/s13229-024-00588-3

  View details for PubMedID 38291493

• Letter to the Editor Regarding "Assessing Methods for Replacement of Soiled Bedding Sentinels in Cage-level Exhaust IVC Racks" by Eichner and Smith. Journal of the American Association for Laboratory Animal Science : JAALAS Manuel, C., Luchins, K., Peterson, N. C., Dodelet-Devillers, A., Pettan-Brewer, C., Phaneuf, L., Garner, J. P., LaFollette, M. 2024

  View details for DOI 10.30802/AALAS-JAALAS-23-000111

  View details for PubMedID 38290718

• Chronic Adaptations in the Dorsal Horn Following a Cervical Spinal Cord Injury in Primates. The Journal of neuroscience : the official journal of the Society for Neuroscience Fisher, K. M., Garner, J. P., Darian-Smith, C. 2024; 44 (3)

  Abstract

  Spinal cord injury (SCI) is devastating, with limited treatment options and variable outcomes. Most in vivo SCI research has focused on the acute and early post-injury periods, and the promotion of axonal growth, so little is understood about the clinically stable chronic state, axonal growth over time, and what plasticity endures. Here, we followed animals into the chronic phase following SCI, to address this gap. Male macaques received targeted deafferentation, affecting three digits of one hand, and were divided into short (4-6 months) or long-term (11-12 months) groups, based on post-injury survival times. Monkeys were assessed behaviorally, where possible, and all exhibited an initial post-injury deficit in manual dexterity, with gradual functional recovery over 2 months. We previously reported extensive sprouting of somatosensory corticospinal (S1 CST) fibers in the dorsal horn in the first five post-injury months. Here, we show that by 1 year, the S1 CST sprouting is pruned, with the terminal territory resembling control animals. This was reflected in the number of putatively "functional" synapses observed, which increased over the first 4-5 months, and then returned to baseline by 1 year. Microglia density also increased in the affected dorsal horn at 4-6 months and then decreased, but did not return to baseline by 1 year, suggesting refinement continues beyond this time. Overall, there is a long period of reorganization and consolidation of adaptive circuitry in the dorsal horn, extending well beyond the initial behavioral recovery. This provides a potential window to target therapeutic opportunities during the chronic phase.

  View details for DOI 10.1523/JNEUROSCI.0877-23.2023

  View details for PubMedID 38233220

• A Cross-sectional Survey on Rodent Environmental Health Monitoring Practices: Benchmarking, Associations, and Barriers. Journal of the American Association for Laboratory Animal Science : JAALAS Luchins, K. R., Gates, K. V., Winn, C. B., Manuel, C. A., Pettan-Brewer, C., Foley, P. L., Peterson, N. C., Garner, J. P., Hanson, W., LaFollette, M. R. 2023; 62 (1): 64-73

  Abstract

  Tens of thousands of rodents are used each year in Rodent Health Monitoring programs. However, Environment Health Monitoring (EHM) could replace sentinel rodent use while maintaining or even improving diagnostic quality. Despite its advantages, widespread implementation of EHM appears to be relatively low. To better understand EHM's prevalence and factors influencing its use, we surveyed research animal professionals. Our hypotheses were (1) EHM prevalence would be low and (2) EHM use would be associated with beliefs and knowledge about EHM. Participants were recruited via online promotion. A total of 158 individuals completed a mixed-methods survey about current practices, beliefs, and knowledge about EHM. Qualitative data were coded using thematic analysis and analyzed using generalized linear models. Results showed that current EHM implementation was low; only 11% of institutions used EHM exclusively. Across the 111 institutions surveyed, over 20,000 soiled bedding sentinels were used each year. However, most participants believed EHM to be advantageous in replacing sentinel animals (78% of participants). Some participants believed EHM could save time (31%), cost less (27%), and be highly accurate (15%). Conversely, some participants believed EHM would be difficult to use due to their current caging type (40%), higher costs (21%), lower accuracy (16%), and personnel attitudes/expertise (14%). Overall, respondents with higher planned EHM use also had more positive attitudes, norms, and control of EHM. We also identified several factors that could promote the implementation of EHM. Communication efforts should emphasize that EHM is compatible with various types of caging, can provide cost savings, has high accuracy, and is consistent with the 3Rs as a replacement. Efforts should also focus on improving attitudes, encouraging peers, and providing resources to facilitate implementation. Implementation in just the surveyed institutions could eliminate the need for well over 20,000 rodents each year, consistent with 3Rs goals.

  View details for DOI 10.30802/AALAS-JAALAS-22-000086

  View details for PubMedID 36755202

• Rhesus monkey sociality is stable across time and linked to variation in the initiation but not receipt of prosocial behavior. American journal of primatology Talbot, C. F., Madrid, J. E., Del Rosso, L. A., Capitanio, J. P., Garner, J. P., Parker, K. J. 2022: e23442

  Abstract

  Rhesus monkeys and humans are highly social primates, yet both species exhibit pronounced variation in social functioning, spanning a spectrum of sociality. Naturally occurring low sociality in rhesus monkeys may be a promising construct by which to model social impairments relevant to human autism spectrum disorder (ASD), particularly if low sociality is found to be stable across time and associated with diminished social motivation. Thus, to better characterize variation in sociality and social communication profiles, we performed quantitative social behavior assessments on N=95 male rhesus macaques (Macaca mulatta) housed in large, outdoor groups. In Study 1, we determined the social classification of our subjects by rank-ordering their total frequency of nonsocial behavior. Monkeys with the greatest frequency of nonsocial behavior were classified as low-social (n=20) and monkeys with the lowest frequency of nonsocial behavior were classified as high-social (n=21). To assess group differences in social communication profiles, in Study 2, we quantified the rates of transient social communication signals, and whether these social signals were initiated by or directed towards the focal subject. Finally, in Study 3, we assessed the within-individual stability of sociality in a subset of monkeys (n=11 low-social, n=11 high-social) 2 years following our initial observations. Nonsocial behavior frequency significantly correlated across the two timepoints (Studies 1 and 3). Likewise, low-social versus high-social classification accurately predicted classification 2 years later. Low-social monkeys initiated less prosocial behavior than high-social monkeys, but groups did not differ in receipt of prosocial behavior, nor did they differ in threat behavior. These findings indicate that sociality is a stable, trait-like characteristic and that low sociality is linked to diminished initiation of prosocial behavior in rhesus macaques. This evidence also suggests that low sociality may be a useful construct for gaining mechanistic insight into the social motivational deficits often observed in people with ASD.

  View details for DOI 10.1002/ajp.23442

  View details for PubMedID 36268602

• Small sensory spinal lesions that affect hand function in monkeys greatly alter primary afferent and motor neuron connections in the cord. The Journal of comparative neurology Fisher, K. M., Garner, J. P., Darian-Smith, C. 2022

  Abstract

  Small sensory spinal injuries induce plasticity across the neuraxis, but little is understood about their effect on segmental connections or motor neuron (MN) function. Here, we begin to address this at two levels. First, we compared afferent input distributions from the skin and muscles of the digits with corresponding MN pools to determine their spatial relationship, in both the normal state and 4-6 months after a unilateral dorsal root/dorsal column lesion (DRL/DCL), affecting digits 1-3. Second, we looked at specific changes to MN inputs and membrane properties that likely impact functional recovery. Monkeys received a targeted unilateral DRL/DCL, and 4-6 months later, cholera toxin subunit B (CT-B) was injected bilaterally into either the distal pads of digits 1-3, or related intrinsic hand muscles, to label inputs to the cord, and corresponding MNs. In controls (unlesioned side), cutaneous and proprioceptive afferents from digits 1-3 showed different distribution patterns but similar rostrocaudal spread within the dorsal horn from C1 to T2. In contrast, MNs were distributed across just two segments (C7-8). Following the lesion, sensory inputs were significantly diminished across all 10 segments, though this did not alter MN distributions. Afferent and monoamine inputs, as well as KCC2 cotransporters, were also significantly altered on the cell membrane of CT-B labeled MNs postlesion. In contrast, inhibitory neurotransmission and perineuronal net integrity were not altered at this prechronic timepoint.  Our findings indicate that even a small sensory injury can significantly impact sensory and motor spinal neurons and provide new insight into the complex process of recovery.

  View details for DOI 10.1002/cne.25395

  View details for PubMedID 35973735

• Propofol Immersion as a Euthanasia Method for Adult Zebrafish (Danio rerio). Comparative medicine Davis, A. K., Garner, J. P., Chu, D. K., Felt, S. A. 2022

  Abstract

  The exponential rise of the zebrafish (Danio rerio) as a model organism in biomedical research has far outstripped our understanding of basic husbandry and welfare for this species. As a case in point, here we investigate the efficacy and welfare impact of different euthanasia methods for zebrafish. Not only is a humane death central to welfare and the 3Rs, but stress during euthanasia can change scientific outcomes. However, the most frequently used methods of euthanasia have multiple shortcomings with regard to animal welfare and human safety. In this study, we propose the use of propofol for immersion euthanasia of adult zebrafish. Propofol has been known to rapidly induce anesthesia in many species, including zebrafish, but its efficacy as a euthanasia agent for zebrafish has not fully been explored. In this study, adult zebrafish were euthanized by immersion on one of 5 different preparations: ice bath, 250 ppm MS222, 600 ppm lidocaine hydrochloride, 100 ppm propofol, or 150 ppm propofol for 20 or 30 min. Display of aversive behaviors, time to loss of righting reflex, time to cessation of opercular movement, and time to recovery after transfer to clean tank water were assessed and recorded. Propofol at both concentrations induced loss of righting reflex and loss of opercular movement more quickly than did MS222 or lidocaine hydrochloride and caused no display of aversive behaviors as seen with ice bath or lidocaine exposure. However, fish exposed to propofol at either concentration for 20 min sometimes recovered, whereas a 30-min exposure was sufficient for euthanasia of all fish tested. These findings suggest that exposure to propofol for a duration of at least 30 min quickly and effectively euthanizes adult zebrafish without compromising end of-life welfare.

  View details for DOI 10.30802/AALAS-CM-22-000050

  View details for PubMedID 35701076

• Autism-associated biomarkers: test-retest reliability and relationship to quantitative social trait variation in rhesus monkeys. Molecular autism Oztan, O., Talbot, C. F., Argilli, E., Maness, A. C., Simmons, S. M., Mohsin, N., Del Rosso, L. A., Garner, J. P., Sherr, E. H., Capitanio, J. P., Parker, K. J. 2021; 12 (1): 50

  Abstract

  BACKGROUND: Rhesus monkeys (Macaca mulatta) exhibit pronounced individual differences in social traits as measured by the macaque Social Responsiveness Scale-Revised. The macaque Social Responsiveness Scale was previously adapted from the Social Responsiveness Scale, an instrument designed to assess social and autistic trait variation in humans. To better understand potential biological underpinnings of this behavioral variation, we evaluated the trait-like consistency of several biological measures previously implicated in autism (e.g., arginine vasopressin, oxytocin, and their receptors, as well as ERK1/2, PTEN, and AKT(1-3) from the RAS-MAPK and PI3K-AKT pathways). We also tested which biological measures predicted macaque Social Responsiveness Scale-Revised scores.METHODS: Cerebrospinal fluid and blood samples were collected from N=76 male monkeys, which, as a sample, showed a continuous distribution on the macaque Social Responsiveness Scale-Revised. In a subset of these subjects (n=43), samples were collected thrice over a 10-month period. The following statistical tests were used: "Case 2A" intra-class correlation coefficients of consistency, principal component analysis, and general linear modeling.RESULTS: All biological measures (except AKT) showed significant test-retest reliability within individuals across time points. We next performed principal component analysis on data from monkeys with complete biological measurement sets at the first time point (n=57), to explore potential correlations between the reliable biological measures and their relationship to macaque Social Responsiveness Scale-Revised score; a three-component solution was found. Follow-up analyses revealed that cerebrospinal fluid arginine vasopressin concentration, but no other biological measure, robustly predicted individual differences in macaque Social Responsiveness Scale-Revised scores, such that monkeys with the lowest cerebrospinal fluid arginine vasopressin concentration exhibited the greatest social impairment. Finally, we confirmed that this result held in the larger study sample (in which cerebrospinal fluid arginine vasopressin values were available from n=75 of the subjects).CONCLUSIONS: These findings indicate that cerebrospinal fluid arginine vasopressin concentration is a stable trait-like measure and that it is linked to quantitative social trait variation in male rhesus monkeys.

  View details for DOI 10.1186/s13229-021-00442-w

  View details for PubMedID 34238350

• Assessment of medical morbidities in a rhesus monkey model of naturally occurring low sociality. Autism research : official journal of the International Society for Autism Research Myers, A. K., Talbot, C. F., Del Rosso, L. A., Maness, A. C., Simmons, S. M., Garner, J. P., Capitanio, J. P., Parker, K. J. 2021

  Abstract

  People with autism spectrum disorder (ASD) exhibit a variety of medical morbidities at significantly higher rates than the general population. Using an established monkey model of naturally occurring low sociality, we investigated whether low-social monkeys show an increased burden of medical morbidities compared to their high-social counterparts. We systematically reviewed the medical records of N = 152 (n = 73 low-social; n = 79 high-social) rhesus macaques (Macaca mulatta) to assess the number of traumatic injury, gastrointestinal, and inflammatory events, as well as the presence of rare medical conditions. Subjects' nonsocial scores, determined by the frequency they were observed in a nonsocial state (i.e., alone), and macaque Social Responsiveness Scale-Revised (mSRS-R) scores were also used to test whether individual differences in social functioning were related to medical morbidity burden. Medical morbidity type significantly differed by group, such that low-social monkeys incurred higher rates of traumatic injury compared to high-social monkeys. Nonsocial scores and mSRS-R scores also significantly and positively predicted traumatic injury rates, indicating that monkeys with the greatest social impairment were most impacted on this health measure. These findings from low-social monkeys are consistent with well-documented evidence that people with ASD incur a greater number of traumatic injuries and receive more peer bullying than their neurotypical peers, and add to growing evidence for the face validity of this primate model. LAY SUMMARY: People with autism exhibit multiple medical problems at higher rates than the general population. We conducted a comprehensive medical record review of monkeys that naturally exhibit differences in sociality and found that low-social monkeys are more susceptible to traumatic injuries than high-social monkeys. These results are consistent with reports that people with autism also incur greater traumatic injury and peer bullying and add to growing evidence for the validity of this monkey model.

  View details for DOI 10.1002/aur.2512

  View details for PubMedID 33847078

• Full closed loop open-source algorithm performance comparison in pigs with diabetes. Clinical and translational medicine Lal, R. A., Maikawa, C. L., Lewis, D., Baker, S. W., Smith, A. A., Roth, G. A., Gale, E. C., Stapleton, L. M., Mann, J. L., Yu, A. C., Correa, S., Grosskopf, A. K., Liong, C. S., Meis, C. M., Chan, D., Garner, J. P., Maahs, D. M., Buckingham, B. A., Appel, E. A. 2021; 11 (4): e387

  Abstract

  Understanding how automated insulin delivery (AID) algorithm features impact glucose control under full closed loop delivery represents a critical step toward reducing patient burden by eliminating the need for carbohydrate entries at mealtimes. Here, we use a pig model of diabetes to compare AndroidAPS and Loop open-source AID systems without meal announcements. Overall time-in-range (70-180mg/dl) for AndroidAPS was 58% ± 5%, while time-in-range for Loop was 35% ± 5%. The effect of the algorithms on time-in-range differed between meals and overnight. During the overnight monitoring period, pigs had an average time-in-range of 90% ± 7% when on AndroidAPS compared to 22% ± 8% on Loop. Time-in-hypoglycemia also differed significantly during the lunch meal, whereby pigs running AndroidAPS spent an average of 1.4% (+0.4/-0.8)% in hypoglycemia compared to 10% (+3/-6)% for those using Loop. As algorithm design for closed loop systems continues to develop, the strategies employed in the OpenAPS algorithm (known as oref1) as implemented in AndroidAPS for unannounced meals may result in a better overall control for full closed loop systems.

  View details for DOI 10.1002/ctm2.387

  View details for PubMedID 33931977

• Behavioral recovery after a spinal deafferentation injury in monkeys does not correlate with extent of corticospinal sprouting. Behavioural brain research Crowley, M., Lilak, A., Garner, J. P., Darian-Smith, C. 2021: 113533

  Abstract

  A long held view in the spinal cord injury field is that corticospinal terminal sprouting is needed for new connections to form, that then mediate behavioral recovery. This makes sense, but tells us little about the relationship between corticospinal sprouting extent and recovery potential. The inference has been that more extensive axonal sprouting predicts greater recovery, though there is little evidence to support this. Here we addressed this by comparing behavioral data from monkeys that had received one of two established deafferentation spinal injury models in monkeys (Darian-Smith et al., 2014, Fisher et al., 2019, 2020). Both injuries cut similar afferent pools supplying the thumb, index and middle fingers of one hand but each resulted in a very different corticospinal tract (CST) sprouting response. Following a cervical dorsal root lesion, the somatosensory CST retracted significantly, while the motor CST stayed largely intact. In contrast, when a dorsal column lesion was combined with the DRL, somatosensory and motor CSTs sprouted dramatically within the cervical cord. How these two responses relate to the behavioral outcome was not clear. Here we analyzed the behavioral outcome for the two lesions, and provide a clear example that sprouting extent does not track with behavioral recovery.

  View details for DOI 10.1016/j.bbr.2021.113533

  View details for PubMedID 34453971

• Natural food intake patterns have little synchronizing effect on peripheral circadian clocks. BMC biology Xie, X., Kukino, A., Calcagno, H. E., Berman, A. M., Garner, J. P., Butler, M. P. 2020; 18 (1): 160

  Abstract

  BACKGROUND: Circadian rhythms across mammalian tissues are coordinated by a master clock in the suprachiasmatic nucleus (SCN) that is principally entrained by light-dark cycles. Prior investigations have shown, however, that time-restricted feeding (TRF)-daily alternation of fasting and food availability-synchronizes peripheral clocks independent of the light-dark cycle and of the SCN. This has led to the idea that downstream peripheral clocks are entrained indirectly by food intake rhythms. However, TRF is not a normal eating pattern, and it imposes non-physiologic long fasts that rodents do not typically experience. Therefore, we tested whether normal feeding patterns can phase-shift or entrain peripheral tissues by measuring circadian rhythms of the liver, kidney, and submandibular gland in mPer2Luc mice under different food schedules.RESULTS: We employed home cage feeders to first measure ad libitum food intake and then to dispense 20-mg pellets on a schedule mimicking that pattern. In both conditions, PER2::LUC bioluminescence peaked during the night as expected. Surprisingly, shifting the scheduled feeding by 12h advanced peripheral clocks by only 0-3h, much less than predicted from TRF protocols. To isolate the effects of feeding from the light-dark cycle, clock phase was then measured in mice acclimated to scheduled feeding over the course of 3 months in constant darkness. In these conditions, peripheral clock phases were better predicted by the rest-activity cycle than by the food schedule, contrary to expectation based on TRF studies. At the end of both experiments, mice were exposed to a modified TRF with food provided in eight equally sized meals over 12h. In the light-dark cycle, this advanced the phase of the liver and kidney, though less so than in TRF with ad libitum access; in darkness, this entrained the liver and kidney but had little effect on the submandibular gland or the rest-activity cycle.CONCLUSIONS: These data suggest that natural feeding patterns can only weakly affect circadian clocks. Instead, in normally feeding mice, the central pacemaker in the brain may set the phase of peripheral organs via pathways that are independent of feeding behavior.

  View details for DOI 10.1186/s12915-020-00872-7

  View details for PubMedID 33158435

• Complex Interplay Between Cognitive Ability and Social Motivation in Predicting Social Skill: A Unique Role for Social Motivation in Children With Autism. Autism research : official journal of the International Society for Autism Research Itskovich, E., Zyga, O., Libove, R. A., Phillips, J. M., Garner, J. P., Parker, K. J. 2020

  Abstract

  Impairment in social interaction is a core feature of autism spectrum disorder (ASD), but the factors which contribute to this social skill deficiency are poorly understood. Previous research has shown that cognitive ability can impact social skill development in ASD. Yet, children with ASD whose cognitive abilities are in the normal range nevertheless demonstrate deficits in social skill. More recently, the social motivation theory of ASD has emerged as a framework by which to understand how failure to seek social experiences may lead to social skill deficits. This study was designed to better understand the relationships between cognitive ability, social motivation, and social skill in a well-characterized cohort of children with ASD (n = 79), their unaffected siblings (n = 50), and unrelated neurotypical controls (n = 60). The following instruments were used: The Stanford-Binet intelligence quotient (IQ), the Social Responsiveness Scale's Social Motivation Subscale, and the Vineland Adaptive Behavior Scales' Socialization Standard Score. We found that lower cognitive ability contributed to diminished social skill, but did so universally in all children. In contrast, social motivation strongly predicted social skill only in children with ASD, such that those with the lowest social motivation exhibited the greatest social skill impairment. Notably, this relationship was observed across a large range of intellectual ability but was most pronounced in those with IQs ≥ 80. These findings establish a unique link between social motivation and social skill in ASD and support the hypothesis that low social motivation may impair social skill acquisition in this disorder, particularly in children without intellectual disability. LAY SUMMARY: The relationships between cognitive ability, social motivation, and social skill are poorly understood. Here we report that cognitive ability predicts social skill in all children, whereas social motivation predicts social skill only in children with autism. These results establish a unique link between social motivation and social skill in autism, and suggest that low social motivation may impair social skill acquisition in this disorder, particularly in those without intellectual disability.

  View details for DOI 10.1002/aur.2409

  View details for PubMedID 33280272

• Complex Interplay Between Cognitive Ability and Social Motivation in Predicting Social Skill: A Unique Role for Social Motivation in Children With Autism AUTISM RESEARCH Itskovich, E., Zyga, O., Libove, R. A., Phillips, J. M., Garner, J. P., Parker, K. J. 2020

  View details for DOI 10.1002/aur.2409

  View details for Web of Science ID 000578768000001

• The epidemiology of fighting in group-housed laboratory mice. Scientific reports Theil, J. H., Ahloy-Dallaire, J., Weber, E. M., Gaskill, B. N., Pritchett-Corning, K. R., Felt, S. A., Garner, J. P. 2020; 10 (1): 16649

  Abstract

  Injurious home-cage aggression (fighting) in mice affects both animal welfare and scientific validity. It is arguably the most commonpotentially preventablemorbidity in mouse facilities. Existing literature on mouse aggression almost exclusively examines territorial aggression induced by introducing a stimulus mouse into the home-cageof a singly housed mouse (i.e. the resident/intruder test). However, fighting occurring in mice living together in long-term groups under standard laboratory housing conditions has barely been studied. We performed a point-prevalence epidemiological survey of fighting at a research institution with an approximate 60,000 cage census. A subset of cages was sampled over the course of a year and factors potentially influencing home-cage fighting were recorded. Fighting was almost exclusively seen in group-housed male mice. Approximately 14% of group-housed male cages were observed with fighting animals in brief behavioral observations, but only 14% of those cages with fighting had skin injuries observable from cage-side. Thus simple cage-side checks may be missing the majority of fighting mice. Housing system (the combination of cage ventilation and bedding type), genetic background, time of year, cage location on the rack, and rack orientation in the room were significant risk factors predicting fighting. Of these predictors, only bedding type is easily manipulated to mitigate fighting. Cage ventilation and rack orientation often cannot be changed in modern vivaria, as they are baked in by cookie-cutter architectural approaches to facility design. This study emphasizes the need to invest in assessing the welfare costs of new housing and husbandry systems before implementing them.

  View details for DOI 10.1038/s41598-020-73620-0

  View details for PubMedID 33024186

• ANIMAL MODELS OF TRICHOTILLOMANIA AND COMPULSIVE SKIN PICKING: A FOCUS ON THERIOEPISTEMOLOGY Garner, J. P. ELSEVIER SCIENCE INC. 2020: S327–S328

  View details for DOI 10.1016/j.jaac.2020.07.784

  View details for Web of Science ID 000579844101475

• A psychometrically robust screening tool to rapidly identify socially impaired monkeys in the general population. Autism research : official journal of the International Society for Autism Research Talbot, C. F., Garner, J. P., Maness, A. C., McCowan, B., Capitanio, J. P., Parker, K. J. 2020

  Abstract

  Naturally, low-social rhesus macaques exhibit social impairments with direct relevance to autism spectrum disorder (ASD). To more efficiently identify low-social individuals in a large colony, we exploited, refined, and psychometrically assessed the macaque Social Responsiveness Scale (mSRS), an instrument previously derived from the human ASD screening tool. We performed quantitative social behavior assessments and mSRS ratings on a total of N = 349 rhesus macaques (Macaca mulatta) housed in large, outdoor corrals. In one cohort (N = 116), we conducted inter-rater and test-retest reliabilities, and in a second cohort (N = 233), we evaluated the convergent construct and predictive validity of the mSRS-Revised (mSRS-R). Only 17 of the original 36 items demonstrated inter-rater and test-retest reliability, resulting in the 17-item mSRS-R. The mSRS-R showed strong validity: mSRS-R scores robustly predicted monkeys' social behavior frequencies in home corrals. Monkeys that scored 1.5 standard deviations from the mean on nonsocial behavior likewise exhibited significantly more autistic-like traits, and mSRS-R scores predicted individuals' social classification (low-social vs. high-social) with 96% accuracy (likelihood ratio chi-square = 25.07; P<0.0001). These findings indicate that the mSRS-R is a reliable, valid, and sensitive measure of social functioning, and like the human SRS, can be used as a high-throughput screening tool to identify socially impaired individuals in the general population. LAY SUMMARY: Variation in autistic traits can be measured in humans using the Social Responsiveness Scale (SRS). Here, we revised this scale for rhesus macaques (i.e., the mSRS-R), and showed that macaques exhibit individual differences in mSRS-R scores, and at the behavioral extremes, low-social vs. high-social monkeys exhibit more autistic-like traits. These results suggest that the mSRS-R can be used as a screening tool to rapidly and accurately identify low-social monkeys in the general population.

  View details for DOI 10.1002/aur.2335

  View details for PubMedID 32677285

• Reorganization of the Primate Dorsal Horn in Response to a Deafferentation Lesion Affecting Hand Function. The Journal of neuroscience : the official journal of the Society for Neuroscience Fisher, K. M., Garner, J., Darian-Smith, C. 2020

  Abstract

  The loss of sensory input following a spinal deafferentation injury can be debilitating, and this is especially true in primates when the hand is involved. While significant recovery of function occurs, little is currently understood about the reorganization of the neuronal circuitry, particularly within the dorsal horn. This region receives primary afferent input from the periphery, and cortical input via the somatosensory subcomponent of the corticospinal tract (S1 CST), and is critically important in modulating sensory transmission, both in normal and lesioned states. To determine how dorsal horn circuitry alters to facilitate recovery post-injury, we used an established deafferentation lesion model (DRL/DCL - dorsal root/dorsal column) in male monkeys to remove sensory input from just the opposing digits (D1-D3) of one hand. This results in a deficit in fine dexterity that recovers over several months. Electrophysiological mapping, tract tracing, and immunolabeling techniques were combined to delineate specific changes to dorsal horn input circuitry. Our main findings show that (1) there is complementary sprouting of the primary afferent and S1 CST populations into an overlapping region of the reorganizing dorsal horn, (2) S1 CST and primary afferent inputs connect in different ways within this region to facilitate sensory integration (3) there is a loss of larger S1 CST terminal boutons in the affected dorsal horn, but no change in the size profile of the spared/sprouted primary afferent terminal boutons post-lesion. Understanding such changes helps to inform new and targeted therapies that best promote recovery.SIGNIFICANCE STATEMENTSpinal injuries that remove sensation from the hand, can be debilitating, though functional recovery does occur. We examined changes to the neuronal circuitry of the dorsal horn in monkeys following a lesion that deafferented three digits of one hand. Little is understood about dorsal horn circuitry, despite the fact that this region loses most of its normal input after such an injury, and is clearly a major focus of reorganization. We found that both the spared primary afferents and somatosensory corticospinal efferents sprouted in an overlapping region of the dorsal horn after injury, and that larger (presumably faster) corticospinal terminals are lost, suggesting a significantly altered cortical modulation of primary afferents. Understanding this changing circuitry is important for designing targeted therapies.

  View details for DOI 10.1523/JNEUROSCI.2330-19.2020

  View details for PubMedID 31959698

• Neonatal CSF vasopressin concentration predicts later medical record diagnoses of autism spectrum disorder. Proceedings of the National Academy of Sciences of the United States of America Oztan, O. n., Garner, J. P., Constantino, J. N., Parker, K. J. 2020

  Abstract

  Autism spectrum disorder (ASD) is a brain disorder characterized by social impairments. ASD is currently diagnosed on the basis of behavioral criteria because no robust biomarkers have been identified. However, we recently found that cerebrospinal fluid (CSF) concentration of the "social" neuropeptide arginine vasopressin (AVP) is significantly lower in pediatric ASD cases vs. controls. As an initial step in establishing the direction of causation for this association, we capitalized upon a rare biomaterials collection of newborn CSF samples to conduct a quasi-prospective test of whether this association held before the developmental period when ASD first manifests. CSF samples had been collected in the course of medical care of 0- to 3-mo-old febrile infants (n = 913) and subsequently archived at -70 °C. We identified a subset of CSF samples from individuals later diagnosed with ASD, matched them 1:2 with appropriate controls (n = 33 total), and quantified their AVP and oxytocin (OXT) concentrations. Neonatal CSF AVP concentrations were significantly lower among ASD cases than controls and individually predicted case status, with highest precision when cases with comorbid attention-deficit/hyperactivity disorder were removed from the analysis. The associations were specific to AVP, as ASD cases and controls did not differ in neonatal CSF concentrations of the structurally related neuropeptide, OXT. These preliminary findings suggest that a neurochemical marker of ASD may be present very early in life, and if replicated in a larger, prospective study, this approach could transform how ASD is detected, both in behaviorally symptomatic children, and in infants at risk for developing it.

  View details for DOI 10.1073/pnas.1919050117

  View details for PubMedID 32341146

• Tell-tale TINT: Does the Time to Incorporate into Nest Test Evaluate Postsurgical Pain or Welfare in Mice? JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE Gallo, M. S., Karas, A. Z., Pritchett-Corning, K., Garner, J. P., Mulder, G., Gaskil, B. N. 2020; 59 (1): 37–45

  Abstract

  Identifying early indicators of distress in mice is difficult using either periodic monitoring or current technology. Likewise, poor pain identification remains a barrier to providing appropriate pain relief in many mouse models. The Time to Incorporate to Nest Test (TINT), a binary measure of the presence or absence of nesting behavior, was developed as a species-specific method of identifying moderate to severe distress and pain in mice. The current study was designed to evaluate alterations in nesting behavior after routine surgery and to validate the TINT's ability to measure pain-related behavioral changes. CD1 mice undergoing carotid artery catheterization as part of a commercial surgical cohort were randomly assigned various nesting, surgery, and analgesia conditions. To provide context for the TINT outcomes, we measured other variables affected by pain, such as weight loss, food consumption, and scores derived from the Mouse Grimace Scale (MGS). Mice that had surgery were more likely to have a negative TINT score as compared with controls. All mice were more likely to fail the TINT after receiving postoperative buprenorphine, suggesting that buprenorphine may have contributed to the failures. The TINT, MGS live scoring, and scoring MGS images all loaded strongly on a single component in a principal component analysis, indicating strong convergent validity between these measures. These data indicate that the TINT can provide a quick, objective indicator of altered welfare in mice, with the potential for a wide range of uses.

  View details for DOI 10.30802/AALAS-JAALAS-19-000044

  View details for Web of Science ID 000510023700006

  View details for PubMedID 31862018

  View details for PubMedCentralID PMC6978574

• Automated monitoring of mouse feeding and body weight for continuous health assessment LABORATORY ANIMALS Ahloy-Dallaire, J., Klein, J. D., Davis, J. K., Garner, J. P. 2019; 53 (4): 342–51

  View details for DOI 10.1177/0023677218797974

  View details for Web of Science ID 000478092800002

• Blood oxytocin concentration positively predicts contagious yawning behavior in children with autism spectrum disorder. Autism research : official journal of the International Society for Autism Research Mariscal, M. G., Oztan, O., Rose, S. M., Libove, R. A., Jackson, L. P., Sumiyoshi, R. D., Trujillo, T. H., Carson, D. S., Phillips, J. M., Garner, J. P., Hardan, A. Y., Parker, K. J. 2019

  Abstract

  Research suggests that children with autism spectrum disorder (ASD) may have reduced empathy, as measured by an impaired contagious yawn response, compared to typically developing (TD) children. Other research has failed to replicate this finding, instead attributing this phenomenon to group differences in attention paid to yawn stimuli. A third possibility is that only a subgroup of children with ASD exhibits the impaired contagious yawn response, and that it can be identified biologically. Here we quantified blood concentrations of the "social" neuropeptide oxytocin (OXT) and evaluated yawning behavior and attention rates during a laboratory task in children with ASD (N=34) and TD children (N=30) aged 6-12years. No group difference in contagious yawning behavior was found. However, a blood OXT concentration*group (ASD vs. TD) interaction positively predicted contagious yawning behavior (F1,50 =7.4987; P=0.0085). Specifically, blood OXT concentration was positively related to contagious yawning behavior in children with ASD, but not in TD children. This finding was not due to delayed perception of yawn stimuli and was observed whether attention paid to test stimuli and clinical symptom severity were included in the analysis or not. These findings suggest that only a biologically defined subset of children with ASD exhibits reduced empathy, as measured by the impaired contagious yawn response, and that prior conflicting reports of this behavioral phenomenon may be attributable, at least in part, to variable mean OXT concentrations across different ASD study cohorts. Autism Res 2019. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with autism may contagiously yawn (i.e., yawn in response to another's yawn) less often than people without autism. We find that people with autism who have lower levels of blood oxytocin (OXT), a hormone involved in social behavior and empathy, show decreased contagious yawning, but those who have higher blood OXT levels do not differ in contagious yawning from controls. This suggests that decreased contagious yawning may only occur in a biologically defined subset of people with autism.

  View details for DOI 10.1002/aur.2135

  View details for PubMedID 31132232

• A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism SCIENCE TRANSLATIONAL MEDICINE Parker, K. J., Oztan, O., Libove, R. A., Mohsin, N., Karhson, D. S., Sumiyoshi, R. D., Summers, J. E., Hinman, K. E., Motonaga, K. S., Phillips, J. M., Carson, D. S., Fung, L. K., Garner, J. P., Hardan, A. Y. 2019; 11 (491)

  View details for DOI 10.1126/scitranslmed.aau7356

  View details for Web of Science ID 000467273900004

• The effect of early life experience, environment, and genetic factors on spontaneous home-cage aggression-related wounding in male C57BL/6 mice (vol 46, pg 176, 2017) LAB ANIMAL Gaskill, B. N., Stottler, A. M., Garner, J. P., Winnicker, C. W., Mulder, G. B., Pritchett-Corning, K. R. 2019; 48 (5): 147–48

  View details for DOI 10.1038/s41684-019-0283-0

  View details for Web of Science ID 000470022100021

• Addendum: The effect of early life experience, environment, and genetic factors on spontaneous home-cage aggression-related wounding in male C57BL/6 mice. Lab animal Gaskill, B. N., Stottler, A. M., Garner, J. P., Winnicker, C. W., Mulder, G. B., Pritchett-Corning, K. R. 2019

  View details for PubMedID 30911175

• Extensive somatosensory and motor corticospinal sprouting occurs following a central dorsal column lesion in monkeys JOURNAL OF COMPARATIVE NEUROLOGY Fisher, K. M., Lilak, A., Garner, J., Darian-Smith, C. 2018; 526 (15): 2373–87

  View details for DOI 10.1002/cne.24491

  View details for Web of Science ID 000447808100003

• Automated monitoring of mouse feeding and body weight for continuous health assessment. Laboratory animals Ahloy-Dallaire, J., Klein, J. D., Davis, J. K., Garner, J. P. 2018: 23677218797974

  Abstract

  Routine health assessment of laboratory rodents can be improved using automated home cage monitoring. Continuous, non-stressful, objective assessment of rodents unaware that they are being watched, including during their active dark period, reveals behavioural and physiological changes otherwise invisible to human caretakers. We developed an automated feeder that tracks feed intake, body weight, and physical appearance of individual radio frequency identification-tagged mice in social home cages. Here, we experimentally induce illness via lipopolysaccharide challenge and show that this automated tracking apparatus reveals sickness behaviour (reduced food intake) as early as 2-4 hours after lipopolysaccharide injection, whereas human observers conducting routine health checks fail to detect a significant difference between sick mice and saline-injected controls. Continuous automated monitoring additionally reveals pronounced circadian rhythms in both feed intake and body weight. Automated home cage monitoring is a non-invasive, reliable mode of health surveillance allowing caretakers to more efficiently detect and respond to early signs of illness in laboratory rodent populations.

  View details for PubMedID 30286683

• Cerebrospinal fluid vasopressin and symptom severity in children with autism ANNALS OF NEUROLOGY Oztan, O., Garner, J. P., Partap, S., Sherr, E. H., Hardan, A. Y., Farmer, C., Thurm, A., Swedo, S. E., Parker, K. J. 2018; 84 (4): 611–15

  View details for DOI 10.1002/ana.25314

  View details for Web of Science ID 000447367000014

• Cerebrospinal fluid vasopressin and symptom severity in children with autism. Annals of neurology Oztan, O., Garner, J. P., Partap, S., Sherr, E. H., Hardan, A. Y., Farmer, C., Thurm, A., Swedo, S. E., Parker, K. J. 2018

  Abstract

  Autism is a brain disorder characterized by social impairments. Progress in understanding autism has been hindered by difficulty in obtaining brain-relevant tissues [e.g., cerebrospinal fluid (CSF)] by which to identify markers of disease and targets for treatment. Here we overcome this barrier by providing evidence that mean CSF concentration of the "social" neuropeptide arginine vasopressin (AVP) is lower in children with autism versus controls. CSF AVP concentration also significantly differentiates individual cases from controls and is associated with greater social symptom severity in children with autism. These findings indicate that AVP may be a promising CSF marker of autism's social deficits. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30152888

• Extensive Somatosensory and Motor Corticospinal Sprouting Occurs Following a Central Dorsal Column Lesion in Monkeys. The Journal of comparative neurology Fisher, K. M., Lilak, A., Garner, J., Darian-Smith, C. 2018

  Abstract

  The corticospinal tract (CST) forms the major descending pathway mediating voluntary hand movements in primates, and originates from nine cortical subdivisions in the macaque. While the terminals of spared motor CST axons are known to sprout locally within the cord in response to spinal injury, little is known about the response of the other CST subcomponents. We previously reported, that following a cervical dorsal root lesion (DRL), the primary somatosensory (S1) CST terminal projection retracts to 60% of its original terminal domain, while the primary motor (M1) projection remains robust (Darian-Smith et al., J. Neurosci., 2013). In contrast, when a dorsal column lesion (DCL) is added to the DRL, the S1 CST, in addition to the M1 CST, extends its terminal projections bilaterally and caudally, well beyond normal range (Darian-Smith et al., J. Neurosci., 2014). Are these dramatic responses linked entirely to the inclusion of a CNS injury (i.e. DCL), or do the two components summate or interact? We addressed this directly, by comparing data from monkeys that received a unilateral DCL alone, with those that received either a DRL or a combined DRL/DCL. Approximately four months post-lesion, the S1 hand region was mapped electrophysiologically, and anterograde tracers were injected bilaterally into the region deprived of normal input, to assess spinal terminal labeling. Using multifactorial analyses, we show that following a DCL alone (i.e. cuneate fasciculus), the S1 and M1 CSTs also sprout significantly and bilaterally beyond normal range, with a termination pattern suggesting some interaction between the peripheral and central lesions. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30014461

• Adaptive developmental plasticity in rhesus macaques: the serotonin transporter gene interacts with maternal care to affect juvenile social behaviour. Proceedings. Biological sciences Madrid, J. E., Mandalaywala, T. M., Coyne, S. P., Ahloy-Dallaire, J., Garner, J. P., Barr, C. S., Maestripieri, D., Parker, K. J. 2018; 285 (1881)

  Abstract

  Research has increasingly highlighted the role that developmental plasticity-the ability of a particular genotype to produce variable phenotypes in response to different early environments-plays as an adaptive mechanism. One of the most widely studied genetic contributors to developmental plasticity in humans and rhesus macaques is a serotonin transporter gene-linked polymorphic region (5-HTTLPR), which determines transcriptional efficiency of the serotonin transporter gene in vitro and modifies the availability of synaptic serotonin in these species. A majority of studies to date have shown that carriers of a loss-of-function variant of the 5-HTTLPR, the short (s) allele, develop a stress-reactive phenotype in response to adverse early environments compared with long (l) allele homozygotes, leading to the prevalent conceptualization of the s-allele as a vulnerability allele. However, this framework fails to address the independent evolution of these loss-of-function mutations in both humans and macaques as well as the high population prevalence of s-alleles in both species. Here we show in free-ranging rhesus macaques that s-allele carriers benefit more from supportive early social environments than l-allele homozygotes, such that s-allele carriers which receive higher levels of maternal protection during infancy demonstrate greater social competence later in life. These findings provide, to our knowledge, the first empirical support for the assertion that the s-allele grants high undirected biological sensitivity to context in primates and suggest a mechanism through which the 5-HTTLPR s-allele is maintained in primate populations.

  View details for PubMedID 29925616

• Adaptive developmental plasticity in rhesus macaques: the serotonin transporter gene interacts with maternal care to affect juvenile social behaviour PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES Madrid, J. E., Mandalaywala, T. M., Coyne, S. P., Ahloy-Dallaire, J., Garner, J. P., Barr, C. S., Maestripieri, D., Parker, K. J. 2018; 285 (1881)

  View details for DOI 10.1098/rspb.2018.0541

  View details for Web of Science ID 000436565200009

• Arginine vasopressin in cerebrospinal fluid is a marker of sociality in nonhuman primates SCIENCE TRANSLATIONAL MEDICINE Parker, K. J., Garner, J. P., Oztan, O., Tarara, E. R., Li, J., Sclafani, V., Del Rosso, L. A., Chun, K., Berquist, S. W., Chez, M. G., Partap, S., Hardan, A. Y., Sherr, E. H., Capitanio, J. P. 2018; 10 (439)

  Abstract

  Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by core social impairments. ASD remains poorly understood because of the difficulty in studying disease biology directly in patients and the reliance on mouse models that lack clinically relevant, complex social cognition abilities. We use ethological observations in rhesus macaques to identify male monkeys with naturally occurring low sociality. These monkeys showed differences in specific neuropeptide and kinase signaling pathways compared to socially competent male monkeys. Using a discovery and replication design, we identified arginine vasopressin (AVP) in cerebrospinal fluid (CSF) as a key marker of group differences in monkey sociality; we replicated these findings in an independent monkey cohort. We also confirmed in an additional monkey cohort that AVP concentration in CSF is a stable trait-like measure. Next, we showed in a small pediatric cohort that CSF AVP concentrations were lower in male children with ASD compared to age-matched male children without ASD (but with other medical conditions). We demonstrated that CSF AVP concentration was sufficient to accurately distinguish ASD cases from medical controls. These data suggest that AVP and its signaling pathway warrant consideration in future research studies investigating new targets for diagnostics and drug development in ASD.

  View details for PubMedID 29720452

• Plasma anandamide concentrations are lower in children with autism spectrum disorder MOLECULAR AUTISM Karhson, D. S., Krasinska, K. M., Dallaire, J., Libove, R. A., Phillips, J. M., Chien, A. S., Garner, J. P., Hardan, A. Y., Parker, K. J. 2018; 9: 18

  Abstract

  Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by restricted, stereotyped behaviors and impairments in social communication. Although the underlying biological mechanisms of ASD remain poorly understood, recent preclinical research has implicated the endogenous cannabinoid (or endocannabinoid), anandamide, as a significant neuromodulator in rodent models of ASD. Despite this promising preclinical evidence, no clinical studies to date have tested whether endocannabinoids are dysregulated in individuals with ASD. Here, we addressed this critical gap in knowledge by optimizing liquid chromatography-tandem mass spectrometry methodology to quantitatively analyze anandamide concentrations in banked blood samples collected from a cohort of children with and without ASD (N = 112).Anandamide concentrations significantly differentiated ASD cases (N = 59) from controls (N = 53), such that children with lower anandamide concentrations were more likely to have ASD (p = 0.041). In keeping with this notion, anandamide concentrations were also significantly lower in ASD compared to control children (p = 0.034).These findings are the first empirical human data to translate preclinical rodent findings to confirm a link between plasma anandamide concentrations in children with ASD. Although preliminary, these data suggest that impaired anandamide signaling may be involved in the pathophysiology of ASD.

  View details for PubMedID 29564080

• Breaking up is hard to do: does splitting cages of mice reduce aggression? Applied Animal Behaviour Science Blankenberger, W. B., Weber, E. M., Chu, D. K., Geronimo, J. T., Theil, J., Gaskill, B. N., Pritchett-Corning, K., Albertelli, M. A., Garner, J. P., Ahloy-Dallaire, J. 2018; 206: 94-101

  View details for DOI 10.1016/j.applanim.2018.06.003

• Biomarker Discovery for Social Impairments: Translation From a Novel Monkey Model to Patients With Autism Parker, K., Garner, J., Oztan, O., Tarara, E., Li, J., Sclafani, V., Del Rosso, L., Chun, K., Berquist, S., Chez, M., Partap, S., Hardan, A., Sherr, E., Capitanio, J. NATURE PUBLISHING GROUP. 2017: S501–S502

  View details for Web of Science ID 000416846303041

• Preference for novel faces in male infant monkeys predicts cerebrospinal fluid oxytocin concentrations later in life. Scientific reports Madrid, J. E., Oztan, O., Sclafani, V., Del Rosso, L. A., Calonder, L. A., Chun, K., Capitanio, J. P., Garner, J. P., Parker, K. J. 2017; 7 (1): 12935

  Abstract

  The ability to recognize individuals is a critical skill acquired early in life for group living species. In primates, individual recognition occurs predominantly through face discrimination. Despite the essential adaptive value of this ability, robust individual differences in conspecific face recognition exist, yet its associated biology remains unknown. Although pharmacological administration of oxytocin has implicated this neuropeptide in face perception and social memory, no prior research has tested the relationship between individual differences in face recognition and endogenous oxytocin concentrations. Here we show in a male rhesus monkey cohort (N = 60) that infant performance in a task used to determine face recognition ability (specifically, the ability of animals to show a preference for a novel face) robustly predicts cerebrospinal fluid, but not blood, oxytocin concentrations up to five years after behavioural assessment. These results argue that central oxytocin biology may be related to individual face perceptual abilities necessary for group living, and that these differences are stable traits.

  View details for DOI 10.1038/s41598-017-13109-5

  View details for PubMedID 29021623

  View details for PubMedCentralID PMC5636831

• Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism. Proceedings of the National Academy of Sciences of the United States of America Parker, K. J., Oztan, O., Libove, R. A., Sumiyoshi, R. D., Jackson, L. P., Karhson, D. S., Summers, J. E., Hinman, K. E., Motonaga, K. S., Phillips, J. M., Carson, D. S., Garner, J. P., Hardan, A. Y. 2017; 114 (30): 8119-8124

  Abstract

  Autism spectrum disorder (ASD) is characterized by core social deficits. Prognosis is poor, in part, because existing medications target only associated ASD features. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may be a blood-based biomarker of social functioning and a possible treatment for ASD. However, prior OXT treatment trials have produced equivocal results, perhaps because of variability in patients' underlying neuropeptide biology, but this hypothesis has not been tested. Using a double-blind, randomized, placebo-controlled, parallel design, we tested the efficacy and tolerability of 4-wk intranasal OXT treatment (24 International Units, twice daily) in 32 children with ASD, aged 6-12 y. When pretreatment neuropeptide measures were included in the statistical model, OXT compared with placebo treatment significantly enhanced social abilities in children with ASD [as measured by the trial's primary outcome measure, the Social Responsiveness Scale (SRS)]. Importantly, pretreatment blood OXT concentrations also predicted treatment response, such that individuals with the lowest pretreatment OXT concentrations showed the greatest social improvement. OXT was well tolerated, and its effects were specific to social functioning, with no observed decrease in repetitive behaviors or anxiety. Finally, as with many trials, some placebo-treated participants showed improvement on the SRS. This enhanced social functioning was mirrored by a posttreatment increase in their blood OXT concentrations, suggesting that increased endogenous OXT secretion may underlie this improvement. These findings indicate that OXT treatment enhances social abilities in children with ASD and that individuals with pretreatment OXT signaling deficits may stand to benefit the most from OXT treatment.

  View details for DOI 10.1073/pnas.1705521114

  View details for PubMedID 28696286

  View details for PubMedCentralID PMC5544319

• Stressed out: providing laboratory animals with behavioral control to reduce the physiological effects of stress LAB ANIMAL Gaskill, B. N., Garner, J. P. 2017; 46 (4): 142-145

  Abstract

  Laboratory animals experience a large amount of environmental stress. An animal's environment can include both physiological and social stressors that may require an animal to adapt to maintain allostatic balance. For example, thermal stress can lead to changes in behavior, reproduction and immune function, which has been detrimental to cancer modeling in mice. Chronic uncontrollable stress is widely acknowledged for its negative alterations to physiology. However, there is a lack in the understanding of how the laboratory environment affects animal physiology and behavior, particularly as it relates to characteristics of the human disease being modeled. Given the evidence on how stressors affect physiology, it is clear that efforts to model human physiology in animal models must consider animal stress as a confounding factor. We present evidence illustrating that providing captive animals with control or predictability is the best way to reduce the negative physiological effects of these difficult-to-manage stressors.

  View details for Web of Science ID 000398431900025

  View details for PubMedID 28328902

• Aggression in group-housed laboratory mice: why can't we solve the problem? LAB ANIMAL Webers, E. M., Dallaire, J. A., Gaskill, B. N., Pritchett-Corning, K. R., Garner, J. P. 2017; 46 (4): 157-161

  Abstract

  Group housing is highly important for social animals. However, it can also give rise to aggression, one of the most serious welfare concerns in laboratory mouse husbandry. Severe fighting can lead to pain, injury and even death. In addition, working with animals that are severely socially stressed, wounded or singly-housed as a result of aggression may compromise scientific validity. Some general recommendations on how to minimize aggression exist, but the problem persists. Thus far, studies attempting to find solutions have mainly focused on social dominance and territorial behavior, but many other aspects of routine housing and husbandry that might influence aggressive behavior have been overlooked. The present way of housing laboratory mice is highly unnatural: mice are prevented from performing many species-typical behaviors and are routinely subjected to painful and aversive stimuli. Giving animals control over their environment is an important aspect of improving animal welfare and has been well-studied in the field of animal welfare science. How control over the environment influences aggression in laboratory mice, however, has not been closely examined. In this article, we challenge current ways of thinking and propose alternative perspectives that we hope will lead to an enhanced understanding of aggression in laboratory mice.

  View details for Web of Science ID 000398431900028

• The effect of early life experience, environment, and genetic factors on spontaneous home-cage aggression-related wounding in male C57BL/6 mice LAB ANIMAL Gaskill, B. N., Stottler, A. M., Garner, J. P., Winnicker, C. W., Mulders, G. B., Pritchett-Corning, K. R. 2017; 46 (4): 176-184

  Abstract

  Aggression is a major welfare issue in mice, particularly when mice unfamiliar to each other are first placed in cages, as happens on receipt from a vendor, and following cage cleaning. Injuries from aggression are the second leading cause of unplanned euthanasia in mice, following ulcerative dermatitis. Commonly employed strategies for reducing aggression-related injury are largely anecdotal, and may even be counterproductive. Here we report a series of experiments testing potential explanations and interventions for post-shipping aggression-related injuries in C57BL/6 mice. First, we examined the effects of weaning: testing whether manipulating weaning age reduced aggression-related injuries, and if repeated mixing of weaned mice before shipping increased these injuries. Contrary to our predictions, repeated mixing did not increase post-shipping injurious aggression, and early weaning reduced aggression-related injuries. Second, we examined potential post-shipping interventions: testing whether lavender essential oil applied to the cage reduced aggression-related injuries, and whether a variety of enrichments decreased injurious aggression. Again, contrary to predictions, lavender increased wounding, and none of the enrichments reduced it. However, consistent with the effects of weaning age in the first experiment, cages with higher mean body weight showed elevated levels of aggression-related wounding. Finally, we tested whether C57BL/6 substrains and identification methods affected levels of intra-cage wounding from aggression. We found no effect of strain, but cages where mice were ear-notched for identification showed higher levels of wounding than cages where mice were tail-tattooed. Overall, these results emphasize the multifactorial nature of home-cage injurious aggression, and the importance of testing received wisdom when it comes to managing complex behavioral and welfare problems. In terms of practical recommendations to reduce aggressive wounding in the home cage, tail tattooing is recommended over ear notching and late weaning should be avoided.

  View details for Web of Science ID 000398431900032

• The effect of early life experience, environment, and genetic factors on spontaneous home-cage aggression-related wounding in male C57BL/6 mice. Lab animal Gaskill, B. N., Stottler, A. M., Garner, J. P., Winnicker, C. W., Mulder, G. B., Pritchett-Corning, K. R. 2017; 46 (4): 176-184

  Abstract

  Aggression is a major welfare issue in mice, particularly when mice unfamiliar to each other are first placed in cages, as happens on receipt from a vendor, and following cage cleaning. Injuries from aggression are the second leading cause of unplanned euthanasia in mice, following ulcerative dermatitis. Commonly employed strategies for reducing aggression-related injury are largely anecdotal, and may even be counterproductive. Here we report a series of experiments testing potential explanations and interventions for post-shipping aggression-related injuries in C57BL/6 mice. First, we examined the effects of weaning: testing whether manipulating weaning age reduced aggression-related injuries, and if repeated mixing of weaned mice before shipping increased these injuries. Contrary to our predictions, repeated mixing did not increase post-shipping injurious aggression, and early weaning reduced aggression-related injuries. Second, we examined potential post-shipping interventions: testing whether lavender essential oil applied to the cage reduced aggression-related injuries, and whether a variety of enrichments decreased injurious aggression. Again, contrary to predictions, lavender increased wounding, and none of the enrichments reduced it. However, consistent with the effects of weaning age in the first experiment, cages with higher mean body weight showed elevated levels of aggression-related wounding. Finally, we tested whether C57BL/6 substrains and identification methods affected levels of intra-cage wounding from aggression. We found no effect of strain, but cages where mice were ear-notched for identification showed higher levels of wounding than cages where mice were tail-tattooed. Overall, these results emphasize the multifactorial nature of home-cage injurious aggression, and the importance of testing received wisdom when it comes to managing complex behavioral and welfare problems. In terms of practical recommendations to reduce aggressive wounding in the home cage, tail tattooing is recommended over ear notching and late weaning should be avoided.

  View details for DOI 10.1038/laban.1225

  View details for PubMedID 28328870

• Aggression in group-housed laboratory mice: why can't we solve the problem? Lab animal Weber, E. M., Dallaire, J. A., Gaskill, B. N., Pritchett-Corning, K. R., Garner, J. P. 2017; 46 (4): 157-161

  Abstract

  Group housing is highly important for social animals. However, it can also give rise to aggression, one of the most serious welfare concerns in laboratory mouse husbandry. Severe fighting can lead to pain, injury and even death. In addition, working with animals that are severely socially stressed, wounded or singly-housed as a result of aggression may compromise scientific validity. Some general recommendations on how to minimize aggression exist, but the problem persists. Thus far, studies attempting to find solutions have mainly focused on social dominance and territorial behavior, but many other aspects of routine housing and husbandry that might influence aggressive behavior have been overlooked. The present way of housing laboratory mice is highly unnatural: mice are prevented from performing many species-typical behaviors and are routinely subjected to painful and aversive stimuli. Giving animals control over their environment is an important aspect of improving animal welfare and has been well-studied in the field of animal welfare science. How control over the environment influences aggression in laboratory mice, however, has not been closely examined. In this article, we challenge current ways of thinking and propose alternative perspectives that we hope will lead to an enhanced understanding of aggression in laboratory mice.

  View details for DOI 10.1038/laban.1219

  View details for PubMedID 28328884

• Preference for novel faces in male infant monkeys predicts cerebrospinal fluid oxytocin concentrations later in life. Scientific Reports Madrid, J. E., Oztan, O., Sclafani, V., Del Rosso, L. A., Calonder, L. A., Chun, K., Capitanio, J. P., Garner, J. P., Parker, K. J. 2017: 12935

  Abstract

  The ability to recognize individuals is a critical skill acquired early in life for group living species. In primates, individual recognition occurs predominantly through face discrimination. Despite the essential adaptive value of this ability, robust individual differences in conspecific face recognition exist, yet its associated biology remains unknown. Although pharmacological administration of oxytocin has implicated this neuropeptide in face perception and social memory, no prior research has tested the relationship between individual differences in face recognition and endogenous oxytocin concentrations. Here we show in a male rhesus monkey cohort (N = 60) that infant performance in a task used to determine face recognition ability (specifically, the ability of animals to show a preference for a novel face) robustly predicts cerebrospinal fluid, but not blood, oxytocin concentrations up to five years after behavioural assessment. These results argue that central oxytocin biology may be related to individual face perceptual abilities necessary for group living, and that these differences are stable traits.

  View details for DOI 10.1038/s41598-017-13109-5

  View details for PubMedCentralID PMC5636831

• Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism. Proceedings of the National Academy of Sciences Parker, K. J., Oztan, O., Libove, R. A., Sumiyoshi, R. D., Jackson, L. P., Karhson, D. S., Summers, J. E., Hinman, K. E., Motonaga, K. S., Phillips, J. M., Carson, D. S., Garner, J. P., Hardan, A. Y. 2017; 114 (30): 8119-8124

  Abstract

  Autism spectrum disorder (ASD) is characterized by core social deficits. Prognosis is poor, in part, because existing medications target only associated ASD features. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may be a blood-based biomarker of social functioning and a possible treatment for ASD. However, prior OXT treatment trials have produced equivocal results, perhaps because of variability in patients' underlying neuropeptide biology, but this hypothesis has not been tested. Using a double-blind, randomized, placebo-controlled, parallel design, we tested the efficacy and tolerability of 4-wk intranasal OXT treatment (24 International Units, twice daily) in 32 children with ASD, aged 6-12 y. When pretreatment neuropeptide measures were included in the statistical model, OXT compared with placebo treatment significantly enhanced social abilities in children with ASD [as measured by the trial's primary outcome measure, the Social Responsiveness Scale (SRS)]. Importantly, pretreatment blood OXT concentrations also predicted treatment response, such that individuals with the lowest pretreatment OXT concentrations showed the greatest social improvement. OXT was well tolerated, and its effects were specific to social functioning, with no observed decrease in repetitive behaviors or anxiety. Finally, as with many trials, some placebo-treated participants showed improvement on the SRS. This enhanced social functioning was mirrored by a posttreatment increase in their blood OXT concentrations, suggesting that increased endogenous OXT secretion may underlie this improvement. These findings indicate that OXT treatment enhances social abilities in children with ASD and that individuals with pretreatment OXT signaling deficits may stand to benefit the most from OXT treatment.

  View details for DOI 10.1073/pnas.1705521114

  View details for PubMedCentralID PMC5544319

• Biomarker discovery for disease status and symptom severity in children with autism. Psychoneuroendocrinology Oztan, O. n., Jackson, L. P., Libove, R. A., Sumiyoshi, R. D., Phillips, J. M., Garner, J. P., Hardan, A. Y., Parker, K. J. 2017; 89: 39–45

  Abstract

  Autism spectrum disorder (ASD) is characterized by social impairments and repetitive behaviors, and affects 1 in 68 US children. Despite ASD's societal impact, its disease mechanisms remain poorly understood. Recent preclinical ASD biomarker discovery research has implicated the neuropeptides oxytocin (OXT) and arginine vasopressin (AVP), and their receptors, OXTR and AVPR1A, in animal models. Efforts to translate these findings to individuals with ASD have typically involved evaluating single neuropeptide measures as biomarkers of ASD and/or behavioral functioning. Given that ASD is a heterogeneous disorder, and unidimensional ASD biomarker studies have been challenging to reproduce, here we employed a multidimensional neuropeptide biomarker analysis to more powerfully interrogate disease status and symptom severity in a well characterized child cohort comprised of ASD patients and neurotypical controls. These blood-based neuropeptide measures, considered as a whole, correctly predicted disease status for 57 out of 68 (i.e., 84%) participants. Further analysis revealed that a composite measure of OXTR and AVPR1A gene expression was the key driver of group classification, and that children with ASD had lower neuropeptide receptor mRNA levels compared to controls. Lower neuropeptide receptor mRNA levels also predicted greater symptom severity for core ASD features (i.e., social impairments and stereotyped behaviors), but were unrelated to intellectual impairment, an associated feature of ASD. Findings from this research highlight the value of assessing multiple related biological measures, and their relative contributions, in the same study, and suggest that low blood neuropeptide receptor availability may be a promising biomarker of disease presence and symptom severity in ASD.

  View details for PubMedID 29309996

• Intranasal Vasopressin Treatment Improves Social Abilities in Children With Autism Parker, K., Oztan, O., Libove, R., Sumiyoshi, R., Summers, J., Hinman, K., Fung, L., Motonaga, K., Carson, D., Phillips, J., Garner, J., Hardan, A. NATURE PUBLISHING GROUP. 2016: S341

  View details for Web of Science ID 000440365600575

• He's getting under my skin! Comparing the sensitivity and specificity of dermal vs subcuticular lesions as a measure of aggression in mice APPLIED ANIMAL BEHAVIOUR SCIENCE Gaskill, B. N., Stottler, A., Pritchett-Corning, K. R., Wong, L. K., Geronimo, J., Garner, J. P. 2016; 183: 77-85

  View details for DOI 10.1016/j.applanim.2016.07.001

  View details for Web of Science ID 000384857000010

• Two of a Kind or a Full House? Reproductive Suppression and Alloparenting in Laboratory Mice PLOS ONE Garner, J. P., Gaskill, B. N., Pritchett-Corning, K. R. 2016; 11 (5)

  Abstract

  Alloparenting, a behavior in which individuals other than the actual parents act in a parental role, is seen in many mammals, including house mice. In wild house mice, alloparental care is only seen when familiar sibling females simultaneously immigrate to a male's territory, so in the laboratory, when a pair of unfamiliar female wild mice are mated with a male, alloparenting does not occur because one female will typically be reproductively suppressed. In contrast, laboratory mice are assumed to alloparent regardless of familiarity or relatedness and are therefore routinely trio bred to increase productivity. Empirical evidence supporting the presence of alloparental care in laboratory mice is lacking. Albino and pigmented inbred mice of the strain C57BL/6NCrl (B6) and outbred mice of the stock Crl:CF1 (CF1) were used to investigate alloparenting in laboratory mice since by mating pigmented and albino females with albino males of the same stock or strain, maternal parentage was easily determined. We housed pairs (M:F) or trios (M:2F) of mice in individually ventilated cages containing nesting material and followed reproductive performance for 16 weeks. Females in trios were tested to determine dominance at the start of the experiment, and again 5 days after the birth of a litter to determine if a female's dominance shifted with the birth of pups. Results showed a significant and expected difference in number of offspring produced by B6 and CF1 (p < 0.0001). Pigmented mice nursed and nested with albino pups and vice-versa, confirming empirical observations from many that group nesting and alloparenting occurs in unrelated laboratory mice. When overall production of both individual mice and cages was examined, reproductive suppression was seen in trio cages. Dominance testing with the tube test did not correlate female reproduction with female dominance in a female-female dyad. Due to the reproductive suppression noted in trios, on a per-mouse basis, pair mating outperformed trio mating (p = 0.02) when the measure was weaned pups/female/week. No infanticide was seen in any cages, so the mechanism of reproductive suppression in trio matings may occur before birth.

  View details for DOI 10.1371/journal.pone.0154966

  View details for Web of Science ID 000375676800103

  View details for PubMedID 27148872

  View details for PubMedCentralID PMC4858245

• A "Pedi" Cures All: Toenail Trimming and the Treatment of Ulcerative Dermatitis in Mice PLOS ONE Adams, S. C., Garner, J. P., Felt, S. A., Geronimo, J. T., Chu, D. K. 2016; 11 (1)

  Abstract

  Ulcerative Dermatitis (UD) is the most common cause of unplanned euthanasia in mice used in research, with prevalence rates reported between 4 and 21%. UD is characterized by a deep, ulcerative lesion that appears most commonly over the dorsal neck and is attendant with an intense pruritus. The underlying cause of UD is currently unknown, and as a consequence, there are no directed therapies that resolve lesions reliably. However, there is a growing body of evidence that suggests a behavioral component to the onset, maintenance, and progression of UD lesions. Scratching behavior in response to the intense pruritus associated with UD lesions may be an effective target for interventional therapies. We hypothesized that interfering with scratching behavior by trimming the toenails of mice with UD, would resolve UD lesions. To test this hypothesis, we first evaluated the efficacy of toenail trims with a single application of Vetericyn at the time of treatment versus our previous standard of care, topical Tresaderm applied daily. We found that toenail trims were significantly more effective at resolving lesions (n = 39 toenail trims, n = 100 Tresaderm, p<0.0001) with 93.3% of animals healing by 14 days (median time to lesion resolution). Furthermore, dorsal neck lesions did not recur by 42 days after a single toenail trim (n = 54); however, flank lesions did not resolve and the outcome of the two lesion distributions following treatment were significantly different (p<0.0001). Finally, we implemented toenail trims at an institutional level and found similar efficacies (approximately 90%) for toenail trims regardless of one-time topical supplement used (triple antibiotic ointment, Tresaderm, and Vetericyn, n = 55, 58, 18, p = 0.63). This is the first report of a highly effective treatment for one of the most serious welfare issues in laboratory mice.

  View details for DOI 10.1371/journal.pone.0144871

  View details for Web of Science ID 000367805100014

  View details for PubMedCentralID PMC4703297

• A "Pedi" Cures All: Toenail Trimming and the Treatment of Ulcerative Dermatitis in Mice. PloS one Adams, S. C., Garner, J. P., Felt, S. A., Geronimo, J. T., Chu, D. K. 2016; 11 (1): e0144871

  Abstract

  Ulcerative Dermatitis (UD) is the most common cause of unplanned euthanasia in mice used in research, with prevalence rates reported between 4 and 21%. UD is characterized by a deep, ulcerative lesion that appears most commonly over the dorsal neck and is attendant with an intense pruritus. The underlying cause of UD is currently unknown, and as a consequence, there are no directed therapies that resolve lesions reliably. However, there is a growing body of evidence that suggests a behavioral component to the onset, maintenance, and progression of UD lesions. Scratching behavior in response to the intense pruritus associated with UD lesions may be an effective target for interventional therapies. We hypothesized that interfering with scratching behavior by trimming the toenails of mice with UD, would resolve UD lesions. To test this hypothesis, we first evaluated the efficacy of toenail trims with a single application of Vetericyn at the time of treatment versus our previous standard of care, topical Tresaderm applied daily. We found that toenail trims were significantly more effective at resolving lesions (n = 39 toenail trims, n = 100 Tresaderm, p<0.0001) with 93.3% of animals healing by 14 days (median time to lesion resolution). Furthermore, dorsal neck lesions did not recur by 42 days after a single toenail trim (n = 54); however, flank lesions did not resolve and the outcome of the two lesion distributions following treatment were significantly different (p<0.0001). Finally, we implemented toenail trims at an institutional level and found similar efficacies (approximately 90%) for toenail trims regardless of one-time topical supplement used (triple antibiotic ointment, Tresaderm, and Vetericyn, n = 55, 58, 18, p = 0.63). This is the first report of a highly effective treatment for one of the most serious welfare issues in laboratory mice.

  View details for DOI 10.1371/journal.pone.0144871

  View details for PubMedID 26735497

  View details for PubMedCentralID PMC4703297

• Early Predictors of Impaired Social Functioning in Male Rhesus Macaques (Macaca mulatta). PloS one Sclafani, V., Del Rosso, L. A., Seil, S. K., Calonder, L. A., Madrid, J. E., Bone, K. J., Sherr, E. H., Garner, J. P., Capitanio, J. P., Parker, K. J. 2016; 11 (10)

  Abstract

  Autism spectrum disorder (ASD) is characterized by social cognition impairments but its basic disease mechanisms remain poorly understood. Progress has been impeded by the absence of animal models that manifest behavioral phenotypes relevant to ASD. Rhesus monkeys are an ideal model organism to address this barrier to progress. Like humans, rhesus monkeys are highly social, possess complex social cognition abilities, and exhibit pronounced individual differences in social functioning. Moreover, we have previously shown that Low-Social (LS) vs. High-Social (HS) adult male monkeys exhibit lower social motivation and poorer social skills. It is not known, however, when these social deficits first emerge. The goals of this study were to test whether juvenile LS and HS monkeys differed as infants in their ability to process social information, and whether infant social abilities predicted later social classification (i.e., LS vs. HS), in order to facilitate earlier identification of monkeys at risk for poor social outcomes. Social classification was determined for N = 25 LS and N = 25 HS male monkeys that were 1-4 years of age. As part of a colony-wide assessment, these monkeys had previously undergone, as infants, tests of face recognition memory and the ability to respond appropriately to conspecific social signals. Monkeys later identified as LS vs. HS showed impairments in recognizing familiar vs. novel faces and in the species-typical adaptive ability to gaze avert to scenes of conspecific aggression. Additionally, multivariate logistic regression using infant social ability measures perfectly predicted later social classification of all N = 50 monkeys. These findings suggest that an early capacity to process important social information may account for differences in rhesus monkeys' motivation and competence to establish and maintain social relationships later in life. Further development of this model will facilitate identification of novel biological targets for intervention to improve social outcomes in at-risk young monkeys.

  View details for DOI 10.1371/journal.pone.0165401

  View details for PubMedID 27788195

  View details for PubMedCentralID PMC5082922

• Systematic Literature Review of Risk Factors and Treatments for Ulcerative Dermatitis in C57BL/6 Mice. Comparative medicine Chu, D. K., Adams, S. C., Felt, S. A., Geronimo, J. n., Garner, J. P. 2016; 66 (2): 89

  View details for PubMedID 27053561

  View details for PubMedCentralID PMC4825956

• SEROTONIN TRANSPORTER AND MATERNAL CARE: A SEX-SPECIFIC G X E EFFECT ON JUVENILE SOCIAL PLAY IN FREE-RANGING RHESUS MACAQUES OF CAYO SANTIAGO Madrid, J. E., Mandalaywala, T. M., Coyne, S. P., Garner, J. P., Barr, C. S., Maestripieri, D., Parker, K. J. WILEY-BLACKWELL. 2015: 107–8

  View details for Web of Science ID 000363560500138

• Cerebrospinal fluid and plasma oxytocin concentrations are positively correlated and negatively predict anxiety in children MOLECULAR PSYCHIATRY Carson, D. S., Berquist, S. W., Trujillo, T. H., Garner, J. P., Hannah, S. L., Hyde, S. A., Sumiyoshi, R. D., Jackson, L. P., MOSS, J. K., Strehlow, M. C., Cheshier, S. H., Partap, S., Hardan, A. Y., Parker, K. J. 2015; 20 (9): 1085-1090

  Abstract

  The neuropeptide oxytocin (OXT) exerts anxiolytic and prosocial effects in the central nervous system of rodents. A number of recent studies have attempted to translate these findings by investigating the relationships between peripheral (e.g., blood, urinary and salivary) OXT concentrations and behavioral functioning in humans. Although peripheral samples are easy to obtain in humans, whether peripheral OXT measures are functionally related to central OXT activity remains unclear. To investigate a possible relationship, we quantified OXT concentrations in concomitantly collected cerebrospinal fluid (CSF) and blood samples from child and adult patients undergoing clinically indicated lumbar punctures or other CSF-related procedures. Anxiety scores were obtained in a subset of child participants whose parents completed psychometric assessments. Findings from this study indicate that plasma OXT concentrations significantly and positively predict CSF OXT concentrations (r=0.56, P=0.0064, N=27). Moreover, both plasma (r=-0.92, P=0.0262, N=10) and CSF (r=-0.91, P=0.0335, N=10) OXT concentrations significantly and negatively predicted trait anxiety scores, consistent with the preclinical literature. Importantly, plasma OXT concentrations significantly and positively (r=0.96, P=0.0115, N=10) predicted CSF OXT concentrations in the subset of child participants who provided behavioral data. This study provides the first empirical support for the use of blood measures of OXT as a surrogate for central OXT activity, validated in the context of behavioral functioning. These preliminary findings also suggest that impaired OXT signaling may be a biomarker of anxiety in humans, and a potential target for therapeutic development in individuals with anxiety disorders.Molecular Psychiatry advance online publication, 4 November 2014; doi:10.1038/mp.2014.132.

  View details for DOI 10.1038/mp.2014.132

  View details for Web of Science ID 000360175500009

• Arginine Vasopressin Is a Blood-Based Biomarker of Social Functioning in Children with Autism PLOS ONE Carson, D. S., Garner, J. P., Hyde, S. A., Libove, R. A., Berquist, S. W., Hornbeak, K. B., Jackson, L. P., Sumiyoshi, R. D., Howerton, C. L., Hannah, S. L., Partap, S., Phillips, J. M., Hardan, A. Y., Parker, K. J. 2015; 10 (7)

  Abstract

  Brain arginine vasopressin (AVP) critically regulates normative social behavior in mammals, and experimental disruption of the AVP signaling pathway produces social impairments in rodent models. We therefore hypothesized that AVP signaling deficits may contribute to social impairments in children with autism spectrum disorder (ASD). Since blood measures (which are far easier to obtain than brain measures) of AVP are most meaningful if they are related to brain AVP activity, Study 1 tested the relationship between AVP concentrations in concomitantly collected blood and CSF samples from children and adults (N = 28) undergoing clinical procedures. Study 2 tested whether blood AVP concentrations: 1) differed between children with ASD (N = 57), their ASD discordant siblings (N = 47), and neurotypical controls (N = 55); and 2) predicted social functioning (using the NEPSY-II Theory of Mind and Affect Recognition tasks and the Social Responsiveness Scale) in this large, well-characterized child cohort. Blood AVP concentrations significantly and positively predicted CSF AVP concentrations (F1,26 = 7.17, r = 0.46, p = 0.0127) in Study 1. In Study 2, blood AVP concentrations did not differ between groups or by sex, but significantly and positively predicted Theory of Mind performance, specifically in children with ASD, but not in non-ASD children (F1,144 = 5.83, p = 0.017). Blood AVP concentrations can be used: 1) as a surrogate for brain AVP activity in humans; and 2) as a robust biomarker of theory of mind ability in children with ASD. These findings also suggest that AVP biology may be a promising therapeutic target by which to improve social cognition in individuals with ASD.

  View details for DOI 10.1371/journal.pone.0132224

  View details for Web of Science ID 000358597100030

  View details for PubMedCentralID PMC4511760

• Antioxidant Therapies for Ulcerative Dermatitis: A Potential Model for Skin Picking Disorder PLOS ONE George, N. M., Whitaker, J., Vieira, G., Geronimo, J. T., Bellinger, D. A., Fletcher, C. A., Garner, J. P. 2015; 10 (7)

  Abstract

  Skin Picking Disorder affects 4% of the general population, with serious quality of life impacts, and potentially life threatening complications. Standard psychoactive medications do not help most patients. Similarly, Mouse Ulcerative Dermatitis (skin lesions caused by excessive abnormal grooming behavior) is very common in widely used inbred strains of mice, and represents a serious animal welfare issue and cause of mortality. Treatment options for Ulcerative Dermatitis are largely palliative and ineffective. We have proposed mouse Ulcerative Dermatitis as a model for human Skin Picking Disorder based on similar epidemiology, behavior, and its comorbidity and mechanistic overlap with hair pulling (trichotillomania). We predicted that mouse Ulcerative Dermatitis would be treated by N-Acetylcysteine, as this compound is highly effective in treating both Skin Picking Disorder and Trichotillomania. Furthermore, we hypothesized that N-Acetylcysteine's mode of action is as a precursor to the production of the endogenous antioxidant glutathione in the brain, and therefore intranasal glutathione would also treat Ulcerative Dermatitis. Accordingly, we show in a heterogenous prospective trial, the significant reduction in Ulcerative Dermatitis lesion severity in mice receiving either N-acetylcysteine (oral administration) or glutathione (intranasal). The majority of mice treated with N-acetylcysteine improved slowly throughout the course of the study. Roughly half of the mice treated with glutathione showed complete resolution of lesion within 2-4 weeks, while the remainder did not respond. These findings are the first to show that the use of N-acetylcysteine and Glutathione can be curative for mouse Ulcerative Dermatitis. These findings lend additional support for mouse Ulcerative Dermatitis as a model of Skin Picking Disorder and also support oxidative stress and glutathione synthesis as the mechanism of action for these compounds. As N-Acetylcysteine is poorly tolerated by many patients, intranasal glutathione warrants further study as potential therapy in Skin Picking, trichotillomania and other body-focused repetitive behavior disorders.

  View details for DOI 10.1371/journal.pone.0132092

  View details for Web of Science ID 000358193100019

  View details for PubMedCentralID PMC4500395

• An initial investigation into the effects of isolation and enrichment on the welfare of laboratory pigs housed in the PigTurn (R) system, assessed using tear staining, behaviour, physiology and haematology ANIMAL WELFARE DeBoer, S. P., Garner, J. P., McCain, R. R., Lay, D. C., Eicher, S. D., Marchant-Forde, J. N. 2015; 24 (1): 15-27

  View details for DOI 10.7120/096277286.24.1.015

  View details for Web of Science ID 000350545600002

• Cerebrospinal fluid and plasma oxytocin concentrations are positively correlated and negatively predict anxiety in children. Molecular psychiatry Carson, D. S., Berquist, S. W., Trujillo, T. H., Garner, J. P., Hannah, S. L., Hyde, S. A., Sumiyoshi, R. D., Jackson, L. P., Moss, J. K., Strehlow, M. C., Cheshier, S. H., Partap, S., Hardan, A. Y., Parker, K. J. 2014

  Abstract

  The neuropeptide oxytocin (OXT) exerts anxiolytic and prosocial effects in the central nervous system of rodents. A number of recent studies have attempted to translate these findings by investigating the relationships between peripheral (e.g., blood, urinary and salivary) OXT concentrations and behavioral functioning in humans. Although peripheral samples are easy to obtain in humans, whether peripheral OXT measures are functionally related to central OXT activity remains unclear. To investigate a possible relationship, we quantified OXT concentrations in concomitantly collected cerebrospinal fluid (CSF) and blood samples from child and adult patients undergoing clinically indicated lumbar punctures or other CSF-related procedures. Anxiety scores were obtained in a subset of child participants whose parents completed psychometric assessments. Findings from this study indicate that plasma OXT concentrations significantly and positively predict CSF OXT concentrations (r=0.56, P=0.0064, N=27). Moreover, both plasma (r=-0.92, P=0.0262, N=10) and CSF (r=-0.91, P=0.0335, N=10) OXT concentrations significantly and negatively predicted trait anxiety scores, consistent with the preclinical literature. Importantly, plasma OXT concentrations significantly and positively (r=0.96, P=0.0115, N=10) predicted CSF OXT concentrations in the subset of child participants who provided behavioral data. This study provides the first empirical support for the use of blood measures of OXT as a surrogate for central OXT activity, validated in the context of behavioral functioning. These preliminary findings also suggest that impaired OXT signaling may be a biomarker of anxiety in humans, and a potential target for therapeutic development in individuals with anxiety disorders.Molecular Psychiatry advance online publication, 4 November 2014; doi:10.1038/mp.2014.132.

  View details for DOI 10.1038/mp.2014.132

  View details for PubMedID 25349162

• Plasma vasopressin concentrations positively predict cerebrospinal fluid vasopressin concentrations in human neonates. Peptides Carson, D. S., Howerton, C. L., Garner, J. P., Hyde, S. A., Clark, C. L., Hardan, A. Y., Penn, A. A., Parker, K. J. 2014; 61: 12-16

  Abstract

  Central arginine vasopressin (AVP) plays a critical role in mammalian social behavior and has been hypothesized to be a biomarker of certain human neurodevelopmental disorders, including autism. However, opportunities to collect post-mortem brain tissue or cerebrospinal fluid (CSF) from children are extremely limited, and the use of less invasive peripheral assessments (e.g., blood, urine, or saliva) of AVP as a proxy for more invasive central measures has not been well validated. Further, almost nothing is known about AVP biology in very young infants. Therefore in the present study we concomitantly collected basal CSF and plasma samples from N=20 neonates undergoing clinical sepsis evaluation (all were sepsis negative) and quantified AVP concentrations via well-validated enzyme-immunoassay methodology. Plasma AVP concentrations significantly and positively predicted CSF AVP concentrations (r=0.73, p=0.0021), and this relationship persisted when variance attributed to sex, gestational age, and sample collection time was controlled for in the statistical model (r=0.75, p=0.0047). These findings provide preliminary support for the use of basal plasma AVP measurement as a proxy for basal brain AVP activity in pediatric populations. Future studies are now required to determine the relationship between behavioral measures and AVP concentrations in both central and peripheral compartments in young infants and older children.

  View details for DOI 10.1016/j.peptides.2014.08.003

  View details for PubMedID 25148831

• Plasma vasopressin concentrations positively predict cerebrospinal fluid vasopressin concentrations in human neonates PEPTIDES Carson, D. S., Howerton, C. L., Garner, J. P., Hyde, S. A., Clark, C. L., Hardan, A. Y., Penn, A. A., Parker, K. J. 2014; 61: 12-16

  Abstract

  Central arginine vasopressin (AVP) plays a critical role in mammalian social behavior and has been hypothesized to be a biomarker of certain human neurodevelopmental disorders, including autism. However, opportunities to collect post-mortem brain tissue or cerebrospinal fluid (CSF) from children are extremely limited, and the use of less invasive peripheral assessments (e.g., blood, urine, or saliva) of AVP as a proxy for more invasive central measures has not been well validated. Further, almost nothing is known about AVP biology in very young infants. Therefore in the present study we concomitantly collected basal CSF and plasma samples from N=20 neonates undergoing clinical sepsis evaluation (all were sepsis negative) and quantified AVP concentrations via well-validated enzyme-immunoassay methodology. Plasma AVP concentrations significantly and positively predicted CSF AVP concentrations (r=0.73, p=0.0021), and this relationship persisted when variance attributed to sex, gestational age, and sample collection time was controlled for in the statistical model (r=0.75, p=0.0047). These findings provide preliminary support for the use of basal plasma AVP measurement as a proxy for basal brain AVP activity in pediatric populations. Future studies are now required to determine the relationship between behavioral measures and AVP concentrations in both central and peripheral compartments in young infants and older children.

  View details for DOI 10.1016/j.peptides.2014.08.003

  View details for Web of Science ID 000344232700003

• The effect of perch availability during pullet rearing and egg laying on the behavior of caged White Leghorn hens POULTRY SCIENCE Hester, P. Y., Garner, J. P., Enneking, S. A., Cheng, H. W., Einstein, M. E. 2014; 93 (10): 2423-2431

  Abstract

  Enriched cages, compared with conventional cages, allow egg laying strains of chickens to meet some behavioral needs, including a high motivation to perch. The objective of this study was to determine if perch availability during rearing affected perch use as adults and if perch presence affected eating and drinking in caged White Leghorn hens. Chickens were assigned to 14 cages each with and without 2 round metal perches from hatch to 16.9 wk of age. At 17 wk of age, pullets were assigned to laying cages consisting of 1 of 4 treatments. Treatment 1 chickens never had access to perches (controls). Treatment 2 chickens only had access to 2 round metal perches during the laying phase (17 to 71 wk of age). Treatment 3 chickens only had access to 2 round perches during the pullet phase (0 to 16.9 wk of age). Treatment 4 chickens had access to the perches during both the pullet and laying phase. Each treatment during the adult phase consisted of 9 cages with 9 birds/cage for a total of 36 cages. Automatic infrared cameras were used to monitor behavior of hens in each cage for a 24-h period at 19, 24, 29, 34, 39, 44, 49, 54, 59, 64, and 69 wk of age. Behavior was also recorded twice weekly by an observer in the room where the hens were housed during photophase from 25 to 68 wk of age. Behavioral data were analyzed using ANOVA with repeated measures and the MIXED model procedure. A greater proportion of hens without perches as pullets used the rear perch more during both photophase and scotophase than hens with prior pullet perching experience. Eating and drinking activities of caged adult Leghorns were not impaired by their prior experience to perches as pullets or by the presence of perches in laying cages. It is concluded that providing perches in cages to White Leghorns during pullet rearing did not facilitate use of perches as adults.

  View details for DOI 10.3382/ps.2014-04038

  View details for Web of Science ID 000343697800001

  View details for PubMedID 25125558

• Corticospinal Sprouting Differs According to Spinal Injury Location and Cortical Origin in Macaque Monkeys JOURNAL OF NEUROSCIENCE Darian-Smith, C., Lilak, A., Garner, J., Irvine, K. 2014; 34 (37): 12267-12279

  Abstract

  The primate corticospinal tract (CST), the major descending pathway mediating voluntary hand movements, comprises nine or more functional subdivisions. The role of subcomponents other than that from primary motor cortex, however, is not well understood. We have previously shown that following a cervical dorsal rhizotomy (Darian-Smith et al., 2013), CST projections originating from primary somatosensory (S1) and motor (M1) cortex responded quite differently to injury. Terminal projections from the S1 (areas 3b/1/2) shrank to <60% of the contralateral side, while M1 CST projections remained robust or expanded (>110%). Here, we asked what happens when a central lesion is added to the equation, to better simulate clinical injury. Monkeys (n = 6) received either a unilateral (1) dorsal root lesion (DRL), (2) or a combined DRL/dorsal column lesion (DRL/DCL), or (3) a DRL/DCL where the DCL was made 4 months following the initial DRL. Electrophysiological recordings were made in S1 4 months postlesion in the first two groups, and 6 weeks after the DCL in the third lesion group, to identify the reorganized region of D1-D3 (thumb, index finger, and middle finger) representation. Anterograde tracers were then injected bilaterally to assess spinal terminal labeling. Remarkably, in all DRL/DCL animals, terminal projections from the S1 and M1 extended bilaterally and caudally well beyond terminal territories in normal animals or following a DRL. These data were highly significant. Extensive sprouting from the S1 CST has not been reported previously, and these data raise important questions about S1 CST involvement in recovery following spinal injury.

  View details for DOI 10.1523/JNEUROSCI.1593-14.2014

  View details for Web of Science ID 000341766900004

  View details for PubMedCentralID PMC4160766

• Corticospinal sprouting differs according to spinal injury location and cortical origin in macaque monkeys. journal of neuroscience Darian-Smith, C., Lilak, A., Garner, J., Irvine, K. 2014; 34 (37): 12267-12279

  Abstract

  The primate corticospinal tract (CST), the major descending pathway mediating voluntary hand movements, comprises nine or more functional subdivisions. The role of subcomponents other than that from primary motor cortex, however, is not well understood. We have previously shown that following a cervical dorsal rhizotomy (Darian-Smith et al., 2013), CST projections originating from primary somatosensory (S1) and motor (M1) cortex responded quite differently to injury. Terminal projections from the S1 (areas 3b/1/2) shrank to <60% of the contralateral side, while M1 CST projections remained robust or expanded (>110%). Here, we asked what happens when a central lesion is added to the equation, to better simulate clinical injury. Monkeys (n = 6) received either a unilateral (1) dorsal root lesion (DRL), (2) or a combined DRL/dorsal column lesion (DRL/DCL), or (3) a DRL/DCL where the DCL was made 4 months following the initial DRL. Electrophysiological recordings were made in S1 4 months postlesion in the first two groups, and 6 weeks after the DCL in the third lesion group, to identify the reorganized region of D1-D3 (thumb, index finger, and middle finger) representation. Anterograde tracers were then injected bilaterally to assess spinal terminal labeling. Remarkably, in all DRL/DCL animals, terminal projections from the S1 and M1 extended bilaterally and caudally well beyond terminal territories in normal animals or following a DRL. These data were highly significant. Extensive sprouting from the S1 CST has not been reported previously, and these data raise important questions about S1 CST involvement in recovery following spinal injury.

  View details for DOI 10.1523/JNEUROSCI.1593-14.2014

  View details for PubMedID 25209269

  View details for PubMedCentralID PMC4160766

• Plasma oxytocin concentrations and OXTR polymorphisms predict social impairments in children with and without autism spectrum disorder PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Parker, K. J., Garner, J. P., Libove, R. A., Hyde, S. A., Hornbeak, K. B., Carson, D. S., Liao, C., Phillips, J. M., Hallmayer, J. F., Hardan, A. Y. 2014; 111 (33): 12258-12263

  Abstract

  The neuropeptide oxytocin (OXT) and its receptor (OXTR) regulate social functioning in animals and humans. Initial clinical research suggests that dysregulated plasma OXT concentrations and/or OXTR SNPs may be biomarkers of social impairments in autism spectrum disorder (ASD). We do not know, however, whether OXT dysregulation is unique to ASD or whether OXT biology influences social functioning more generally, thus contributing to, but not causing, ASD phenotypes. To distinguish between these possibilities, we tested in a child ASD cohort, which included unaffected siblings and unrelated neurotypical controls (ages 3-12 y; n = 193), whether plasma OXT concentrations and OXTR SNPs (i) interact to produce ASD phenotypes, (ii) exert differential phenotypic effects in ASD vs. non-ASD children, or (iii) have similar phenotypic effects independent of disease status. In the largest cohort tested to date, we found no evidence to support the OXT deficit hypothesis of ASD. Rather, OXT concentrations strongly and positively predicted theory of mind and social communication performance in all groups. Furthermore, OXT concentrations showed significant heritability between ASD-discordant siblings (h(2) = 85.5%); a heritability estimate on par with that of height in humans. Finally, carriers of the "G" allele of rs53576 showed impaired affect recognition performance and carriers of the "A" allele of rs2254298 exhibited greater global social impairments in all groups. These findings indicate that OXT biology is not uniquely associated with ASD, but instead exerts independent, additive, and highly heritable influences on individual differences in human social functioning, including the severe social impairments which characterize ASD.

  View details for DOI 10.1073/pnas.1402236111

  View details for Web of Science ID 000340438800080

  View details for PubMedID 25092315

• Letter-to-the-editor on "Not so hot: Optimal housing temperatures for mice to mimic the thermal environment of humans". Molecular metabolism Gaskill, B. N., Garner, J. P. 2014; 3 (4): 335-336

  View details for DOI 10.1016/j.molmet.2013.05.003

  View details for PubMedID 24944886

  View details for PubMedCentralID PMC4060287

• Plasma Vasopressin Levels Positively Predict Social Cognition in Children with Autism Spectrum Disorder but not in Siblings of Probands or Healthy Controls Carson, D. S., Howerton, C. L., Garner, J. P., Libove, R. A., Hyde, S. A., Phillips, J. M., Hardan, A. Y., Parker, K. J. ELSEVIER SCIENCE INC. 2014: 255S–256S

  View details for Web of Science ID 000334101801368

• Plasma oxytocin concentrations are lower in depressed vs. healthy control women and are independent of cortisol. Journal of psychiatric research Yuen, K. W., Garner, J. P., Carson, D. S., Keller, J., Lembke, A., Hyde, S. A., Kenna, H. A., Tennakoon, L., Schatzberg, A. F., Parker, K. J. 2014; 51: 30-36

  Abstract

  The neuropeptide oxytocin (OT) promotes social behavior and attenuates stress responsivity in mammals. Recent clinical evidence suggests OT concentrations may be dysregulated in major depression. This study extends previous research by testing whether: 1) OT concentrations vary systematically in depressive disorders with and without hypercortisolemia, 2) gender differences in OT concentrations are observed in depressed vs. healthy control participants, and 3) OT concentrations are predictive of clinical phenotypes. Plasma OT concentrations of psychotic major depressive (PMD; n = 14: 10 female, 4 male), non-psychotic major depressive (NPMD; n = 17: 12 female, 5 male), and non-depressed, healthy control (n = 19: 11 female, 8 male) participants were assayed at 2000, 2400, 0400, and 0800 h. Plasma cortisol concentrations were quantified at 2300 h, and clinical phenotypes were determined. As expected, PMD participants, compared to NPMD and healthy control participants, showed higher plasma cortisol concentrations. Although both depressed groups showed similar OT concentrations, a significant interaction effect between group and gender was observed. Specifically, depressed females exhibited lower mean OT concentrations than depressed males. Further, depressed vs. healthy control female participants exhibited lower mean OT concentrations, whereas depressed vs. healthy control male participants showed a trend in the opposite direction. OT concentrations were also predictive of desirability, drug dependence, and compulsivity scores as measured by the Million Clinical Multiaxial Inventory-III. All findings were independent of cortisol. These data suggest that OT signaling may provide a mechanism by which to better understand female-biased risk to develop depressive disorders and that plasma OT concentrations may be a useful biomarker of certain clinical phenotypes.

  View details for DOI 10.1016/j.jpsychires.2013.12.012

  View details for PubMedID 24405552

• An automated maze task for assessing hippocampus-sensitive memory in mice BEHAVIOURAL BRAIN RESEARCH Pioli, E. Y., Gaskill, B. N., Gilmour, G., Tricklebank, M. D., Dix, S. L., Bannerman, D., Garner, J. P. 2014; 261: 249-257

  Abstract

  Memory deficits associated with hippocampal dysfunction are a key feature of a number of neurodegenerative and psychiatric disorders. The discrete-trial rewarded alternation T-maze task is highly sensitive to hippocampal dysfunction. Normal mice have spontaneously high levels of alternation, whereas hippocampal-lesioned mice are dramatically impaired. However, this is a hand-run task and handling has been shown to impact crucially on behavioural responses, as well as being labour-intensive and therefore unsuitable for high-throughput studies. To overcome this, a fully automated maze was designed. The maze was attached to the mouse's home cage and the subject earned all of its food by running through the maze. In this study the hippocampal dependence of rewarded alternation in the automated maze was assessed. Bilateral hippocampal-lesioned mice were assessed in the standard, hand-run, discrete-trial rewarded alternation paradigm and in the automated paradigm, according to a cross-over design. A similarly robust lesion effect on alternation performance was found in both mazes, confirming the sensitivity of the automated maze to hippocampal lesions. Moreover, the performance of the animals in the automated maze was not affected by their handling history whereas performance in the hand-run maze was affected by prior testing history. By having more stable performance and by decreasing human contact the automated maze may offer opportunities to reduce extraneous experimental variation and therefore increase the reproducibility within and/or between laboratories. Furthermore, automation potentially allows for greater experimental throughput and hence suitability for use in assessment of cognitive function in drug discovery.

  View details for DOI 10.1016/j.bbr.2013.12.009

  View details for Web of Science ID 000331497000031

  View details for PubMedID 24333574

  View details for PubMedCentralID PMC3923974

• The Significance of Meaning: Why Do Over 90% of Behavioral Neuroscience Results Fail to Translate to Humans, and What Can We Do to Fix It? ILAR JOURNAL Garner, J. P. 2014; 55 (3): 438-456

  Abstract

  The vast majority of drugs entering human trials fail. This problem (called "attrition") is widely recognized as a public health crisis, and has been discussed openly for the last two decades. Multiple recent reviews argue that animals may be just too different physiologically, anatomically, and psychologically from humans to be able to predict human outcomes, essentially questioning the justification of basic biomedical research in animals. This review argues instead that the philosophy and practice of experimental design and analysis is so different in basic animal work and human clinical trials that an animal experiment (as currently conducted) cannot reasonably predict the outcome of a human trial. Thus, attrition does reflect a lack of predictive validity of animal experiments, but it would be a tragic mistake to conclude that animal models cannot show predictive validity. A variety of contributing factors to poor validity are reviewed. The need to adopt methods and models that are highly specific (i.e., which can identify true negative results) in order to complement the current preponderance of highly sensitive methods (which are prone to false positive results) is emphasized. Concepts in biomarker-based medicine are offered as a potential solution, and changes in the use of animal models required to embrace a translational biomarker-based approach are outlined. In essence, this review advocates a fundamental shift, where we treat every aspect of an animal experiment that we can as if it was a clinical trial in a human population. However, it is unrealistic to expect researchers to adopt a new methodology that cannot be empirically justified until a successful human trial. "Validation with known failures" is proposed as a solution. Thus new methods or models can be compared against existing ones using a drug that has translated (a known positive) and one that has failed (a known negative). Current methods should incorrectly identify both as effective, but a more specific method should identify the negative compound correctly. By using a library of known failures we can thereby empirically test the impact of suggested solutions such as enrichment, controlled heterogenization, biomarker-based models, or reverse-translated measures.

  View details for DOI 10.1093/ilar/ilu047

  View details for Web of Science ID 000348058400008

  View details for PubMedID 25541546

  View details for PubMedCentralID PMC4342719

• Nest Building as an Indicator of Health and Welfare in Laboratory Mice JOVE-JOURNAL OF VISUALIZED EXPERIMENTS Gaskill, B. N., Karas, A. Z., Garner, J. P., Pritchett-Corning, K. R. 2013

  Abstract

  The minimization and alleviation of suffering has moral and scientific implications. In order to mitigate this negative experience one must be able to identify when an animal is actually in distress. Pain, illness, or distress cannot be managed if unrecognized. Evaluation of pain or illness typically involves the measurement of physiologic and behavioral indicators which are either invasive or not suitable for large scale assessment. The observation of nesting behavior shows promise as the basis of a species appropriate cage-side assessment tool for recognizing distress in mice. Here we demonstrate the utility of nest building behavior in laboratory mice as an ethologically relevant indicator of welfare. The methods presented can be successfully used to identify thermal stressors, aggressive cages, sickness, and pain. Observation of nest building behavior in mouse colonies provides a refinement to health and well-being assessment on a day to day basis.

  View details for DOI 10.3791/51012

  View details for Web of Science ID 000209229000057

• Can seeds help mice with the daily grind? LABORATORY ANIMALS Pritchett-Corning, K. R., Keefe, R., Garner, J. P., Gaskill, B. N. 2013; 47 (4): 312-315

  Abstract

  Some laboratory mice gnaw food pellets without ingesting much of the gnawed material, resulting in the production of waste material called 'orts'. The fact that this food grinding behavior is not seen in all individuals of a particular strain suggests that it might be abnormal, and thus indicate a welfare concern. Furthermore, the increased rate of feed consumption and cage soiling is undesirable from a husbandry perspective. To try to determine possible motivations for the behavior, and identify potential treatments, outbred Crl:CD1(Icr) mice exhibiting food grinding were selected for one of three treatments placed in the feeder: no enrichment, a chewing device, or sunflower seeds. Both enrichment groups showed a significant decrease (P < 0.05) in ort production when compared with baseline measurements, but only mice provided with sunflower seeds maintained the decreased rate of food wastage after the treatment was withdrawn. A relationship between body weight and ort production was also found, in that cages with greater average body weights had lower levels of ort production. This suggests that a simple need to gnaw cannot alone explain food grinding, and that a nutritional motivation may also be involved.

  View details for DOI 10.1177/0023677213491403

  View details for Web of Science ID 000324486100011

  View details for PubMedID 23760566

• The World is a Natural Laboratory, and Social Media is the New Petri Dish ETHOLOGY Rault, J., Elmore, M. R., Biehl, D. J., Russell, M. A., Garner, J. P. 2013; 119 (10): 803-806

  View details for DOI 10.1111/eth.12125

  View details for Web of Science ID 000323729900002

• Prenatal stress puzzle, the oxytocin piece: Prenatal stress alters the behaviour and autonomic regulation in piglets, insights from oxytocin APPLIED ANIMAL BEHAVIOUR SCIENCE Rault, J., Mack, L. A., Carter, C. S., Garner, J. P., Marchant-Forde, J. N., Richert, B. T., Lay, D. C. 2013; 148 (1-2): 99-107

  View details for DOI 10.1016/j.applanim.2013.07.001

  View details for Web of Science ID 000325663800012

• Winning the Genetic Lottery: Biasing Birth Sex Ratio Results in More Grandchildren PLOS ONE Thogerson, C. M., Brady, C. M., Howard, R. D., Mason, G. J., Pajor, E. A., Vicino, G. A., Garner, J. P. 2013; 8 (7)

  Abstract

  Population dynamics predicts that on average parents should invest equally in male and female offspring; similarly, the physiology of mammalian sex determination is supposedly stochastic, producing equal numbers of sons and daughters. However, a high quality parent can maximize fitness by biasing their birth sex ratio (SR) to the sex with the greatest potential to disproportionately outperform peers. All SR manipulation theories share a fundamental prediction: grandparents who bias birth SR should produce more grandoffspring via the favored sex. The celebrated examples of biased birth SRs in nature consistent with SR manipulation theories provide compelling circumstantial evidence. However, this prediction has never been directly tested in mammals, primarily because the complete three-generation pedigrees needed to test whether individual favored offspring produce more grandoffspring for the biasing grandparent are essentially impossible to obtain in nature. Three-generation pedigrees were constructed using 90 years of captive breeding records from 198 mammalian species. Male and female grandparents consistently biased their birth SR toward the sex that maximized second-generation success. The most strongly male-biased granddams and grandsires produced respectively 29% and 25% more grandoffspring than non-skewing conspecifics. The sons of the most male-biasing granddams were 2.7 times as fecund as those of granddams with a 50∶50 bias (similar results are seen in grandsires). Daughters of the strongest female-biasing granddams were 1.2 times as fecund as those of non-biasing females (this effect is not seen in grandsires). To our knowledge, these results are the first formal test of the hypothesis that birth SR manipulation is adaptive in mammals in terms of grandchildren produced, showing that SR manipulation can explain biased birth SR in general across mammalian species. These findings also have practical implications: parental control of birth SR has the potential to accelerate genetic loss and risk of extinction within captive populations of endangered species.

  View details for DOI 10.1371/journal.pone.0067867

  View details for Web of Science ID 000321765300015

  View details for PubMedID 23874458

  View details for PubMedCentralID PMC3707872

• Reply to: "Reanalysis of Richter et al. (2010) on reproducibility". Nature methods Würbel, H., Richter, S. H., Garner, J. P. 2013; 10 (5): 374-?

  View details for DOI 10.1038/nmeth.2446

  View details for PubMedID 23629412

• Repeated intranasal oxytocin administration in early life dysregulates the HPA axis and alters social behavior. Physiology & behavior Rault, J., Carter, C. S., Garner, J. P., Marchant-Forde, J. N., Richert, B. T., Lay, D. C. 2013; 112-113: 40-48

  Abstract

  Agonistic interactions are a powerful stressor. Conversely, positive social interactions can reduce the adverse effects of social stress. This possibly occurs through the action of oxytocin (OT), a neuropeptide able to reduce activation of the hypothalamo-pituitary-adrenal (HPA) axis. We hypothesized that repeated OT intranasal administration to neonatal pigs could provide long-lasting protective effects against social stress. In each of six litters, two pigs per litter received 0.5 mL of saline containing 24 IU (or 50 μg) of OT intranasally and two control littermates received 0.5 mL of saline as a control at 1, 2 and 3 days of age. Contrary to our predictions, when socially mixed after weaning at 17 days of age, neonatally OT-administered pigs received more aggressive interactions and performed more aggressive interactions in return, showed greater locomotion, spent less time in social contact, and had greater cortisol concentrations than control pigs. When this social mixing was repeated at 8 weeks of age, OT pigs still performed more aggressive interactions and had greater adrenocorticotropic hormone concentrations than control pigs. A dexamethasone suppression test and corticotropic releasing hormone administration challenge at 11 weeks of age revealed that OT pigs were less responsive to dexamethasone than control pigs, suggesting a deficient HPA axis' negative feedback control. Postnatal repeated OT administration altered social behavior and resulted in a long-term dysregulation of the HPA axis. These findings highlight the complex, fine-tuning of the neurobiological mechanisms regulating the development of social behavior and suggest caution in the application of neonatal peptide treatments during early development.

  View details for DOI 10.1016/j.physbeh.2013.02.007

  View details for PubMedID 23481917

• Repeated intranasal oxytocin administration in early life dysregulates the HPA axis and alters social behavior PHYSIOLOGY & BEHAVIOR Rault, J., Carter, C. S., Garner, J. P., Marchant-Forde, J. N., Richert, B. T., Lay, D. C. 2013; 112: 40-48

  View details for DOI 10.1016/j.physbeh.2013.02.007

  View details for Web of Science ID 000318260000006

• Impact of nesting material on mouse body temperature and physiology. Physiology & behavior Gaskill, B. N., Gordon, C. J., Pajor, E. A., Lucas, J. R., Davis, J. K., Garner, J. P. 2013; 110-111: 87-95

  Abstract

  In laboratories, mice are housed at 20-24 °C, which is below their lower critical temperature (≈30 °C). Thus, mice are potentially cold stressed, which can alter metabolism, immune function, and reproduction. These physiological changes reflect impaired wellbeing, and affect scientific outcomes. We hypothesized that nesting material would allow mice to alleviate cold stress by controlling their thermal microenvironment, thus insulating them, reducing heat loss and thermogenic processes. Naïve C57BL/6, CD-1, and BALB/c mice (24 male and 24 female/strain in groups of 3) were housed in standard cages at 20 °C either with or without 8 g nesting material for 4 weeks. Core body temperature was followed using intraperitoneal radio telemetry. The thermal properties of the nests were assessed using a thermal imaging camera, and related to nest quality. Higher scoring nests were negatively correlated with the mean radiated temperature and were thus more insulating. No effects of nesting material on body temperature were found. CD-1 mice with nesting material had higher end body weights than controls. No effect was seen in the other two strains. Mice with the telemetry implant had larger spleens than controls, possibly indicating an immune response to the implant or low level infection from the surgery. BALB/c mice express less mRNA for the UCP1 protein than mice without nesting material. This indicates that BALB/c's with nesting material do not utilize their brown fat to create heat as readily as controls. Nests can alleviate thermal discomfort by decreasing the amount of radiated heat and reduce the need for non-shivering thermogenesis. However, different strains appear to use different behavioral (through different primary modes of behavioral thermoregulation) and physiological strategies (utilizing thermogenesis to different degrees) to maintain a constant body temperature under cool standard laboratory ambient temperatures.

  View details for DOI 10.1016/j.physbeh.2012.12.018

  View details for PubMedID 23313562

• Impact of nesting material on mouse body temperature and physiology PHYSIOLOGY & BEHAVIOR Gaskill, B. N., Gordon, C. J., Pajor, E. A., Lucas, J. R., Davis, J. K., Garner, J. P. 2013; 110: 87-95

  Abstract

  In laboratories, mice are housed at 20-24 °C, which is below their lower critical temperature (≈30 °C). Thus, mice are potentially cold stressed, which can alter metabolism, immune function, and reproduction. These physiological changes reflect impaired wellbeing, and affect scientific outcomes. We hypothesized that nesting material would allow mice to alleviate cold stress by controlling their thermal microenvironment, thus insulating them, reducing heat loss and thermogenic processes. Naïve C57BL/6, CD-1, and BALB/c mice (24 male and 24 female/strain in groups of 3) were housed in standard cages at 20 °C either with or without 8 g nesting material for 4 weeks. Core body temperature was followed using intraperitoneal radio telemetry. The thermal properties of the nests were assessed using a thermal imaging camera, and related to nest quality. Higher scoring nests were negatively correlated with the mean radiated temperature and were thus more insulating. No effects of nesting material on body temperature were found. CD-1 mice with nesting material had higher end body weights than controls. No effect was seen in the other two strains. Mice with the telemetry implant had larger spleens than controls, possibly indicating an immune response to the implant or low level infection from the surgery. BALB/c mice express less mRNA for the UCP1 protein than mice without nesting material. This indicates that BALB/c's with nesting material do not utilize their brown fat to create heat as readily as controls. Nests can alleviate thermal discomfort by decreasing the amount of radiated heat and reduce the need for non-shivering thermogenesis. However, different strains appear to use different behavioral (through different primary modes of behavioral thermoregulation) and physiological strategies (utilizing thermogenesis to different degrees) to maintain a constant body temperature under cool standard laboratory ambient temperatures.

  View details for DOI 10.1016/j.physbeh.2012.12.018

  View details for Web of Science ID 000318132100014

• Does the presence of a human affect the preference of enrichment items in young, isolated pigs? APPLIED ANIMAL BEHAVIOUR SCIENCE DeBoer, S. P., Garner, J. P., Lay, D. C., Eicher, S. D., Lucas, J. R., Marchant-Forde, J. N. 2013; 143 (2-4): 96-103

  View details for DOI 10.1016/j.applanim.2012.10.007

  View details for Web of Science ID 000316154100003

• Biology, behavior, and environmental enrichment for the captive African clawed frog (Xenopus spp) APPLIED ANIMAL BEHAVIOUR SCIENCE Chum, H., Felt, S., Garner, J., Green, S. 2013; 143 (2-4): 150-156

  View details for DOI 10.1016/j.applanim.2012.10.013

  View details for Web of Science ID 000316154100009

• Nest building as an indicator of health and welfare in laboratory mice. Journal of visualized experiments : JoVE Gaskill, B. N., Karas, A. Z., Garner, J. P., Pritchett-Corning, K. R. 2013: 51012-?

  Abstract

  The minimization and alleviation of suffering has moral and scientific implications. In order to mitigate this negative experience one must be able to identify when an animal is actually in distress. Pain, illness, or distress cannot be managed if unrecognized. Evaluation of pain or illness typically involves the measurement of physiologic and behavioral indicators which are either invasive or not suitable for large scale assessment. The observation of nesting behavior shows promise as the basis of a species appropriate cage-side assessment tool for recognizing distress in mice. Here we demonstrate the utility of nest building behavior in laboratory mice as an ethologically relevant indicator of welfare. The methods presented can be successfully used to identify thermal stressors, aggressive cages, sickness, and pain. Observation of nest building behavior in mouse colonies provides a refinement to health and well-being assessment on a day to day basis.

  View details for DOI 10.3791/51012

  View details for PubMedID 24429701

• Energy Reallocation to Breeding Performance through Improved Nest Building in Laboratory Mice. PloS one Gaskill, B. N., Pritchett-Corning, K. R., Gordon, C. J., Pajor, E. A., Lucas, J. R., Davis, J. K., Garner, J. P. 2013; 8 (9)

  Abstract

  Mice are housed at temperatures (20-26°C) that increase their basal metabolic rates and impose high energy demands to maintain core temperatures. Therefore, energy must be reallocated from other biological processes to increase heat production to offset heat loss. Supplying laboratory mice with nesting material may provide sufficient insulation to reduce heat loss and improve both feed conversion and breeding performance. Naïve C57BL/6, BALB/c, and CD-1breeding pairs were provided with bedding alone, or bedding supplemented with either 8g of Enviro-Dri, 8g of Nestlets, for 6 months. Mice provided with either nesting material built more dome-like nests than controls. Nesting material improved feed efficiency per pup weaned as well as pup weaning weight. The breeding index (pups weaned/dam/week) was higher when either nesting material was provided. Thus, the sparing of energy for thermoregulation of mice given additional nesting material may have been responsible for the improved breeding and growth of offspring.

  View details for DOI 10.1371/journal.pone.0074153

  View details for PubMedID 24040193

  View details for PubMedCentralID PMC3770541

• The naked truth: Breeding performance in nude mice with and without nesting material APPLIED ANIMAL BEHAVIOUR SCIENCE Gaskill, B. N., Winnicker, C., Garner, J. P., Pritchett-Corning, K. R. 2013; 143 (2-4): 110-116

  View details for DOI 10.1016/j.applanim.2012.10.009

  View details for Web of Science ID 000316154100005

• ENU mutagenesis reveals that Notchless homolog 1 (Drosophila) affects Cdkn1a and several members of the Wnt pathway during murine pre-implantation development BMC GENETICS Lossie, A. C., Lo, C., Baumgarner, K. M., Cramer, M. J., Garner, J. P., Justice, M. J. 2012; 13

  Abstract

  Our interests lie in determining the genes and genetic pathways that are important for establishing and maintaining maternal-fetal interactions during pregnancy. Mutation analysis targeted to a 34 Mb domain flanked by Trp53 and Wnt3 demonstrates that this region of mouse chromosome 11 contains a large number of essential genes. Two mutant alleles (l11Jus1 and l11Jus4), which fall into the same complementation group, survive through implantation but fail prior to gastrulation.Through a positional cloning strategy, we discovered that these homozygous mutant alleles contain non-conservative missense mutations in the Notchless homolog 1 (Drosophila) (Nle1) gene. NLE1 is a member of the large WD40-repeat protein family, and is thought to signal via the canonical NOTCH pathway in vertebrates. However, the phenotype of the Nle1 mutant mice is much more severe than single Notch receptor mutations or even in animals in which NOTCH signaling is blocked. To test the hypothesis that NLE1 functions in multiple signaling pathways during pre-implantation development, we examined expression of multiple Notch downstream target genes, as well as select members of the Wnt pathway in wild-type and mutant embryos. We did not detect altered expression of any primary members of the Notch pathway or in Notch downstream target genes. However, our data reveal that Cdkn1a, a NOTCH target, was upregulated in Nle1 mutants, while several members of the Wnt pathway are downregulated. In addition, we found that Nle1 mutant embryos undergo caspase-mediated apoptosis as hatched blastocysts, but not as morulae or blastocysts.Taken together, these results uncover potential novel functions for NLE1 in the WNT and CDKN1A pathways during embryonic development in mammals.

  View details for DOI 10.1186/1471-2156-13-106

  View details for Web of Science ID 000314224600001

  View details for PubMedID 23231322

  View details for PubMedCentralID PMC3558363

• Differing results for motivation tests and measures of resource use: The value of environmental enrichment to gestating sows housed in stalls APPLIED ANIMAL BEHAVIOUR SCIENCE Elmore, M. R., Garner, J. P., Johnson, A. K., Kirkden, R. D., Patterson-Kane, E. G., Richert, B. T., Pajor, E. A. 2012; 141 (1-2): 9-19

  View details for DOI 10.1016/j.applanim.2012.07.010

  View details for Web of Science ID 000309569600002

• A standardized cage measurement system: A versatile tool for calculating usable cage space JOURNAL OF APPLIED POULTRY RESEARCH Kiess, A. S., Hester, P. Y., Mench, J. A., Newberry, R. C., Garner, J. P. 2012; 21 (3): 657-668

  View details for DOI 10.3382/japr.2011-00491

  View details for Web of Science ID 000310512900027

• A system utilizing radio frequency identification (RFID) technology to monitor individual rodent behavior in complex social settings JOURNAL OF NEUROSCIENCE METHODS Howerton, C. L., Garner, J. P., Mench, J. A. 2012; 209 (1): 74-78

  Abstract

  Pre-clinical investigation of human CNS disorders relies heavily on mouse models. However these show low predictive validity for translational success to humans, partly due to the extensive use of rapid, high-throughput behavioral assays. Improved assays to monitor rodent behavior over longer time scales in a variety of contexts while still maintaining the efficiency of data collection associated with high-throughput assays are needed. We developed an apparatus that uses radio frequency identification device (RFID) technology to facilitate long-term automated monitoring of the behavior of mice in socially or structurally complex cage environments. Mice that were individually marked and implanted with transponders were placed in pairs in the apparatus, and their locations continuously tracked for 24 h. Video observation was used to validate the RFID readings. The apparatus and its associated software accurately tracked the locations of all mice, yielding information about each mouse's location over time, its diel activity patterns, and the amount of time it was in the same location as the other mouse in the pair. The information that can be efficiently collected in this apparatus has a variety of applications for pre-clinical research on human CNS disorders, for example major depressive disorder and autism spectrum disorder, in that it can be used to quantify validated endophenotypes or biomarkers of these disorders using rodent models. While the specific configuration of the apparatus described here was designed to answer particular experimental questions, it can be modified in various ways to accommodate different experimental designs.

  View details for DOI 10.1016/j.jneumeth.2012.06.001

  View details for Web of Science ID 000307132700009

  View details for PubMedID 22698663

• The effect of cage and house design on egg production and egg weight of White Leghorn hens: An epidemiological study POULTRY SCIENCE Garner, J. P., Kiess, A. S., Mench, J. A., Newberry, R. C., Hester, P. Y. 2012; 91 (7): 1522-1535

  Abstract

  Hen performance can be affected by many interacting variables related to cage design, such as floor area, height, tier arrangement, and feeder and drinker type and placement within the cage. Likewise, features of house design such as waste management and lighting can also affect hen productivity. The influence of these design aspects on hen performance has not been fully assessed. Determining the effects of numerous, interacting variables is impractical in a traditional experiment; therefore, an epidemiological approach, using variability in cage and house design among and within commercial producers, was employed to identify features that affect egg production and egg weight. A universal cage measurement system was created to calculate cage design variables. A database for recording information on cage design, resource location, waste management, environmental conditions, and hen productivity was developed. Production outcomes were assessed from placement to 60 wk of age in White Leghorns (n = 165-168 houses). Using GLM, a statistical model was identified that best described the variance in egg traits. Eggs/hen-housed increased with greater feeder space allocation (P = 0.031); taller cages (P = 0.029); rear (vs. front) drinker location in vertical cages (P = 0.026); and regular removal of manure from the house (P = 0.005). Case weight of eggs was greater in A-frame houses where manure was removed regularly instead of being left in the house (P < 0.001); with increasing cage floor slope (P = 0.001); in cages where drinkers were placed more toward the front or back of the cage as compared with the middle of the cage (P < 0.001); with more space/hen (P = 0.024); and with higher caloric intake (P < 0.001). Perhaps because of its negative correlation with egg production, case weight of eggs increased with less feeder space allocation (P = 0.004) and shorter cage heights (P < 0.001). These results reveal important effects of feeder space, floor space, cage height, drinker position, and waste management on hen productivity.

  View details for DOI 10.3382/ps.2011-01969

  View details for Web of Science ID 000305590200004

  View details for PubMedID 22700495

• Heat or Insulation: Behavioral Titration of Mouse Preference for Warmth or Access to a Nest PLOS ONE Gaskill, B. N., Gordon, C. J., Pajor, E. A., Lucas, J. R., Davis, J. K., Garner, J. P. 2012; 7 (3)

  Abstract

  In laboratories, mice are housed at 20-24°C, which is below their lower critical temperature (≈30°C). This increased thermal stress has the potential to alter scientific outcomes. Nesting material should allow for improved behavioral thermoregulation and thus alleviate this thermal stress. Nesting behavior should change with temperature and material, and the choice between nesting or thermotaxis (movement in response to temperature) should also depend on the balance of these factors, such that mice titrate nesting material against temperature. Naïve CD-1, BALB/c, and C57BL/6 mice (36 male and 36 female/strain in groups of 3) were housed in a set of 2 connected cages, each maintained at a different temperature using a water bath. One cage in each set was 20°C (Nesting cage; NC) while the other was one of 6 temperatures (Temperature cage; TC: 20, 23, 26, 29, 32, or 35°C). The NC contained one of 6 nesting provisions (0, 2, 4, 6, 8, or 10g), changed daily. Food intake and nest scores were measured in both cages. As the difference in temperature between paired cages increased, feed consumption in NC increased. Nesting provision altered differences in nest scores between the 2 paired temperatures. Nest scores in NC increased with increasing provision. In addition, temperature pairings altered the difference in nest scores with the smallest difference between locations at 26°C and 29°C. Mice transferred material from NC to TC but the likelihood of transfer decreased with increasing provision. Overall, mice of different strains and sexes prefer temperatures between 26-29°C and the shift from thermotaxis to nest building is seen between 6 and 10 g of material. Our results suggest that under normal laboratory temperatures, mice should be provided with no less than 6 grams of nesting material, but up to 10 grams may be needed to alleviate thermal distress under typical temperatures.

  View details for DOI 10.1371/journal.pone.0032799

  View details for Web of Science ID 000305339100018

  View details for PubMedID 22479340

  View details for PubMedCentralID PMC3316552

• If You Knew What Was Good For You! The Value of Environmental Enrichments With Known Welfare Benefits Is Not Demonstrated by Sows Using Operant Techniques JOURNAL OF APPLIED ANIMAL WELFARE SCIENCE Elmore, M. R., Garner, J. P., Johnson, A. K., Kirkden, R. D., Richert, B. T., Pajor, E. A. 2012; 15 (3): 254-271

  Abstract

  This study assessed the motivation of gestating sows housed in standard, barren gestation stalls (used for breeding/implantation and/or gestation) for access to environmental enrichment. Enrichment consisted of a cotton rope or rubber mat in comparison to positive (additional food when fed at commercial levels) and negative (empty trough) controls. Although environmental enrichment may improve animal welfare, sows' valuation of enrichments is largely unknown. This study used an operant panel and obtained behavioral measures to quantify motivation. As indicated by a higher price paid and lower latencies to press the panel and enter the treatment stall (all comparisons, p < .05), sows demonstrated higher motivation for food compared with all treatments. Sows housed in gestation stalls did not demonstrate high motivation via operant responding for a cotton rope or a rubber mat; nor did they demonstrate any differences in behavioral measures (all comparisons, p > .10). Although sows' motivation for a mat did not differ from that for an empty trough, previous work has demonstrated the welfare benefits associated with comfort flooring.

  View details for DOI 10.1080/10888705.2012.683982

  View details for Web of Science ID 000305950000005

  View details for PubMedID 22742201

• The Possibilities and Limitations of Animal Models for Psychiatric Disorders DRUG DISCOVERY FOR PSYCHIATRIC DISORDERS Tricklebank, M. D., Garner, J. P., Rankovic, Z., Hargreaves, R., Bingham, M. 2012; 28: 534–57

  View details for DOI 10.1039/9781849734943-00534

  View details for Web of Science ID 000326734700021

• Retained Fetal Membranes in C57BL/6NCrl Mice: Description of Clinical Case Presentations and Related Epidemiologic Findings COMPARATIVE MEDICINE Johnson, J. K., Vemulapalli, T. H., Van Alstine, W. G., Roberts, C. S., Garner, J. P., Hickman, D. L. 2011; 61 (6): 505-509

  Abstract

  During a triinstitutional study to test whether individually ventilated caging systems impaired welfare and reproduction relative to static housing systems, varying numbers (2 to 7) of discoid-shaped, fleshy structures were found in utero of 17 postpartum female mice on study. Further investigation revealed these structures to be retained fetal membranes (RFM). A point prevalence of 24.3% was calculated based on a total population of 70 postpartum female mice on study. This finding was preceded by 3 typical clinical presentations, which are described here. We designed a case-control matched cross-sectional epidemiologic study to identify associated risk factors and antemortem indicators of RFM. Housing on the bottom shelves and attachment to the rack systems were factors associated with a diagnosis of the condition. In addition, neutrophilia, monocytosis, lymphopenia, and decreasing hematocrit values were associated with the diagnosis of RFM. These results confirmed that a CBC can be a useful antemortem screening test for the identification of affected mice. We conclude that RFM are likely an incidental finding although they may present concurrent with other pregnancy complications.

  View details for Web of Science ID 000297910100004

  View details for PubMedID 22330577

• Recurrent perseveration correlates with abnormal repetitive locomotion in adult mink but is not reduced by environmental enrichment BEHAVIOURAL BRAIN RESEARCH Dallaire, J. A., Meagher, R. K., Diez-Leon, M., Garner, J. P., Mason, G. J. 2011; 224 (2): 213-222

  Abstract

  We analysed the relationship between abnormal repetitive behaviour (ARB), the presence/absence of environmental enrichment, and two types of behavioural disinhibition in farmed American mink, Neovison vison. The first type, recurrent perseveration, the inappropriate repetition of already completed responses, was assessed using three indices of excessive response repetition and patterning in a bias-corrected serial two-choice guessing task. The second type, disinhibition of prepotent responses to reward cues, a form of impulsivity, was tested in a locomotive detour task adapted from primate reaching tasks: subjects were required to walk around, rather than directly into, a transparent barrier behind which food was visible. In older adult females, recurrent perseveration positively predicted pre-feeding abnormal repetitive locomotion (ARL) in Non-enriched housing. High-ARL subjects also performed repeated (same-choice) responses more rapidly than low-ARL animals, even when statistically controlling for alternated (different-choice) response latency. Mink performed much less ARL following transfer to Enriched housing, but there was no corresponding change in recurrent perseveration. Thus, elevated recurrent perseveration is not sufficient for frequent ARL; and while captive environments do determine ARL frequency, in mink, they do not necessarily do so by modifying levels of perseveration. Disinhibition of prepotent responses to reward cues, meanwhile, did not predict ARL. In a separate sample of differentially housed young adults, neither type of behavioural disinhibition predicted ARL, and again, whether or not housing was enriched did not affect behavioural disinhibition despite affecting ARL. Thus, the relationship between recurrent perseveration and ARB may only develop with age; longitudinal studies are now required for confirmation.

  View details for DOI 10.1016/j.bbr.2011.03.061

  View details for Web of Science ID 000294795600001

  View details for PubMedID 21466825

• Getting around social status: Motivation and enrichment use of dominant and subordinate sows in a group setting APPLIED ANIMAL BEHAVIOUR SCIENCE Elmore, M. R., Garner, J. P., Johnson, A. K., Kirkden, R. D., Richert, B. T., Pajor, E. A. 2011; 133 (3-4): 154-163

  View details for DOI 10.1016/j.applanim.2011.05.017

  View details for Web of Science ID 000293430200003

• Reverse-translational biomarker validation of Abnormal Repetitive Behaviors in mice: An illustration of the 4P's modeling approach BEHAVIOURAL BRAIN RESEARCH Garner, J. P., Thogerson, C. M., Dufour, B. D., Wuerbel, H., Murray, J. D., Mench, J. A. 2011; 219 (2): 189-196

  Abstract

  The NIMH's new strategic plan, with its emphasis on the "4P's" (Prediction, Pre-emption, Personalization, and Populations) and biomarker-based medicine requires a radical shift in animal modeling methodology. In particular 4P's models will be non-determinant (i.e. disease severity will depend on secondary environmental and genetic factors); and validated by reverse-translation of animal homologues to human biomarkers. A powerful consequence of the biomarker approach is that different closely related disorders have a unique fingerprint of biomarkers. Animals can be validated as a highly specific model of a single disorder by matching this 'fingerprint'; or as a model of a symptom seen in multiple disorders by matching common biomarkers. Here we illustrate this approach with two Abnormal Repetitive Behaviors (ARBs) in mice: stereotypies and barbering (hair pulling). We developed animal versions of the neuropsychological biomarkers that distinguish human ARBs, and tested the fingerprint of the different mouse ARBs. As predicted, the two mouse ARBs were associated with different biomarkers. Both barbering and stereotypy could be discounted as models of OCD (even though they are widely used as such), due to the absence of limbic biomarkers which are characteristic of OCD and hence are necessary for a valid model. Conversely barbering matched the fingerprint of trichotillomania (i.e. selective deficits in set-shifting), suggesting it may be a highly specific model of this disorder. In contrast stereotypies were correlated only with a biomarker (deficits in response shifting) correlated with stereotypies in multiple disorders, suggesting that animal stereotypies model stereotypies in multiple disorders.

  View details for DOI 10.1016/j.bbr.2011.01.002

  View details for Web of Science ID 000289703700003

  View details for PubMedID 21219937

• Working with what you've got: Changes in thermal preference and behavior in mice with or without nesting material JOURNAL OF THERMAL BIOLOGY Gaskill, B. N., Rohr, S. A., Pajor, E. A., Lucas, J. R., Garner, J. P. 2011; 36 (3): 193-199

  View details for DOI 10.1016/j.jtherbio.2011.02.004

  View details for Web of Science ID 000291086800007

• Little and often? Maintaining continued performance in an automated T-maze for mice BEHAVIOURAL PROCESSES Gaskill, B. N., Lucas, J. R., Pajor, E. A., Garner, J. P. 2011; 86 (2): 272-278

  Abstract

  Operant and maze tasks in mice are limited by the small number of trials possible in a session before mice lose motivation. We hypothesized that by manipulating reward size and session length, motivation, and hence performance, would be maintained in an automated T-maze. We predicted that larger rewards and shorter sessions would improve acquisition; and smaller rewards and shorter sessions would maintain higher and less variable performance. Eighteen C57BL/6J mice (9 per sex) acquired (criterion 8/10 correct) and performed a spatial discrimination, with one of 3 reward sizes (.02, .04, or .08 g) and one of 3 session schedules (15, 30, or 45 min sessions). Each mouse had a total of 360 min of access to the maze per night, for two nights, and averaged 190 trials. Analysis used split-plot GLM with contrasts testing for linear effects. Acquisition of the discrimination was unaffected by reward size or session length/interval. After-criterion average performance improved as reward size decreased. After-criterion variability in performance was also affected. Variability increased as reward size increased. Session length/interval did not affect any outcome. We conclude that an automated maze, with suitable reward sizes, can sustain performance with low variability, at 5-10 times faster than traditional methods.

  View details for DOI 10.1016/j.beproc.2010.12.007

  View details for Web of Science ID 000287984900015

  View details for PubMedID 21187130

• Effect of Population Heterogenization on the Reproducibility of Mouse Behavior: A Multi-Laboratory Study PLOS ONE Richter, S. H., Garner, J. P., Zipser, B., Lewejohann, L., Sachser, N., Touma, C., Schindler, B., Chourbaji, S., Brandwein, C., Gass, P., van Stipdonk, N., van der Harst, J., Spruijt, B., Voikar, V., Wolfer, D. P., Wuerbel, H. 2011; 6 (1)

  Abstract

  In animal experiments, animals, husbandry and test procedures are traditionally standardized to maximize test sensitivity and minimize animal use, assuming that this will also guarantee reproducibility. However, by reducing within-experiment variation, standardization may limit inference to the specific experimental conditions. Indeed, we have recently shown in mice that standardization may generate spurious results in behavioral tests, accounting for poor reproducibility, and that this can be avoided by population heterogenization through systematic variation of experimental conditions. Here, we examined whether a simple form of heterogenization effectively improves reproducibility of test results in a multi-laboratory situation. Each of six laboratories independently ordered 64 female mice of two inbred strains (C57BL/6NCrl, DBA/2NCrl) and examined them for strain differences in five commonly used behavioral tests under two different experimental designs. In the standardized design, experimental conditions were standardized as much as possible in each laboratory, while they were systematically varied with respect to the animals' test age and cage enrichment in the heterogenized design. Although heterogenization tended to improve reproducibility by increasing within-experiment variation relative to between-experiment variation, the effect was too weak to account for the large variation between laboratories. However, our findings confirm the potential of systematic heterogenization for improving reproducibility of animal experiments and highlight the need for effective and practicable heterogenization strategies.

  View details for DOI 10.1371/journal.pone.0016461

  View details for Web of Science ID 000286834300066

  View details for PubMedID 21305027

• Cage-induced stereotypies in female ICR CD-1 mice do not correlate with recurrent perseveration BEHAVIOURAL BRAIN RESEARCH Gross, A. N., Engel, A. K., Richter, S. H., Garner, J. P., Wuerbel, H. 2011; 216 (2): 613-620

  Abstract

  Stereotypies are repetitive, unvarying, apparently purposeless behavioural patterns. They develop in animals kept in barren environments and are highly prevalent in laboratory mice (Mus musculus), yet their underlying mechanisms have remained elusive. In humans, stereotypies are associated with several psychiatric disorders and are thought to reflect dysfunction of inhibition of motor programs mediated by the corticostriatal circuitry, resulting in recurrent perseveration (=inappropriate repetition of behavioural responses). Several studies in captive animals of different species have reported a correlation between stereotypy performance and perseverative behaviour, indicating a similar dysfunction. To examine whether stereotypies in mice correlate with recurrent perseveration and whether they are causally related, we raised 40 female ICR CD-1 mice in either barren or enriched cages from three to either six or 16 weeks of age (2 × 2 factorial design) and assessed stereotypic behaviour in the home cage and recurrent perseveration on a two-choice guessing task. Enrichment significantly reduced stereotypic behaviour both at six and 16 weeks of age and recurrent perseveration increased with age. Although enriched housing reduced the number of repetitions in the guessing task significantly, there was no clear evidence for an effect on recurrent perseveration, and recurrent perseveration did not correlate positively with stereotypy level. These findings indicate either that this test did not measure recurrent perseveration or that cage stereotypies in these mice do not reflect behavioural disinhibition as measured by recurrent perseveration.

  View details for DOI 10.1016/j.bbr.2010.09.003

  View details for Web of Science ID 000285217300017

  View details for PubMedID 20837068

• Working with what you've got: Changes in thermal preference and behavior in mice with or without nesting material Journal of Thermal Biology Gaskill BN, Rohr SA, Pajor EA, Lucas JR, Garner JP 2011; 36 (3): 193-199
• Nutritional up-regulation of serotonin paradoxically induces compulsive behavior NUTRITIONAL NEUROSCIENCE Dufour, B. D., Adeola, O., Cheng, H., Donkin, S. S., Klein, J. D., Pajor, E. A., Garner, J. P. 2010; 13 (6): 256-264

  Abstract

  Dietary etiologies or treatments for complex mental disorder are highly controversial in psychiatry. Nevertheless, diet affects brain chemistry (particularly serotonin), and can reduce abnormal behavior in humans and animals. We formulated a diet that elevated brain serotonin and tested whether it would reduce hair pulling in a mouse model of trichotillomania. In a double-blind crossover trial, dietary elevation of brain serotonin unexpectedly increased hair pulling (P = 0.0006) and induced ulcerative dermatitis (UD; P = 0.001). The causative agent for UD is unknown. Therefore, we fed the treatment diet to a second group of mice to test whether UD is behavioral in origin. The diet increased scratching behavior (P < 0.0001). However, high scratching behavior (P = 0.027) and low barbering (P = 0.040) prior to treatment predicted the development of UD. Thus diet can trigger the onset of a complex disorder in the absence of an underlying metabolic deficit. Furthermore, we propose UD as model of compulsive skin-picking.

  View details for DOI 10.1179/147683010X12611460764688

  View details for Web of Science ID 000283672400002

  View details for PubMedID 21040623

• Aggressiveness and brain amine concentration in dominant and subordinate finishing pigs fed the beta-adrenoreceptor agonist ractopamine JOURNAL OF ANIMAL SCIENCE Poletto, R., Cheng, H. W., Meisel, R. L., Garner, J. P., Richert, B. T., Marchant-Forde, J. N. 2010; 88 (9): 3107-3120

  Abstract

  Under farm conditions, aggression related to the formation of social hierarchy and competition for resources can be a major problem because of associated injuries, social stress, and carcass losses. Any factor that may affect the regulation and amount of aggression within a farmed system, for instance, feeding the beta-adrenoreceptor agonist ractopamine (RAC), is therefore worthy of investigation. The objectives of this study were to assess the effects of the widely used swine feed additive RAC, considering also the effects of sex and social rank on aggressiveness and concentrations of brain amines, neurotransmitters essential for controlling aggression, in finishing pigs. Thirty-two barrows and 32 gilts (4 pigs/pen by sex) were fed either a control diet or a diet with RAC (Paylean, Elanco Animal Health, Greenfield, IN) added (5 mg/kg for 2 wk, followed by 10 mg/kg for 2 wk). The top dominant and bottom subordinate pigs (16 pigs/sex) in each pen were determined after mixing by a 36-h period of continuous behavioral observation. These pigs were then subjected to resident-intruder tests (maximum 300 s) during the feeding trial to measure aggressiveness. At the end of wk 4, the amygdala, frontal cortex, hypothalamus, and raphe nuclei were dissected and analyzed for concentrations of dopamine (DA); serotonin (5-HT); their metabolites 3,4-dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid, and 5-hydroxyindoleacetic acid (5-HIAA), respectively; norepinephrine; and epinephrine using HPLC. Ractopamine-fed gilts performed more attacks during the first 30 s of testing than pigs in all other subgroups (P < 0.05). By the end of the resident-intruder test (300 s), the dominant control gilts and barrows, and both dominant and subordinate RAC-fed gilts performed the greatest percentage of attacks (P < 0.05). Gilts had decreased norepinephrine and DOPAC concentrations in the amygdala and frontal cortex, and when fed RAC, gilts also had the least 5-HIAA concentration and greatest DA turnover rate in the amygdala (P < 0.05). The 5-HT concentration was less in the frontal cortex of gilts compared with barrows and in the raphe nuclei (single site for brain 5-HT synthesis) of dominant gilts (P < 0.05). Ractopamine may be affecting aggressive behavior through indirect action on central regulatory mechanisms such as the DA system. The aggressive pattern observed in the tested pigs, especially in gilts, is likely linked to brain monoamine profiling of a deficient serotonergic system in the raphe nuclei, amygdala, and frontal cortex, and enhanced DA metabolism in the amygdala, brain areas vital for aggression regulation.

  View details for DOI 10.2527/jas.2009-1876

  View details for Web of Science ID 000280866200025

  View details for PubMedID 20495130

• A flooring comparison: The impact of rubber mats on the health, behavior, and welfare of group-housed sows at breeding APPLIED ANIMAL BEHAVIOUR SCIENCE Elmore, M. R., Garner, J. P., Johnson, A. K., Richert, B. T., Pajor, E. A. 2010; 123 (1-2): 7-15

  View details for DOI 10.1016/j.applanim.2009.11.012

  View details for Web of Science ID 000275344300002

• A flooring comparison: The impact of rubber mats on the health, behavior, and welfare of group-housed sows at breeding Applied Animal Behaviour Science Elmore MRP, Garner JP, Johnson AK 2010; 123 (1-2): 7-15
• The effect of feeder space allocation on productivity and physiology of Hy-Line W-36 hens housed in conventional cages POULTRY SCIENCE Thogerson, C. M., Hester, P. Y., Mench, J. A., Newberry, R. C., Okura, C. M., Pajor, E. A., Talaty, P. N., Garner, J. P. 2009; 88 (9)

  Abstract

  Insufficient feeder space for laying hens could increase competition at the feed trough, leading to disrupted feeding, inadequate nutrient intake, stress, and reduced productivity. The effects of feeder space allocation (FSA) on physiology and productivity were evaluated in beak-trimmed Hy-Line W-36 hens (n=480). They were obtained at 16.5 wk of age and housed on 4 tiers of shallow conventional cages. Five pullets/cage were housed at a stocking density of 434 cm2/hen and a feeder space of 12.2 cm/hen. After 1.5 wk of acclimation, baseline measurements were taken for feed utilization, bone mineralization, and heterophil:lymphocyte ratios. At 20 wk of age, pullets were given 5.8, 7.1, 8.4, 9.7, 10.9, or 12.2 cm of feeder space/bird (16 cages/treatment). Physiological and production measures were calculated monthly or twice a month for 12 mo. The heart, spleen, and right adrenal gland were collected from each hen at the end of the study. Data were analyzed using a repeated measures GLM incorporating cage, tier, FSA, and hen age. There were no effects of FSA on total egg production, bone mineral density, bone mineral content, heterophil:lymphocyte ratios, or organ weights. Hens with reduced FSA utilized more feed (P<0.001), had poorer feed conversion (P<0.001), and laid eggs with slightly thicker and heavier shells (P<0.001). There were effects of FSA on total egg weight (P<0.001) and hen-day egg production (P<0.001), but they were of low magnitude and not linear (P>0.05). Because BW was similar among FSA treatments, the results suggest that reduced feeder space did not limit feed intake. In addition, reduced FSA did not lower bone mineralization or cause physiological stress in W-36 hens housed in shallow cages, suggesting that it did not impair hen welfare. However, it did result in poorer feed efficiency, possibly related to greater feed wastage, predictive of an adverse economic effect from reducing feeder space.

  View details for DOI 10.3382/ps.2009-00011

  View details for Web of Science ID 000269043600003

  View details for PubMedID 19687261

• The effect of feeder space allocation on behavior of Hy-Line W-36 hens housed in conventional cages POULTRY SCIENCE Thogerson, C. M., Hester, P. Y., Mench, J. A., Newberry, R. C., Pajor, E. A., Garner, J. P. 2009; 88 (8): 1544-1552

  Abstract

  Insufficient feeder space for laying hens could increase competition at the feed trough, resulting in exclusion of low-ranking hens from the feeder. To test this hypothesis, the effects of feeder space allocation (FSA) on feeding behavior, aggression, feather scores, BW, and mortality were evaluated in a common commercial strain of egg-laying chickens. Beak-trimmed Hy-Line W-36 hens (n = 480) were obtained as pullets at 16.5 wk of age and housed in conventional cages on 4 tiers. Five pullets/cage were housed at a stocking density of 434 cm(2)/pullet and an FSA of 12.2 cm/pullet. After 1.5 wk of acclimation, baseline measurements were taken for 2 wk and then pullets were given either 5.8, 7.1, 8.4, 9.7, 10.9, or 12.2 cm of feeder space/hen (16 cages/treatment). Feeding behavior was evaluated in each cage over a 24-h period each month. For each hen, percentage of time spent feeding and synchrony (mean number of additional hens feeding at the same time) were determined and scores were averaged for each cage. For each cage, feeder switching (number of observations in which hens changed from feeding to not feeding) and feeder sharing (probability that feeder access was equally distributed among all hens) were calculated. At monthly intervals, individual hens were weighed and their feathers scored using a 5-point scale on 8 body regions. Data were analyzed using a repeated measures GLM incorporating cage, tier, FSA, and age of the hen. Hens with reduced feeder space spent less time feeding (P < 0.001), synchronized their feeding bouts to a lesser extent (P < 0.001), made fewer switches at the feeder (P < 0.001), and shared the feeder less (P < 0.001). However, feather scores, BW, and BW uniformity were not affected by FSA. There was almost no aggressive behavior and little mortality. These results demonstrate that Hy-Line W-36 hens did not respond to reduced feeder space by aggressively excluding cage-mates from the feeder but instead desynchronized their feeding behavior.

  View details for DOI 10.3382/ps.2009-00010

  View details for Web of Science ID 000268128100004

  View details for PubMedID 19590067

• Thermonociception in fish: Effects of two different doses of morphine on thermal threshold and post-test behaviour in goldfish (Carassius auratus) APPLIED ANIMAL BEHAVIOUR SCIENCE Nordgreen, J., Garner, J. P., Janczak, A. M., Ranheim, B., Muir, W. M., Horsberg, T. E. 2009; 119 (1-2): 101-107

  View details for DOI 10.1016/j.applanim.2009.03.015

  View details for Web of Science ID 000266414200013

• Environmental standardization: cure or cause of poor reproducibility in animal experiments? NATURE METHODS Richter, S. H., Garner, J. P., Wuerbel, H. 2009; 6 (4): 257-261

  Abstract

  It is widely believed that environmental standardization is the best way to guarantee reproducible results in animal experiments. However, mounting evidence indicates that even subtle differences in laboratory or test conditions can lead to conflicting test outcomes. Because experimental treatments may interact with environmental conditions, experiments conducted under highly standardized conditions may reveal local 'truths' with little external validity. We review this hypothesis here and present a proof of principle based on data from a multilaboratory study on behavioral differences between inbred mouse strains. Our findings suggest that environmental standardization is a cause of, rather than a cure for, poor reproducibility of experimental outcomes. Environmental standardization can contribute to spurious and conflicting findings in the literature and unnecessary animal use. This conclusion calls for research into practicable and effective ways of systematic environmental heterogenization to attenuate these scientific, economic and ethical costs.

  View details for DOI 10.1038/NMETH.1312

  View details for Web of Science ID 000264738800012

  View details for PubMedID 19333241

• Some like it hot: Mouse temperature preferences in laboratory housing APPLIED ANIMAL BEHAVIOUR SCIENCE Gaskill, B. N., Rohr, S. A., Pajor, E. A., Lucas, J. R., Garner, J. P. 2009; 116 (2-4): 279-285

  View details for DOI 10.1016/j.applanim.2008.10.002

  View details for Web of Science ID 000262739200025

• Thermonociception in fish: Effects of two different doses of morphine on thermal threshold and post-test behaviour in goldfish (Carassius auratus) APPLIED ANIMAL BEHAVIOUR SCIENCE Nordgreen J, Garner JP, Janczak Am, Ranheim B, Muir WM, Horsberg TE 2009; 119 (1-2): 101-107
• Some like it hot: Mouse temperature preferences in laboratory housing APPLIED ANIMAL BEHAVIOUR SCIENCE Gaskill BN, Rohr SA, Pajor EA, Lucas JR, Garner JP 2009; 116 (2-4): 279-285
• Impact of Nesting Material on Mouse Thermoregulation and Variability JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE Gaskill BN, Gordon CJ, Pajor EA, Garner JP 2009; 48 (5): 549-549
• Preferences of Orange-winged Amazon parrots (Amazona amazonica) for cage enrichment devices Applied Animal Behaviour Science Kim LC, Garner JP, Millam JR 2009; 120 (3-4): 216-223
• Effects of a running wheel-igloo enrichment on aggression, hierarchy linearity, and stereotypy in group-housed male CD-1 (ICR) mice APPLIED ANIMAL BEHAVIOUR SCIENCE Howerton, C. L., Garner, J. P., Mench, J. A. 2008; 115 (1-2): 90-103

  View details for DOI 10.1016/j.applanim.2008.05.004

  View details for Web of Science ID 000261125400008

• Home Improvement: C57BL/6J Mice Given More Naturalistic Nesting Materials Build Better Nests JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE Hess, S. E., Rohr, S., Dufour, B. D., Gaskill, B. N., Pajor, E. A., Garner, J. P. 2008; 47 (6): 25-31

  Abstract

  Environmental enrichment of laboratory mice can improve the quality of research, but debate arises over the means of enrichment and its ability to be used in a sterile environment. One important form of enrichment is nesting material. Mice in the wild build dome-shaped, complex, multilayered nests, but this behavior is not seen in the laboratory, perhaps due to inappropriate nesting material rather than the nest-building ability of the mice. Here we focus on the use of naturalistic nesting materials to test whether they improve nest quality through the use of a 'naturalistic nest score' system; we also focus on materials that can be sterilized and easily used in existing housing systems. We first determined whether C57BL/6J mice build naturalistic nests when given shredded paper strips. We then compared these shredded paper strips with other commonly used nesting enrichments (facial tissues and compressed cotton squares). Nests were scored for 6 d. We found that the shredded paper strips allowed the mice to build higher quality nests than those built with any of the other materials. Nests built with tissues were of intermediate quality, and nests built with compressed cotton squares were of poor quality, similar to those built by the control group. These results suggest that C57BL/6J mice given appropriate nesting materials can build nests similar to those built by their wild counterparts.

  View details for Web of Science ID 000261438400006

  View details for PubMedID 19049249

• A note on the effects of co-mingling piglet litters on pre-weaning growth, injuries and responses to behavioural tests APPLIED ANIMAL BEHAVIOUR SCIENCE Kanaan, V. T., Pajor, E. A., Lay, D. C., Richert, B. T., Garner, J. P. 2008; 110 (3-4): 386-391

  View details for DOI 10.1016/j.applanim.2007.05.002

  View details for Web of Science ID 000254778900015

• A note on the effects of co-mingling piglet litters on pre-weaning growth, injuries and responses to behavioural tests APPLIED ANIMAL BEHAVIOUR SCIENCE Kanaan VT, Pajor EA, Lay DC, Richter BT, Garner JP 2008; 110 (3-4): 386-391
• Effects of a running wheel-igloo enrichment on aggression, hierarchy linearity, and stereotypy in group-housed male CD-1 (ICR) mice APPLIED ANIMAL BEHAVIOUR SCIENCE Howerton CL, Garner JP, Mench JA 2008; 115 (1-2): 90-103
• The effects of different bill-trimming methods on the well-being of pekin ducks POULTRY SCIENCE Gustafson, L. A., Cheng, H., Garner, J. P., Pajor, E. A., Mench, J. A. 2007; 86 (9): 1831-1839

  Abstract

  Pekin ducks are often bill-trimmed to prevent feather pecking and cannibalism, but this practice has been criticized because of the resulting potential for acute and chronic pain. The goal of this experiment was to compare 2 different bill-trimming methods, hot blade trimming with cautery (TRIM) and cautery only (tip-searing; SEAR), on the behavior, bill morphology, and weight gain of Pekin ducks. Ducklings (n = 192, 96 per sex) were trimmed at the hatchery and assigned to 12 floor pens (3.66 x0.91 m) by treatment. Behavior was evaluated by scan sampling, and plumage condition was scored using a 0 to 3 scoring system. Thirty-six ducks were randomly euthanized at 3 and 6 wk of age, and their bills were collected for examination. Following fixation and decalcification, the bills were embedded in paraffin wax and sectioned longitudinally. Alternate sections were stained with hematoxylin and eosin and Masson's trichrome for the connective tissues, and with Bielschowsky's silver impregnation, Bodian's staining, and Holmes' staining for the nerve fibers. Trimmed ducks engaged in fewer bill-related behaviors and rested more than untrimmed ducks (NOTRIM) during the first 2 wk posttrim. Ducks in the SEAR and NOTRIM groups showed similar patterns of weight gain, but those in the TRIM group had a lower rate of gain than ducks in the SEAR group during the first week posttrim and had a lower rate of gain than those in the NOTRIM group for 2 wk posttrim. Feather scores of ducks in the NOTRIM group were significantly worse than those in the TRIM or SEAR group by 18 d, and scores continued to deteriorate at a greater rate than those of trimmed ducks throughout the study. Both trimming methods caused connective tissue proliferation in the bill stumps, but the TRIM method caused thicker scar tissue than the SEAR method. No neuromas were found with either trimming method, but there were more nerve fibers in bill stumps of the SEAR ducks than the TRIM ducks. These results suggest that acute pain is associated with both trimming methods, but that SEAR may be a preferable method, causing less check in weight gain and fewer bill morphological changes while still being effective in minimizing feather pecking damage.

  View details for Web of Science ID 000249016700004

  View details for PubMedID 17704368

• Trichotillomania, stereotypic movement disorder, and related disorders. Current psychiatry reports Stein, D. J., Garner, J. P., Keuthen, N. J., Franklin, M. E., Walkup, J. T., Woods, D. W. 2007; 9 (4): 301-302

  Abstract

  Trichotillomania is currently classified as an impulse control disorder not otherwise classified, whereas body-focused behaviors other than hair-pulling may be diagnosed as stereotypic movement disorder. A number of disorders characterized by repetitive, body-focused behaviors (eg, skin-picking) are prevalent and disabling and may have phenomenological and psychobiological overlap. Such disorders deserve greater recognition in the official nosology, and there would seem to be clinical utility in classifying them in the same diagnostic category.

  View details for PubMedID 17880861

• Effects of bill-trimming Muscovy ducks on behavior, body weight gain, and bill morphopathology APPLIED ANIMAL BEHAVIOUR SCIENCE Gustafson, L. A., Cheng, H., Garner, J. P., Pajor, E. A., Mench, J. A. 2007; 103 (1-2): 59-74

  View details for DOI 10.1016/j.applanim.2006.04.003

  View details for Web of Science ID 000244571400006

• Effects of bill-trimming Muscovy ducks on behavior, body weight gain, and bill morphopathology APPLIED ANIMAL BEHAVIOUR SCIENCE Gustafson LA, Cheng HW, Garner JP, Pajor EA, Mench JA 2007; 103 (1-2): 59-74
• Refinement of rodent research though environmental enrichment and systematic randomization NC3Rs WRBEL H, GARNER JP 2007; 9: 1-9
• Animal neuropsychology: Validation of the Intra-Dimensional Extra-Dimensional set shifting task for mice BEHAVIOURAL BRAIN RESEARCH Garner, J. P., Thogerson, C. M., Wuerbel, H., Murray, J. D., Mench, J. A. 2006; 173 (1): 53-61

  Abstract

  Research in animal neuropsychology is providing an exciting new generation of behavioral tests for mice that promise to overcome many of the limitations of current high-throughput testing, and provide direct animal homologues of clinically important measures in human research. Set shifting tasks are some of the best understood and widely used human neuropsychological tasks, with clinical relevance to traumatic brain injury, schizophrenia, autism, obsessive compulsive disorder, trichotillomania, and many other disorders. Here we report the first successful modification of a human set shifting neuropsychological task, the Intra-Dimensional Extra-Dimensional (IDED) task, for use with mice. We presented mice with a series of compound discrimination and reversal tasks where one stimulus dimension consistently cued reward. Task performance improved with a new set of compound stimuli, as did reversal performance--indicating the formation of a cognitive-attentional set. We then overtrained a subset of the mice, and presented control and overtrained mice with a new compound discrimination where a novel stimulus dimension cued reward. As is the case in human control subjects, control mice persisted in responding to the now-incorrect stimulus dimension, performing poorly on this extra-dimensional shift compared with the previous intra-dimensional shift, thereby validating the task as a measure of set shifting. Furthermore, overtrained mice were impaired on this extra-dimensional shift compared with controls, further validating the task. The advantages and disadvantages of the IDED task compared to high-throughput approaches are discussed.

  View details for DOI 10.1016/j.bbr.2006.06.002

  View details for Web of Science ID 000240652500007

  View details for PubMedID 16842867

• Is fearfulness a trait that can be measured with behavioural tests? A validation of four fear tests for Japanese quail ANIMAL BEHAVIOUR Miller, K. A., Garner, J. P., Mench, J. A. 2006; 71: 1323-1334

  View details for DOI 10.1016/j.anbehav.2005.08.018

  View details for Web of Science ID 000239236900009

• Genetic, environmental, and neighbor effects on the severity of stereotypies and feather picking in Orange-winged Amazon parrots (Amazona amazonica): An epidemiological study APPLIED ANIMAL BEHAVIOUR SCIENCE Garner JP, Meehan Cl, Famula TR 2006; 96
• Genetic, environmental, and neighbor effects on the severity of stereotypies and feather picking in Orange-winged Amazon parrots (Amazona amazonica): An epidemiological study APPLIED ANIMAL BEHAVIOUR SCIENCE Garner, J. P., Meehan, C. L., Famula, T. R., Mench, J. A. 2006; 96 (1-2): 153-168

  View details for DOI 10.1016/j.applanim.2005.09.009

  View details for Web of Science ID 000235262600013

• Genetic, environmental, and neighbor effects on the severity of stereotypies and feather picking in Orange-winged Amazon parrots (Amazona amazonica): An epidemiological study APPLIED ANIMAL BEHAVIOUR SCIENCE Garner JR, Meehan CL, Famula TR, Mench JA 2006; 96 (1-2): 153-168
• Is fearfulness a trait that can be measured with behavioural tests? A validation of four fear tests for Japanese quail ANIMAL BEHAVIOUR Miller KA, Garner JP, Mench JA 2006; 71 (6): 1323-1334
• Effect of sand and wood-shavings bedding on the behavior of broiler chickens POULTRY SCIENCE Shields, S. J., Garner, J. P., Mench, J. A. 2005; 84 (12): 1816-1824

  Abstract

  The purpose of this study was to determine the effect of 2 different bedding types, sand and wood shavings, on the behavior of broiler chickens. In experiment 1, 6 pens were divided down the center and bedded half with sand and half with wood shavings. Male broilers (10/pen) were observed by scan sampling at 5- or 12-min intervals throughout the 6-wk growth period during the morning (between 0800 to 0900 h), afternoon (1200 to 1500 h), and night (2300 to 0600 h). There was a significant behavior x substrate x week interaction during the day (P < 0.0001) and at night (P < 0.0002). Drinking, dustbathing, preening, and sitting increased in frequency on the sand side but decreased on the wood shavings side during the day, as did resting at night. In general, broilers performed a greater proportion of their total behavioral time budget on the sand (P < 0.0001) as they aged. Broilers used the divider between the 2 bedding types to perch; perching behavior peaked during wk 4. In experiment 2, male broilers were housed in 8 pens (50 birds/pen) bedded only in sand or wood shavings. Bedding type had no effect on behavioral time budgets (P = 0.8946), although there were age-related changes in behavior on both bedding types. These results indicate that when given a choice, broilers increasingly performed many of their behaviors on sand, but if only one bedding type was provided they performed those behaviors with similar frequency on sand or wood shavings.

  View details for Web of Science ID 000233605200002

  View details for PubMedID 16479936

• The test-retest reliability of four behavioural tests of fearfulness for quail: a critical evaluation APPLIED ANIMAL BEHAVIOUR SCIENCE Miller, K. A., Garner, J. P., Mench, J. A. 2005; 92 (1-2): 113-127

  View details for DOI 10.1016/j.applanim.2004.10.016

  View details for Web of Science ID 000229872500010

• The test-retest reliability of four behavioural tests of fearfulness for quail; a critical evaluation Applied Animal Behaviour Science Miller KA, Garner JP, Mench JA 2005; 92 (1-2): 113-127
• Stereotypies and other abnormal repetitive behaviors: Potential impact on validity, reliability, and replicability of scientific outcomes ILAR JOURNAL Garner, J. P. 2005; 46 (2): 106-117

  Abstract

  Normal behavior plays a key role in facilitating homeostasis, especially by allowing the animal to control and modify its environment. Captive environments may interfere with these behavioral responses, and the resulting stress may alter many physiological parameters. Abnormal behaviors indicate that an animal is unable to adjust behaviorally to the captive environment and, hence, may be expressing abnormal physiology. Therefore, captive environments may affect the following aspects of an experiment: validity, by introducing abnormal animals into experiments; reliability, by increasing interindividual variation through the introduction of such individuals; and replicability, by altering the number and type of such individuals between laboratories. Thus, far from increasing variability, enrichment may actually improve validity, reliability, and replicability by reducing the number of abnormal animals introduced into experiments. In this article, the specific example of abnormal repetitive behaviors (ARBs) is explored. ARBs in captive animals appear to involve the same mechanisms as ARBs in human psychiatry, which reflect underlying abnormalities of brain function. ARBs are also correlated with a wide range of behavioral changes that affect experimental outcomes. Thus, ARBs in laboratory animals may compromise validity, reliability, and replicability, especially in behavioral experiments; and enrichments that prevent ARB may enhance validity, reliability, and replicability. Although many links in this argument have been tested experimentally, key issues still remain in the interpretation of these data. In particular, it is currently unclear (1) whether or not the differences in brain function seen in animals performing ARB are abnormal, (2) which common behavioral paradigms are affected by ARB, and (3) whether enrichment does indeed improve the quality of behavioral data. Ongoing and future work addressing these issues is outlined.

  View details for Web of Science ID 000227259000004

  View details for PubMedID 15775020

• Social and husbandry factors affecting the prevalence and severity of barbering ('whisker trimming') by laboratory mice APPLIED ANIMAL BEHAVIOUR SCIENCE Garner, J. P., Dufour, B., Gregg, L. E., Weisker, S. M., Mench, J. A. 2004; 89 (3-4): 263-282

  View details for DOI 10.1016/j.applanim.2004.07.004

  View details for Web of Science ID 000225168300007

• Dustbathing by broiler chickens: a comparison of preference for four different substrates APPLIED ANIMAL BEHAVIOUR SCIENCE Shields, S. J., Garner, J. P., Mench, J. A. 2004; 87 (1-2): 69-82

  View details for Web of Science ID 000221993300006

• Environmental enrichment and development of cage stereotypy in Orange-winged Amazon parrots (Amazona amazonica) DEVELOPMENTAL PSYCHOBIOLOGY Meehan, C. L., Garner, J. P., Mench, J. A. 2004; 44 (4): 209-218

  Abstract

  Stereotypies are abnormal repetitive behaviors that often develop in animals housed in impoverished environments. Stereotypy represents the interaction of several complex developmental phenomena. To characterize the temporal nature of stereotypy increase (escalation) and decrease (attenuation), we monitored changes in stereotypy performance in young Orange-winged Amazon parrots reared either in barren cages or cages provided with enrichments designed to facilitate foraging and locomotion. Unenriched parrots developed significantly more stereotypy than enriched parrots, and the mean time to stereotypy onset and the rate and magnitude of stereotypy increase also differed between the two groups. We then provided enrichment to the birds that had been reared in the barren cages. Following a 4-week delay, stereotypy was significantly reduced. These results show that stereotypy can be both prevented and reversed with appropriate environmental modification and illustrate how studying this behavior at many points over time can provide insights into its ontogeny.

  View details for DOI 10.1002/dev.20007

  View details for Web of Science ID 000221157700001

  View details for PubMedID 15103731

• Barbering (Fur and whisker trimming) by laboratory mice as a model of human trichotillomania and obsessive-compulsive spectrum disorders COMPARATIVE MEDICINE Garner, J. P., Weisker, S. M., Dufour, B., Mench, J. A. 2004; 54 (2): 216-224

  Abstract

  Animal diseases that develop spontaneously in a limited subpopulation can provide powerful models of human disease because they provide a means to investigate the interaction of a broad range of biological and environmental etiologic processes. In contrast, with experimentally induced animal models, the etiology of the model is inherently fixed, and can only speak to a limited subset of those involved in the human disease. 'Barbering' (abnormal whisker- and fur-plucking behavior) in mice resembles human trichotillomania (compulsive hair plucking) in that barbering mice pluck focused areas of hair, and engage in post-plucking manipulatory and oral behaviors. We performed a cross-sectional epidemiologic survey of a population of 2,950 laboratory mice to further assess the face validity of barbering as a spontaneous model of trichotillomania. Patterns of hair loss and demographic and etiologic risk factors were recorded for each mouse, and were analyzed by use of logistic regression. Barbering paralleled trichotillomania in terms of phenomenology, demography, and etiology. Thus, similar to trichotillomania, barbers predominately plucked hair from the scalp and around the eyes and the genitals; barbering was female biased, and had its onset during puberty; and etiologic factors included reproductive status and genetic background. Therefore, barbering has excellent face validity as a model of trichotillomania, and may represent a refined and non-invasive model, especially for studies of the complex genetic/environmental etiologies of this disorder.

  View details for Web of Science ID 000221213400013

  View details for PubMedID 15134369

• A behavioral comparison of New Zealand White rabbits (Oryctolagus cuniculus) housed individually or in pairs in conventional laboratory cages APPLIED ANIMAL BEHAVIOUR SCIENCE Chu, L. R., Garner, J. P., Mench, J. A. 2004; 85 (1-2): 121-139

  View details for DOI 10.1016/j.applanim.2003.09.011

  View details for Web of Science ID 000187741100010

• Social and husbandry factors affecting the prevalence and severity of barbering ('whisker trimming') by laboratory mice APPLIED ANIMAL BEHAVIOUR SCIENCE Garner JP, Dufour B, Gregg LE, Weisker SM, Mench JA 2004; 89 (3-4): 263-282
• Dustbathing by broiler chickens: a comparison of preference for four different substrates APPLIED ANIMAL BEHAVIOUR SCIENCE Shields SJ, Garner JP, Mench JA 2004; 87 (1-2): 69-82
• A behavioral comparison of New Zealand White rabbits (Oryctolagus cuniculus) housed individually or in pairs in conventional laboratory cages APPLIED ANIMAL BEHAVIOUR SCIENCE Chu LR, Garner JP, Mench JA 2004; 85 (1-2): 121-139
• Stereotypies in caged parrots, schizophrenia and autism: evidence for a common mechanism BEHAVIOURAL BRAIN RESEARCH Garner, J. P., Meehan, C. L., Mench, J. A. 2003; 145 (1-2): 125-134

  Abstract

  Spontaneously occurring abnormal behaviors in animals have recently received considerable attention, both in veterinary medicine and as a potential model for abnormal behavior in several human mental disorders. Stereotypies are abnormal repetitive, unvarying, and functionless behaviors that are often performed by captive and domesticated animals housed in barren environments. They closely resemble the stereotypies of autistic and mentally retarded patients, stereotypies of unmedicated chronic schizophrenic patients, certain classes of simple tic in Tourette's syndrome, and several drug-induced behaviors. However, evidence for a common mechanism has been lacking. Stereotypies in human mental disorders are indicative of profound brain dysfunction involving the basal ganglia, and are associated with pervasive voluntary-motor impairments and psychological distress. Here we show that stereotypy in captive Orange-Wing Amazon Parrots (Amazona amazonica) is correlated with poor performance on the same psychiatric task (the 'gambling task') as stereotypy in autistic and schizophrenic patients. The task measures recurrent perseveration-the tendency to inappropriately repeat responses. Thus, the more stereotypy a parrot performed, the more likely it was to inappropriately repeat itself from trial-to-trial on the task; and the more rapidly it made repeated, but not switched, responses. These results parallel the executive motor impairments seen in human patients, and therefore suggest that, like in human patients, stereotypy in caged parrots reflects a general disinhibition of the behavioral control mechanisms of the dorsal basal ganglia. If this result holds true in other laboratory species, stereotypic animals are likely to be of questionable utility in behavior, neuroscience, and neuropharmacological experiments. In humans, stereotypies and obsessive-compulsive behaviors are considered to be mutually exclusive categories of behavior, with different neural substrates, and different treatment strategies. These results, therefore, suggest that the pharmacological treatment of stereotypies in veterinary medicine based on the assumption that they are equivalent to human Obsessive-Compulsive Disorder may be inappropriate. As stereotypies in captive animals develop in response to the captive environment, these results also emphasize the role that the environment may play in eliciting or exacerbating stereotypy in human patients. Finally, by parallel to human patients, there is a potential psychological distress in animals showing these behaviors.

  View details for DOI 10.1016/S0166-4328(03)00115-3

  View details for Web of Science ID 000186073300013

  View details for PubMedID 14529811

• Stereotypic route-tracing in experimentally caged songbirds correlates with general behavioural disinhibition ANIMAL BEHAVIOUR Garner, J. P., Mason, G. J., Smith, R. 2003; 66: 711-727

  View details for DOI 10.1006/anbe.2003.2254

  View details for Web of Science ID 000186138800013

• Isosexual pair housing improves the welfare of young Amazon parrots APPLIED ANIMAL BEHAVIOUR SCIENCE Meehan, C. L., Garner, J. P., Mench, J. A. 2003; 81 (1): 73-88

  View details for Web of Science ID 000180991600006

• Stereotypic route-tracing in experimentally caged songbirds correlates with general behavioural disinhibition ANIMAL BEHAVIOUR Garner JP, Meehan CL, Mench JA 2003; 66: 711-727
• Isosexual pair housing improves the welfare of young Amazon parrots APPLIED ANIMAL BEHAVIOUR SCIENCE Meehan CL, Garner JP, Mench JA 2003; 81 (1): 73-88
• Evidence for a relationship between cage stereotypies and behavioural disinhibition in laboratory rodents BEHAVIOURAL BRAIN RESEARCH Garner, J. P., Mason, G. J. 2002; 136 (1): 83-92

  Abstract

  Cage stereotypies-abnormal, repetitive, unvarying and apparently functionless behaviours-are common in many captive animals, sometimes resulting in self-injury or decreased reproductive success. However, a general mechanistic or neurophysiological understanding of cage stereotypies has proved elusive. In contrast, stereotypies in human mental disorder, or those induced by drugs or brain lesions, are well understood, and are thought to result from the disinhibition of behavioural selection by the basal ganglia. In this study, we found that the cage stereotypies of captive bank voles also correlate with signs of altered response selection by the basal ganglia. Stereotypic bar-mouthing in the caged voles correlated with inappropriate responding in extinction learning, impairments of response timing, evidence of a knowledge-action dissociation, increased rates of behavioural activation, and hyperactivity. Furthermore, all these signs intercorrelated, implicating a single underlying deficit consistent with striatal disinhibition of response selection. Bar-mouthing thus appears fundamentally similar to the stereotypies of autists, schizophrenics, and subjects treated with amphetamine or basal ganglial lesions. These results represent the first evidence for a neural substrate of cage stereotypy. They also suggest that stereotypic animals may experience novel forms of psychological distress, and that stereotypy might well represent a potential confound in many behavioural experiments.

  View details for Web of Science ID 000178776300009

  View details for PubMedID 12385793

• Reliability and validity of a modified gait scoring system and its use in assessing tibial dyschondroplasia in broilers BRITISH POULTRY SCIENCE Garner, J. P., Falcone, C., Wakenell, P., Martin, M., Mench, J. A. 2002; 43 (3): 355-363

  Abstract

  1. The gait scoring system for broilers developed by Kestin et al. (Veterinary Record, 131: 190-194, 1992) has been widely used to evaluate leg problems. The many factors and measures associated with this scale have empirically established its external (biological) validity. However, published test-retest (within-observer) reliabilities are poor, and inter-observer reliabilities are unknown. We evaluated several modifications to this scale aimed at improving its objectivity and reliability. 2. Eighteen naïve observers scored a standardised video of birds exhibiting varying degrees of lameness, either using Kestin et al.'s system, or our modified system. 3. Test-retest reliability (0.906) for Kestin et al.'s system was higher than previously reported. Inter-rater reliability was also good (0.892). The modified system offered significantly better test-retest (0.948) and inter-rater reliabilities (0.943), without incurring costs in terms of time taken or difficulty of use. The systems were consistent, assigning individual birds the same score on average. 4. It is concluded that the modified system offers the advantages of reduced error within and between studies. 5. In a second experiment, we used our modified scoring system to examine the relationship between tibial dyschondroplasia (TD) and gait score in 267 selected broilers. 6. Neither the presence nor severity of TD affected gait score, suggesting that, at least in this strain of broilers, other leg problems like slipped tendons or torsional deformities had more influence on gait impairment than did TD.

  View details for DOI 10.1080/00071660120103620

  View details for Web of Science ID 000177314500003

  View details for PubMedID 12195794

• Adult attachment and the defensive regulation of attention and memory: Examining the role of preemptive and postemptive defensive processes 107th Annual Convention of the American-Psychological-Association Fraley, R. C., Garner, J. P., Shaver, P. R. AMER PSYCHOLOGICAL ASSOC. 2000: 816–26

  Abstract

  Previous research has found that avoidant adults have more difficulty recalling emotional experiences than do less avoidant adults. It is unclear, however, whether such findings reflect differences in the degree to which avoidant adults (a) attend to and encode emotional information, (b) elaborate emotional information they have encoded, or (c) do both. Two studies were conducted to distinguish between the effects of these processes. Participants listened to an interview about attachment-related issues and were asked to recall details from the interview either immediately or at variable delays. An analysis of forgetting curves revealed that avoidant adults initially encoded less information about the interview than did nonavoidant adults, although avoidant and nonavoidant adults forgot the information they did encode at the same rate. The implications of these findings for current views on the nature and efficacy of defenses are discussed.

  View details for Web of Science ID 000165096200010

  View details for PubMedID 11079243

• Arable habitat use by wood mice (Apodemus sylvaticus). 3. A farm-scale experiment on the effects of crop rotation JOURNAL OF ZOOLOGY MacDonald DW, Tew TE, Todd IA, Garner JP, Johnson PJ 2000; 250: 313-320
• On the origins of birds: the sequence of character acquisition in the evolution of avian flight PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES Garner, J. P., Taylor, G. K., Thomas, A. L. 1999; 266 (1425): 1259-1266

  View details for Web of Science ID 000081155500010

• On the origins of birds: the sequence of character acquisition in the evolution of avian flight PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES Garner JP, Taylor GK, Thomas ALR 1999; 266 (1425): 1259-1266
• Are birds dinosaurs? TRENDS IN ECOLOGY & EVOLUTION Thomas, A. L., Garner, J. P. 1998; 13 (4): 129-130

  View details for Web of Science ID 000072744200001

  View details for PubMedID 21238228

• Assesing animal priorities: future directions Animal Behaviour Mason G, Garner JP, McFarland D 1998; 55: 1082-1083
• A demanding task: using economic techniques to assess animal priorities ANIMAL BEHAVIOUR Mason G, McFarland D, Garner JP 1998; 55: 1071-1075
• Counting the Fingers of Birds and Dinosaurs Science Garner JP, Thomas ALR 1998; 280 (5362)