David Lyons

All Publications

• Ecological validity of social defeat stressors in mouse models of vulnerability and resilience. Neuroscience and biobehavioral reviews Lyons, D. M., Ayash, S., Schatzberg, A. F., Muller, M. B. 2023: 105032

  Abstract

  Laboratory mouse models offer opportunities to bridge the gap between basic neuroscience and applied stress research. Here we consider the ecological validity of social defeat stressors in mouse models of emotional vulnerability and resilience. Reports identified in PubMed from 1980 to 2020 are reviewed for the ecological validity of social defeat stressors, sex of subjects, and whether results are discussed in terms of vulnerability alone, resilience alone, or both vulnerability and resilience. Most of the 318 reviewed reports (95%) focus on males, and many reports (71%) discuss vulnerability and resilience. Limited ecological validity is associated with increased vulnerability and decreased resilience. Elements of limited ecological validity include frequent and repeated exposure to defeat stressors without opportunities to avoid or escape from unfamiliar conspecifics that are pre-screened and selected for aggressive behavior. These elements ensure defeat and may be required to induce vulnerability, but they are not representative of naturalistic conditions. Research aimed at establishing causality is needed to determine whether ecologically valid stressors build resilience in both sexes of mice.

  View details for DOI 10.1016/j.neubiorev.2023.105032

  View details for PubMedID 36608919

• Long-term effects of intermittent early life stress on primate prefrontal-subcortical functional connectivity. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology Yuan, R., Nechvatal, J. M., Buckmaster, C. L., Ayash, S., Parker, K. J., Schatzberg, A. F., Lyons, D. M., Menon, V. 2021

  Abstract

  Correlational studies of humans suggest that exposure to early life stress has long-term effects on neural circuits involved in vulnerability and resilience to mental health disorders. Stress-related mental health disorders are more prevalent in women than in men. Here, female squirrel monkeys are randomized to intermittently stressful (IS) social separations or a non-separated (NS) control condition conducted from 17 to 27 weeks of age. Nine years later in mid-life adulthood, resting-state functional magnetic resonance imaging was employed to parcellate prefrontal cortex (PFC). Resulting subdivisions were then used to characterize functional connectivity within PFC, and between PFC subdivisions and subcortical regions that are known to be altered by stress. Extensive hyper-connectivity of medial and orbitofrontal PFC with amygdala, hippocampus, and striatum was observed in IS compared to NS monkeys. Functional hyper-connectivity in IS monkeys was associated with previously reported indications of diminished anxiety-like behavior induced by prepubertal stress. Hyper-connectivity of PFC with amygdala and with hippocampus was also associated with increased ventral striatal dopamine D2 and/or D3 receptor (DRD2/3) availability assessed with positron emission tomography (PET) of [11C]raclopride binding in adulthood. Ventral striatal DRD2/3 availability has been linked to cognitive control, which plays a key role in stress coping as an aspect of emotion regulation. These findings provide causal support for enduring neurobiological effects of early life stress and suggest novel targets for new treatments of stress-related mental health disorders.

  View details for DOI 10.1038/s41386-021-00956-0

  View details for PubMedID 33495547

• Decoding the temporal nature of brain GR activity in the NFκB signal transition leading to depressive-like behavior. Molecular psychiatry Han, Y. M., Kim, M. S., Jo, J. n., Shin, D. n., Kwon, S. H., Seo, J. B., Kang, D. n., Lee, B. D., Ryu, H. n., Hwang, E. M., Kim, J. M., Patel, P. D., Lyons, D. M., Schatzberg, A. F., Her, S. n. 2021

  Abstract

  The fine-tuning of neuroinflammation is crucial for brain homeostasis as well as its immune response. The transcription factor, nuclear factor-κ-B (NFκB) is a key inflammatory player that is antagonized via anti-inflammatory actions exerted by the glucocorticoid receptor (GR). However, technical limitations have restricted our understanding of how GR is involved in the dynamics of NFκB in vivo. In this study, we used an improved lentiviral-based reporter to elucidate the time course of NFκB and GR activities during behavioral changes from sickness to depression induced by a systemic lipopolysaccharide challenge. The trajectory of NFκB activity established a behavioral basis for the NFκB signal transition involved in three phases, sickness-early-phase, normal-middle-phase, and depressive-like-late-phase. The temporal shift in brain GR activity was differentially involved in the transition of NFκB signals during the normal and depressive-like phases. The middle-phase GR effectively inhibited NFκB in a glucocorticoid-dependent manner, but the late-phase GR had no inhibitory action. Furthermore, we revealed the cryptic role of basal GR activity in the early NFκB signal transition, as evidenced by the fact that blocking GR activity with RU486 led to early depressive-like episodes through the emergence of the brain NFκB activity. These results highlight the inhibitory action of GR on NFκB by the basal and activated hypothalamic-pituitary-adrenal (HPA)-axis during body-to-brain inflammatory spread, providing clues about molecular mechanisms underlying systemic inflammation caused by such as COVID-19 infection, leading to depression.

  View details for DOI 10.1038/s41380-021-01016-1

  View details for PubMedID 33483691

• Resilience as a process instead of a trait STRESS RESILIENCE: MOLECULAR AND BEHAVIORAL ASPECTS Lyons, D. M., Schatzberg, A. F., Chen, A. 2020: 33–44

  View details for DOI 10.1016/B978-0-12-813983-7.00003-3

  View details for Web of Science ID 000539146600004

• Stress inoculation in mice induces global resilience. Translational psychiatry Ayash, S. n., Schmitt, U. n., Lyons, D. M., Müller, M. B. 2020; 10 (1): 200

  Abstract

  Each year, more than half a billion people in the world are affected by stress-related health disorders. Consequently, there is an urgent need for new insights to guide interventions designed to increase stress resilience. Studies of humans and various animals have uncovered the process of stress inoculation, in which exposure to mild stressors enhances subsequent stress resilience. Here, we investigate whether stress inoculation-induced resilience in mice consistently occurs across a multiplicity of different stress contexts (tests). C57BL/6 J adult male mice were randomised either to stress inoculation training (n = 36) or to a non-inoculated, but handled control condition (n = 36). Thereafter, indications of coping and resilience were assessed during (i) acute social defeat in a context similar to that used for stress inoculation training, and (ii) fear conditioning and learned extinction in a novel context. Stress inoculation effects were also assessed during (iii) tail-suspension and (iv) open-field tests that each represent milder stressors. Stress-inoculated mice showed more active defence behaviour during acute social defeat, higher sociability before and after defeat, and greater indications of learned extinction of conditioned fear compared to non-inoculated control mice. Stress-inoculated mice also responded with diminished tail-suspension immobility and open-field defecation. Results suggest that stress inoculation protects against various stressors that differ in quality and relative intensity. Stress inoculation research in mice may serve as the basis for mechanistic studies of global resilience in humans.

  View details for DOI 10.1038/s41398-020-00889-0

  View details for PubMedID 32561821

• Multisensory modulation of body ownership in mice. Neuroscience of consciousness Buckmaster, C. L., Rathmann-Bloch, J. E., de Lecea, L. n., Schatzberg, A. F., Lyons, D. M. 2020; 2020 (1): niz019

  Abstract

  Body ownership is a fundamental aspect of self-consciousness that reflects more than the presence of physical body parts. As demonstrated by the rubber hand illusion (RHI), human brains construct body ownership experiences using available multisensory information. Experimental conditions similar to those that induce the RHI in humans have been recently adapted to induce the rubber tail illusion (RTI) in mice. Here, we show that the RTI is enhanced in both sexes of mice by repetitive synchronous stroking comprised of correlated visual and tactile stimulation of real and rubber tails compared to visual-only mimicked stroking conducted without tactile stimulation. The RTI also appears to be enhanced in female but not male mice by slow compared to fast stroking that reflects an interoceptive manipulation associated with affective touch in humans. Sex differences in slow stroking effects are exploratory and require replication in mice. Sex differences have not been reported for the RHI in healthy humans, but women rate slow stroking as more affectively pleasant compared to the ratings of men. Results suggest that the RHI in humans resembles aspects of the RTI in mice. Studies of mice may therefore provide neurobiological insights on evolutionarily conserved mechanisms of bodily self-consciousness in humans.

  View details for DOI 10.1093/nc/niz019

  View details for PubMedID 31988796

  View details for PubMedCentralID PMC6977007

• Attenuation of Anti-Suicidal Effects of Ketamine by Opioid Receptor Antagonism Williams, N., Heifets, B., Bentzley, B., Blasey, C., Sudheimer, K., Lyons, D., Schatzberg, A. ELSEVIER SCIENCE INC. 2019: S113

  View details for DOI 10.1016/j.biopsych.2019.03.284

  View details for Web of Science ID 000472661000271

• Neural cell adhesion molecule peptide mimetics modulate emotionality: pharmacokinetic and behavioral studies in rats and non-human primates NEUROPSYCHOPHARMACOLOGY Turner, C. A., Lyons, D. M., Buckmaster, C. L., Aurbach, E. L., Watson, S. J., Schatzberg, A. F., Akil, H. 2019; 44 (2): 356–63

  Abstract

  Recent evidence highlights the fibroblast growth factor (FGF) family in emotion modulation. Although ligands that activate FGF receptors have antidepressant and anxiolytic effects in animal models, FGF ligands have a broad range of actions both in the brain and the periphery. Therefore, identifying molecular partners that may function as allosteric modulators could offer new avenues for drug development. Since neural cell adhesion molecule (NCAM) activates FGF receptors, we asked whether peripherally administered NCAM peptide mimetics penetrate the brain and alter the behavior of standardized tests that have predictive validity for drug treatments of anxiety or depression. The NCAM peptide mimetic, plannexin, acutely increased and chronically decreased anxiety, but did not have antidepressant effects in rats. Another NCAM peptide mimetic, FGLL, had acute anxiogenic effects and chronic antidepressant effects in rats. A related NCAM peptide mimetic, FGLS, had antidepressant effects without modulating anxiety-like behavior, and these antidepressant effects were blocked by an AMPA receptor antagonist. Cisternal cerebrospinal fluid (CSF) levels of FGLs correlated with blood plasma levels in rats and non-human primates, and CSF-to-blood ratios of FGLS were comparable in both species. Results indicate that NCAM peptide mimetics penetrate the brain and support the suggestion that FGLS may be a candidate for further development as a novel treatment for major depressive disorder in humans.

  View details for PubMedID 29703997

  View details for PubMedCentralID PMC6300554

• Attenuation of antidepressant and antisuicidal effects of ketamine by opioid receptor antagonism. Molecular psychiatry Williams, N. R., Heifets, B. D., Bentzley, B. S., Blasey, C. n., Sudheimer, K. D., Hawkins, J. n., Lyons, D. M., Schatzberg, A. F. 2019

  Abstract

  We recently reported that naltrexone blocks antidepressant effects of ketamine in humans, indicating that antidepressant effects of ketamine require opioid receptor activation. However, it is unknown if opioid receptors are also involved in ketamine's antisuicidality effects. Here, in a secondary analysis of our recent clinical trial, we test whether naltrexone attenuates antisuicidality effects of ketamine. Participants were pretreated with naltrexone or placebo prior to intravenous ketamine in a double-blinded crossover design. Suicidality was measured with the Hamilton Depression Rating Scale item 3, Montgomery-Åsberg Depression Rating Scale item 10, and Columbia Suicide Severity Rating Scale. In the 12 participants who completed naltrexone and placebo conditions, naltrexone attenuated the antisuicidality effects of ketamine on all three suicidality scales/subscales (linear mixed model, fixed pretreatment effect, p < 0.01). Results indicate that opioid receptor activation plays a significant role in the antisuicidality effects of ketamine.

  View details for DOI 10.1038/s41380-019-0503-4

  View details for PubMedID 31467392

• Nonlinear relationship between early life stress exposure and subsequent resilience in monkeys. Scientific reports Parker, K. J., Buckmaster, C. L., Hyde, S. A., Schatzberg, A. F., Lyons, D. M. 2019; 9 (1): 16232

  Abstract

  Retrospective correlational studies of humans suggest that moderate but not minimal or substantial early life stress exposure promotes the development of stress inoculation-induced resilience. Here we test for a nonlinear relationship between early life stress and resilience by comparing varying "doses" of early life stress. Juvenile squirrel monkeys underwent one of five treatment conditions between 17-27 weeks of age: Stress inoculation (SI) with continuous access to mother (SI + Mom; one stress element), SI without continuous access to mother (SI; two stress elements), SI without continuous access to mother and with alprazolam injection pretreatments (SI + Alz; three stress elements), SI without continuous access to mother and with vehicle injection pretreatments (SI + Veh; three stress elements), or standard housing (No SI; zero stress elements). Alprazolam was used to test whether anxiolytic medication diminished SI effects. Subjects exposed to one or two early life stressors subsequently responded with fewer indications of anxiety (e.g., decreased maternal clinging, increased object exploration, smaller cortisol increases) compared to No SI subjects. Subjects exposed to three early life stressors did not differ on most measures from one another or from No SI subjects. These findings provide empirical support for a nonlinear J-shaped relationship between early life stress exposure and subsequent resilience.

  View details for DOI 10.1038/s41598-019-52810-5

  View details for PubMedID 31700103

• Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism Williams, N. R., Heifets, B. D., Blasey, C., Sudheimer, K., Pannu, J., Pankow, H., Hawkins, J., Birnbaum, J., Lyons, D. M., Rodriguez, C. I., Schatzberg, A. F. AMER PSYCHIATRIC PUBLISHING, INC. 2018: 1205–15

  View details for DOI 10.1176/appi.ajp.2018.18020138

  View details for Web of Science ID 000451749000012

• Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism. The American journal of psychiatry Williams, N. R., Heifets, B. D., Blasey, C., Sudheimer, K., Pannu, J., Pankow, H., Hawkins, J., Birnbaum, J., Lyons, D. M., Rodriguez, C. I., Schatzberg, A. F. 2018: appiajp201818020138

  Abstract

  OBJECTIVE: In addition to N-methyl-d-aspartate receptor antagonism, ketamine produces opioid system activation. The objective of this study was to determine whether opioid receptor antagonism prior to administration of intravenous ketamine attenuates its acute antidepressant or dissociative effects.METHOD: In a proposed double-blind crossover study of 30 adults with treatment-resistant depression, the authors performed a planned interim analysis after studying 14 participants, 12 of whom completed both conditions in randomized order: placebo or 50 mg of naltrexone preceding intravenous infusion of 0.5 mg/kg of ketamine. Response was defined as a reduction ≥50% in score on the 17-item Hamilton Depression Rating Scale (HAM-D) score on postinfusion day 1.RESULTS: In the interim analysis, seven of 12 adults with treatment-resistant depression met the response criterion during the ketamine plus placebo condition. Reductions in 6-item and 17-item HAM-D scores among participants in the ketamine plus naltrexone condition were significantly lower than those of participants in the ketamine plus placebo condition on postinfusion days 1 and 3. Secondary analysis of all participants who completed the placebo and naltrexone conditions, regardless of the robustness of response to ketamine, showed similar results. There were no differences in ketamine-induced dissociation between conditions. Because naltrexone dramatically blocked the antidepressant but not the dissociative effects of ketamine, the trial was halted at the interim analysis.CONCLUSIONS: The findings suggest that ketamine's acute antidepressant effect requires opioid system activation. The dissociative effects of ketamine are not mediated by the opioid system, and they do not appear sufficient without the opioid effect to produce the acute antidepressant effects of ketamine in adults with treatment-resistant depression.

  View details for PubMedID 30153752

• Learning to actively cope with stress in female mice. Psychoneuroendocrinology Lyons, D. M., Buckmaster, C. L., Schatzberg, A. F. 2018; 96: 78–83

  Abstract

  Repeated exposure to a same-sex resident stranger enhances subsequent indications of active coping that generalize across multiple contexts in intruder male mice. Here we investigate female mice for comparable learning to cope training effects. Stress coping research focused on females is important because stress related mood and anxiety disorders are more prevalent in women than men. Female mice were monitored for coping behavior in open-field, object-exploration, and tail-suspension tests conducted after repeated exposure to a same-sex resident stranger. During repeated exposure sessions of training staged in the resident's home cage, behavioral measures of aggression and risk assessment were collected and plasma measures of the stress hormone corticosterone were obtained from separate samples of mice. Repeated exposure to a same-sex resident stranger subsequently enhanced active coping behavior exemplified by diminished freezing and increased center entries in the open-field, shorter object-exploration latencies, and a tendency toward decreased immobility on tail-suspension tests. Open-field locomotion considered as an index of non-specific activity was not increased by repeated sessions of exposure and did not correlate significantly with any measure of active coping. During repeated sessions of exposure to a same-sex resident stranger, risk assessment behavior and consistent but limited aggression occurred and corticosterone responses increased over repeated sessions. Exposure to a same-sex resident stranger is mildly stressful and promotes learning to actively cope in mice assessed in three different contexts.

  View details for PubMedID 29909293

• KETAMINE'S ANTIDEPRESSANT EFFECT IS BLOCKED BY A MU-OPIOID RECEPTOR ANTAGONIST IN HUMANS AND MICE Heifets, B. D., Williams, N., Sudheimer, K., Pankow, H., Blasey, C., Lyons, D., Schatzberg, A. F. LIPPINCOTT WILLIAMS & WILKINS. 2018: 343

  View details for Web of Science ID 000460106500197

• Integration of neural and epigenetic contributions to posttraumatic stress symptoms: The role of hippocampal volume and glucocorticoid receptor gene methylation PLOS ONE McNerney, M., Sheng, T., Nechvatal, J. M., Lee, A. G., Lyons, D. M., Soman, S., Liao, C., O'Hara, R., Hallmayer, J., Taylor, J., Ashford, J., Yesavage, J., Adamson, M. M. 2018; 13 (2): e0192222

  Abstract

  Many Veterans exposed to physical and psychological trauma experience symptoms of posttraumatic stress disorder (PTSD). As the etiology of PTSD symptoms is complex, a better understanding of the underlying biological mechanisms may improve preventative care and treatment for PTSD. Recent findings from the fields of neuroimaging and epigenetics offer important insights into the potential brain structures and biochemical pathways of modified gene expression associated with PTSD. We combined neuroimaging and epigenetic measures to assess current PTSD symptoms by measuring overall hippocampal volume and methylation of the glucocorticoid receptor (GR) gene (promoter region). Multiple regression analyses indicated that the hippocampal volume/GR methylation interaction was a predictor of PTSD symptoms. Our findings suggest that neuroimaging and epigenetic measures contribute interactively to PTSD symptoms. Incorporation of these metrics may aid in the identification and treatment of PTSD patients.

  View details for DOI 10.1371/journal.pone.0192222

  View details for Web of Science ID 000424325300060

  View details for PubMedID 29415058

  View details for PubMedCentralID PMC5802910

• Stress amplifies sex differences in primate prefrontal profiles of gene expression BIOLOGY OF SEX DIFFERENCES Lee, A. G., Hagenauer, M., Absher, D., Morrison, K. E., Bale, T. L., Myers, R. M., Watson, S. J., Akil, H., Schatzberg, A. F., Lyons, D. M. 2017; 8: 36

  Abstract

  Stress is a recognized risk factor for mood and anxiety disorders that occur more often in women than men. Prefrontal brain regions mediate stress coping, cognitive control, and emotion. Here, we investigate sex differences and stress effects on prefrontal cortical profiles of gene expression in squirrel monkey adults.Dorsolateral, ventrolateral, and ventromedial prefrontal cortical regions from 18 females and 12 males were collected after stress or no-stress treatment conditions. Gene expression profiles were acquired using HumanHT-12v4.0 Expression BeadChip arrays adapted for squirrel monkeys.Extensive variation between prefrontal cortical regions was discerned in the expression of numerous autosomal and sex chromosome genes. Robust sex differences were also identified across prefrontal cortical regions in the expression of mostly autosomal genes. Genes with increased expression in females compared to males were overrepresented in mitogen-activated protein kinase and neurotrophin signaling pathways. Many fewer genes with increased expression in males compared to females were discerned, and no molecular pathways were identified. Effect sizes for sex differences were greater in stress compared to no-stress conditions for ventromedial and ventrolateral prefrontal cortical regions but not dorsolateral prefrontal cortex.Stress amplifies sex differences in gene expression profiles for prefrontal cortical regions involved in stress coping and emotion regulation. Results suggest molecular targets for new treatments of stress disorders in human mental health.

  View details for PubMedID 29096718

• Striatal dopamine D2/3 receptor regulation by stress inoculation in squirrel monkeys. Neurobiology of stress Lee, A. G., Nechvatal, J. M., Shen, B., Buckmaster, C. L., Levy, M. J., Chin, F. T., Schatzberg, A. F., Lyons, D. M. 2016; 3: 68-73

  Abstract

  Intermittent mildly stressful situations provide opportunities to learn, practice, and improve coping in a process called stress inoculation. Stress inoculation also enhances cognitive control and response inhibition of impulsive motivated behavior. Cognitive control and motivation have been linked to striatal dopamine D2 and/or D3 receptors (DRD2/3) in rodents, monkeys, and humans. Here, we study squirrel monkeys randomized early in life to stress inoculation with or without maternal companionship and a no-stress control treatment condition. Striatal DRD2/3 availability in adulthood was measured in vivo by [(11)C]raclopride binding using positron emission tomography (PET). DRD2/3 availability was greater in caudate and putamen compared to ventral striatum as reported in PET studies of humans and other non-human primates. DRD2/3 availability in ventral striatum was also consistently greater in stress inoculated squirrel monkeys compared to no-stress controls. Squirrel monkeys exposed to stress inoculation in the presence of their mother did not differ from squirrel monkeys exposed to stress inoculation without maternal companionship. Similar effects in different social contexts extend the generality of our findings and together suggest that stress inoculation increases striatal DRD2/3 availability as a correlate of cognitive control in squirrel monkeys.

  View details for PubMedID 27981179

• Learning to cope with stress modulates anterior cingulate cortex stargazin expression in monkeys and mice NEUROBIOLOGY OF LEARNING AND MEMORY Lee, A. G., Capanzana, R., Brockhurst, J., Cheng, M. Y., Buckmaster, C. L., Absher, D., Schatzberg, A. F., Lyons, D. M. 2016; 131: 95-100

  Abstract

  Intermittent mildly stressful situations provide opportunities to learn, practice, and improve coping with gains in subsequent emotion regulation. Here we investigate the effects of learning to cope with stress on anterior cingulate cortex gene expression in monkeys and mice. Anterior cingulate cortex is involved in learning, memory, cognitive control, and emotion regulation. Monkeys and mice were randomized to either stress coping or no-stress treatment conditions. Profiles of gene expression were acquired with HumanHT-12v4.0 Expression BeadChip arrays adapted for monkeys. Three genes identified in monkeys by arrays were then assessed in mice by quantitative real-time polymerase chain reaction. Expression of a key gene (PEMT) involved in acetylcholine biosynthesis was increased in monkeys by coping but this result was not verified in mice. Another gene (SPRY2) that encodes a negative regulator of neurotrophic factor signaling was decreased in monkeys by coping but this result was only partly verified in mice. The CACNG2 gene that encodes stargazin (also called TARP gamma-2) was increased by coping in monkeys as well as mice randomized to coping with or without subsequent behavioral tests of emotionality. As evidence of coping effects distinct from repeated stress exposures per se, increased stargazin expression induced by coping correlated with diminished emotionality in mice. Stargazin modulates glutamate receptor signaling and plays a role in synaptic plasticity. Molecular mechanisms of synaptic plasticity that mediate learning and memory in the context of coping with stress may provide novel targets for new treatments of disorders in human mental health.

  View details for DOI 10.1016/j.nlm.2016.03.015

  View details for Web of Science ID 000376224900012

  View details for PubMedID 27003116

  View details for PubMedCentralID PMC4862929

• Temporal variability of glucocorticoid receptor activity is functionally important for the therapeutic action of fluoxetine in the hippocampus MOLECULAR PSYCHIATRY Lee, M., Kim, Y., Park, W., Park, O., Kwon, S., Hong, K. S., Rhim, H., Shim, I., Morita, K., Wong, D. L., Patel, P. D., Lyons, D. M., Schatzberg, A. F., Her, S. 2016; 21 (2): 252-260

  Abstract

  Previous studies have shown inconsistent results regarding the actions of antidepressants on glucocorticoid receptor (GR) signalling. To resolve these inconsistencies, we used a lentiviral-based reporter system to directly monitor rat hippocampal GR activity during stress adaptation. Temporal GR activation was induced significantly by acute stress, as demonstrated by an increase in the intra-individual variability of the acute stress group compared with the variability of the non-stress group. However, the increased intra-individual variability was dampened by exposure to chronic stress, which was partly restored by fluoxetine treatment without affecting glucocorticoid secretion. Immobility in the forced-swim test was negatively correlated with the intra-individual variability, but was not correlated with the quantitative GR activity during fluoxetine therapy; this highlights the temporal variability in the neurobiological links between GR signalling and the therapeutic action of fluoxetine. Furthermore, we demonstrated sequential phosphorylation between GR (S224) and (S232) following fluoxetine treatment, showing a molecular basis for hormone-independent nuclear translocation and transcriptional enhancement. Collectively, these results suggest a neurobiological mechanism by which fluoxetine treatment confers resilience to the chronic stress-mediated attenuation of hypothalamic-pituitary-adrenal axis activity.Molecular Psychiatry advance online publication, 21 October 2014; doi:10.1038/mp.2014.137.

  View details for DOI 10.1038/mp.2014.137

  View details for Web of Science ID 000370817800012

  View details for PubMedID 25330740

• Cup tool use by squirrel monkeys AMERICAN JOURNAL OF PRIMATOLOGY Buckmaster, C. L., Hyde, S. A., Parker, K. J., Lyons, D. M. 2015; 77 (12): 1323-1332

  Abstract

  Captive-born male and female squirrel monkeys spontaneously 'invented' a cup tool use technique to Contain (i.e., hold and control) food they reduced into fragments for consumption and to Contain water collected from a valve to drink. Food cup use was observed more frequently than water cup use. Observations indicate that 68% (n = 39/57) of monkeys in this population used a cup (a plastic slip cap) to Contain food, and a subset of these monkeys, 10% (n = 4/39), also used a cup to Contain water. Cup use was optional and did not replace, but supplemented, the hand/arm-to-mouth eating and direct valve drinking exhibited by all members of the population. Strategies monkeys used to bring food and cups together for food processing activity at preferred upper-level perching areas, in the arboreal-like environment in which they lived, provides evidence that monkeys may plan food processing activity with the cups. Specifically, prior to cup use monkeys obtained a cup first before food, or obtained food and a cup from the floor simultaneously, before transporting both items to upper-level perching areas. After food processing activity with cups monkeys rarely dropped the cups and more often placed the cups onto perching. Monkeys subsequently returned to use cups that they previously placed on perching after food processing activity. The latter behavior is consistent with the possibility that monkeys may keep cups at preferred perching sites for future food processing activity and merits experimental investigation. Reports of spontaneous tool use by squirrel monkeys are rare and this is the first report of population-level tool use. These findings offer insights into the cognitive abilities of squirrel monkeys and provide a new context for behavior studies with this genus and for comparative studies with other primates. Am. J. Primatol. © 2015 Wiley Periodicals, Inc.

  View details for DOI 10.1002/ajp.22486

  View details for Web of Science ID 000363892500008

  View details for PubMedID 26436899

• Stress inoculation modeled in mice TRANSLATIONAL PSYCHIATRY Brockhurst, J., Cheleuitte-Nieves, C., Buckmaster, C. L., Schatzberg, A. F., Lyons, D. M. 2015; 5

  View details for DOI 10.1038/tp.2015.34

  View details for Web of Science ID 000367655000003

• Stress inoculation modeled in mice. Translational psychiatry Brockhurst, J., Cheleuitte-Nieves, C., Buckmaster, C. L., Schatzberg, A. F., Lyons, D. M. 2015; 5

  Abstract

  Stress inoculation entails intermittent exposure to mildly stressful situations that present opportunities to learn, practice and improve coping in the context of exposure psychotherapies and resiliency training. Here we investigate behavioral and hormonal aspects of stress inoculation modeled in mice. Mice randomized to stress inoculation or a control treatment condition were assessed for corticosterone stress hormone responses and behavior during open-field, object-exploration and tail-suspension tests. Stress inoculation training sessions that acutely increased plasma levels of corticosterone diminished subsequent immobility as a measure of behavioral despair on tail-suspension tests. Stress inoculation also decreased subsequent freezing in the open field despite comparable levels of thigmotaxis in mice from both treatment conditions. Stress inoculation subsequently decreased novel-object exploration latencies and reduced corticosterone responses to repeated restraint. These results demonstrate that stress inoculation acutely stimulates glucocorticoid signaling and then enhances subsequent indications of active coping behavior in mice. Unlike mouse models that screen for the absence of vulnerability to stress or presence of traits that occur in resilient individuals, stress inoculation training reflects an experience-dependent learning-like process that resembles interventions designed to build resilience in humans. Mouse models of stress inoculation may provide novel insights for new preventive strategies or therapeutic treatments of human psychiatric disorders that are triggered and exacerbated by stressful life events.

  View details for DOI 10.1038/tp.2015.34

  View details for PubMedID 25826112

  View details for PubMedCentralID PMC4354359

• Coping and glucocorticoid receptor regulation by stress inoculation PSYCHONEUROENDOCRINOLOGY Lee, A. G., Buckmaster, C. L., Yi, E., Schatzberg, A. F., Lyons, D. M. 2014; 49: 272-279

  Abstract

  Intermittent exposure to mildly stressful situations provides opportunities to practice coping in the context of exposure psychotherapies and stress inoculation training. Previously, we showed that stress inoculation modeled in juvenile monkeys enhances subsequent indications of resilience. Here we examine stress inoculation effects in adult female monkeys. We found that stress inoculation prevents social separation stress induced anhedonia measured using sucrose preference tests and reduces the hypothalamic pituitary adrenal (HPA) axis stress hormone response to a novel environment. Stress inoculation also increases glucocorticoid receptor (NR3C1) gene expression in anterior cingulate cortex but not hippocampus. Increased anterior cingulate cortex NR3C1 expression induced by stress inoculation is not associated with significant changes in GR1F promoter DNA methylation. On average, low levels of promoter DNA methylation and limited GR1F expression were evident in monkey anterior cingulate cortex as observed in corticolimbic brain regions of adult humans. Taken together these findings suggest that stress inoculation in adulthood enhances behavioral and hormonal aspects of coping without significantly influencing GR1F promoter DNA methylation as a mechanism for NR3C1 transcription regulation.

  View details for DOI 10.1016/j.psyneuen.2014.07.020

  View details for Web of Science ID 000343342900027

  View details for PubMedCentralID PMC4165807

• Coping and glucocorticoid receptor regulation by stress inoculation. Psychoneuroendocrinology Lee, A. G., Buckmaster, C. L., Yi, E., Schatzberg, A. F., Lyons, D. M. 2014; 49: 272-279

  Abstract

  Intermittent exposure to mildly stressful situations provides opportunities to practice coping in the context of exposure psychotherapies and stress inoculation training. Previously, we showed that stress inoculation modeled in juvenile monkeys enhances subsequent indications of resilience. Here we examine stress inoculation effects in adult female monkeys. We found that stress inoculation prevents social separation stress induced anhedonia measured using sucrose preference tests and reduces the hypothalamic pituitary adrenal (HPA) axis stress hormone response to a novel environment. Stress inoculation also increases glucocorticoid receptor (NR3C1) gene expression in anterior cingulate cortex but not hippocampus. Increased anterior cingulate cortex NR3C1 expression induced by stress inoculation is not associated with significant changes in GR1F promoter DNA methylation. On average, low levels of promoter DNA methylation and limited GR1F expression were evident in monkey anterior cingulate cortex as observed in corticolimbic brain regions of adult humans. Taken together these findings suggest that stress inoculation in adulthood enhances behavioral and hormonal aspects of coping without significantly influencing GR1F promoter DNA methylation as a mechanism for NR3C1 transcription regulation.

  View details for DOI 10.1016/j.psyneuen.2014.07.020

  View details for PubMedID 25127085

• Evaluation of s-1 receptor radioligand 18F-FTC-146 in rats and squirrel monkeys using PET. Journal of nuclear medicine : official publication, Society of Nuclear Medicine James, M. L., Shen, B., Nielsen, C. H., Behera, D., Buckmaster, C. L., Mesangeau, C., Zavaleta, C., Vuppala, P. K., Jamalapuram, S., Avery, B. A., Lyons, D. M., McCurdy, C. R., Biswal, S., Gambhir, S. S., Chin, F. T. 2014; 55 (1): 147-153

  Abstract

  The noninvasive imaging of σ-1 receptors (S1Rs) could provide insight into their role in different diseases and lead to novel diagnostic/treatment strategies. The main objective of this study was to assess the S1R radiotracer (18)F-FTC-146 in rats. Preliminary squirrel monkey imaging and human serum/liver microsome studies were performed to gain information about the potential of (18)F-FTC-146 for eventual clinical translation.The distribution and stability of (18)F-FTC-146 in rats were assessed via PET/CT, autoradiography, γ counting, and high-performance liquid chromatography (HPLC). Preliminary PET/MRI of squirrel monkey brain was conducted along with HPLC assessment of (18)F-FTC-146 stability in monkey plasma and human serum.Biodistribution studies showed that (18)F-FTC-146 accumulated in S1R-rich rat organs, including the lungs, pancreas, spleen, and brain. Pretreatment with known S1R compounds, haloperidol, or BD1047, before radioligand administration, significantly attenuated (18)F-FTC-146 accumulation in all rat brain regions by approximately 85% (P < 0.001), suggesting radiotracer specificity for S1Rs. Similarly, PET/CT and autoradiography results demonstrated accumulation of (18)F-FTC-146 in rat brain regions known to contain S1Rs and that this uptake could be blocked by BD1047 pretreatment. Ex vivo analysis of (18)F-FTC-146 in the brain showed that only intact radiotracer was present at 15, 30, and 60 min, whereas rapid metabolism of residual (18)F-FTC-146 was observed in rat plasma. Preliminary monkey PET/MRI studies demonstrated specific accumulation of (18)F-FTC-146 in the brain (mainly in cortical structures, cerebellum, and vermis) that could be attenuated by pretreatment with haloperidol. HPLC of monkey plasma suggested radioligand metabolism, whereas (18)F-FTC-146 appeared to be stable in human serum. Finally, liver microsome studies revealed that (18)F-FTC-146 has a longer half-life in human microsomes, compared with rodents.Together, these results indicate that (18)F-FTC-146 is a promising tool for visualizing S1Rs in preclinical studies and that it has potential for mapping these sites in the human brain.

  View details for DOI 10.2967/jnumed.113.120261

  View details for PubMedID 24337599

• Evaluation of s-1 Receptor Radioligand 18F-FTC-146 in Rats and Squirrel Monkeys Using PET. Journal of nuclear medicine : official publication, Society of Nuclear Medicine James, M. L., Shen, B., Nielsen, C. H., Behera, D., Buckmaster, C. L., Mesangeau, C., Zavaleta, C., Vuppala, P. K., Jamalapuram, S., Avery, B. A., Lyons, D. M., McCurdy, C. R., Biswal, S., Gambhir, S. S., Chin, F. T. 2014; 55 (1): 147-153

  Abstract

  The noninvasive imaging of σ-1 receptors (S1Rs) could provide insight into their role in different diseases and lead to novel diagnostic/treatment strategies. The main objective of this study was to assess the S1R radiotracer (18)F-FTC-146 in rats. Preliminary squirrel monkey imaging and human serum/liver microsome studies were performed to gain information about the potential of (18)F-FTC-146 for eventual clinical translation.The distribution and stability of (18)F-FTC-146 in rats were assessed via PET/CT, autoradiography, γ counting, and high-performance liquid chromatography (HPLC). Preliminary PET/MRI of squirrel monkey brain was conducted along with HPLC assessment of (18)F-FTC-146 stability in monkey plasma and human serum.Biodistribution studies showed that (18)F-FTC-146 accumulated in S1R-rich rat organs, including the lungs, pancreas, spleen, and brain. Pretreatment with known S1R compounds, haloperidol, or BD1047, before radioligand administration, significantly attenuated (18)F-FTC-146 accumulation in all rat brain regions by approximately 85% (P < 0.001), suggesting radiotracer specificity for S1Rs. Similarly, PET/CT and autoradiography results demonstrated accumulation of (18)F-FTC-146 in rat brain regions known to contain S1Rs and that this uptake could be blocked by BD1047 pretreatment. Ex vivo analysis of (18)F-FTC-146 in the brain showed that only intact radiotracer was present at 15, 30, and 60 min, whereas rapid metabolism of residual (18)F-FTC-146 was observed in rat plasma. Preliminary monkey PET/MRI studies demonstrated specific accumulation of (18)F-FTC-146 in the brain (mainly in cortical structures, cerebellum, and vermis) that could be attenuated by pretreatment with haloperidol. HPLC of monkey plasma suggested radioligand metabolism, whereas (18)F-FTC-146 appeared to be stable in human serum. Finally, liver microsome studies revealed that (18)F-FTC-146 has a longer half-life in human microsomes, compared with rodents.Together, these results indicate that (18)F-FTC-146 is a promising tool for visualizing S1Rs in preclinical studies and that it has potential for mapping these sites in the human brain.

  View details for DOI 10.2967/jnumed.113.120261

  View details for PubMedID 24337599

• Early Life Stress Inoculation Changes Brain Development Nechvatal, J. M., Qiu, D., Buckmaster, C. L., Schatzberg, A. F., Moseley, M. E., Lyons, D. M. ELSEVIER SCIENCE INC. 2013: 84S

  View details for Web of Science ID 000318671800259

• Coping changes the brain FRONTIERS IN BEHAVIORAL NEUROSCIENCE Nechvatal, J. M., Lyons, D. M. 2013; 7

  Abstract

  One of the earliest and most consistent findings in behavioral neuroscience research is that learning changes the brain. Here we consider how learning as an aspect of coping in the context of stress exposure induces neuroadaptations that enhance emotion regulation and resilience. A systematic review of the literature identified 15 brain imaging studies in which humans with specific phobias or post-traumatic stress disorder (PTSD) were randomized to stress exposure therapies that diminished subsequent indications of anxiety. Most of these studies focused on functional changes in the amygdala and anterior corticolimbic brain circuits that control cognitive, motivational, and emotional aspects of physiology and behavior. Corresponding structural brain changes and the timing, frequency, and duration of stress exposure required to modify brain functions remain to be elucidated in future research. These studies will advance our understanding of coping as a learning process and provide mechanistic insights for the development of new interventions that promote stress coping skills.

  View details for DOI 10.3389/fnbeh.2013.00013

  View details for Web of Science ID 000315183400001

  View details for PubMedID 23439935

  View details for PubMedCentralID PMC3579178

• Coping changes the brain. Frontiers in behavioral neuroscience Nechvatal, J. M., Lyons, D. M. 2013; 7: 13-?

  Abstract

  One of the earliest and most consistent findings in behavioral neuroscience research is that learning changes the brain. Here we consider how learning as an aspect of coping in the context of stress exposure induces neuroadaptations that enhance emotion regulation and resilience. A systematic review of the literature identified 15 brain imaging studies in which humans with specific phobias or post-traumatic stress disorder (PTSD) were randomized to stress exposure therapies that diminished subsequent indications of anxiety. Most of these studies focused on functional changes in the amygdala and anterior corticolimbic brain circuits that control cognitive, motivational, and emotional aspects of physiology and behavior. Corresponding structural brain changes and the timing, frequency, and duration of stress exposure required to modify brain functions remain to be elucidated in future research. These studies will advance our understanding of coping as a learning process and provide mechanistic insights for the development of new interventions that promote stress coping skills.

  View details for DOI 10.3389/fnbeh.2013.00013

  View details for PubMedID 23439935

  View details for PubMedCentralID PMC3579178

• Prokineticin 2 is an endangering mediator of cerebral ischemic injury PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Cheng, M. Y., Lee, A. G., Culbertson, C., Sun, G., Talati, R. K., Manley, N. C., Li, X., Zhao, H., Lyons, D. M., Zhou, Q., Steinberg, G. K., Sapolsky, R. M. 2012; 109 (14): 5475-5480

  Abstract

  Stroke causes brain dysfunction and neuron death, and the lack of effective therapies heightens the need for new therapeutic targets. Here we identify prokineticin 2 (PK2) as a mediator for cerebral ischemic injury. PK2 is a bioactive peptide initially discovered as a regulator of gastrointestinal motility. Multiple biological roles for PK2 have been discovered, including circadian rhythms, angiogenesis, and neurogenesis. However, the role of PK2 in neuropathology is unknown. Using primary cortical cultures, we found that PK2 mRNA is up-regulated by several pathological stressors, including hypoxia, reactive oxygen species, and excitotoxic glutamate. Glutamate-induced PK2 expression is dependent on NMDA receptor activation and extracellular calcium. Enriched neuronal culture studies revealed that neurons are the principal source of glutamate-induced PK2. Using in vivo models of stroke, we found that PK2 mRNA is induced in the ischemic cortex and striatum. Central delivery of PK2 worsens infarct volume, whereas PK2 receptor antagonist decreases infarct volume and central inflammation while improving functional outcome. Direct central inhibition of PK2 using RNAi also reduces infarct volume. These findings indicate that PK2 can be activated by pathological stimuli such as hypoxia-ischemia and excitotoxic glutamate and identify PK2 as a deleterious mediator for cerebral ischemia.

  View details for DOI 10.1073/pnas.1113363109

  View details for Web of Science ID 000302294700073

  View details for PubMedID 22431614

  View details for PubMedCentralID PMC3325724

• Time-course of cerebrospinal fluid histamine in the wake-consolidated squirrel monkey JOURNAL OF SLEEP RESEARCH Zeitzer, J. M., Kodama, T., Buckmaster, C. L., Honda, Y., Lyons, D. M., Nishino, S., Mignot, E. 2012; 21 (2): 189-194

  Abstract

  Central nervous system (CNS) histamine is low in individuals with narcolepsy, a disease characterized by severe fragmentation of both sleep and wake. We have developed a primate model, the squirrel monkey, with which we can examine the role of the CNS in the wake-consolidation process, as these primates are day-active, have consolidated wake and sleep and have cerebrospinal fluid (CSF) that is readily accessible. Using this model and three distinct protocols, we report herein on the role of CNS histamine in the wake consolidation process. CSF histamine has a robust daily rhythm, with a mean of 24.9 ± 3.29 pg mL(-1) , amplitude of 31.7 ± 6.46 pg mL(-1) and a peak at 17:49 ± 70.3 min (lights on 07:00-19:00 hours). These levels are not significantly affected by increases (up to 161 ± 40.4% of baseline) or decreases (up to 17.2 ± 2.50% of baseline) in locomotion. In direct contrast to the effects of sleep deprivation in non-wake-consolidating mammals, in whom CSF histamine increases, pharmacologically induced sleep (γ-hydroxybutyrate) and wake (modafinil) have no direct effects on CSF histamine concentrations. These data indicate that the time-course of histamine in CSF in the wake-consolidated squirrel monkey is robust against variation in activity and sleep and wake-promoting pharmacological compounds, and may indicate that histamine physiology plays a role in wake-consolidation such as is present in the squirrel monkey and humans.

  View details for DOI 10.1111/j.1365-2869.2011.00957.x

  View details for Web of Science ID 000301931500010

  View details for PubMedID 21910776

  View details for PubMedCentralID PMC3237761

• Hypothalamic-pituitary-adrenal axis physiology and cognitive control of behavior in stress inoculated monkeys 2nd Herzliyah Symposium on Developmental Psychopathology Parker, K. J., Buckmaster, C. L., Lindley, S. E., Schatzberg, A. F., Lyons, D. M. SAGE PUBLICATIONS LTD. 2012: 45–52

  View details for DOI 10.1177/0165025411406864

  View details for Web of Science ID 000298188500007

• Hypothalamic-pituitary-adrenal axis physiology and cognitive control of behavior in stress inoculated monkeys. International journal of behavioral development Parker, K. J., Buckmaster, C. L., Lindley, S. E., Schatzberg, A. F., Lyons, D. M. 2012; 36 (1)

  Abstract

  Monkeys exposed to stress inoculation protocols early in life subsequently exhibit diminished neurobiological responses to moderate psychological stressors and enhanced cognitive control of behavior during juvenile development compared to non-inoculated monkeys. The present experiments extended these findings and revealed that stress inoculated monkeys: (a) mount neurobiological responses equivalent to non-inoculated monkeys when the stressor is of sufficient intensity, and (b) continue to exhibit enhanced cognitive control as young adults compared to non-inoculated monkeys. These results suggest that stress inoculation protocols alter the appraisal of and response to moderate stressors as less threatening and permanently enhance cognitive control, at least through early adulthood. These data therefore support the notion that the stress inoculation phenotype reflects stress resilience rather than stress pathology.

  View details for PubMedID 24353360

• The neurobiology of the stress-resistant brain STRESS-THE INTERNATIONAL JOURNAL ON THE BIOLOGY OF STRESS Fleshner, M., Maier, S. F., Lyons, D. M., Raskind, M. A. 2011; 14 (5): 498-502

  Abstract

  The 2010 Neurobiology of Stress Workshop brought together scientists from all over the world to share and discuss their results from studies examining the consequences of acute, repeated, and chronic stressor exposure on health and disease. Session IV entitled "The neurobiology of the stress-resistant brain" explored how we can intervene to promote stress resistance and stress resilience. Four scientists, who explore this topic from unique and convergent perspectives, presented their experimental results derived from studies in rat (Fleshner and Maier), non-human primates (Lyons), and human (Raskind). Summaries of each presentation, supporting publications, and overall take-home messages from the session are presented.

  View details for DOI 10.3109/10253890.2011.596865

  View details for Web of Science ID 000294008400005

  View details for PubMedID 21790482

  View details for PubMedCentralID PMC3287388

• A novel form of oxytocin in New World monkeys BIOLOGY LETTERS Lee, A. G., Cool, D. R., Grunwald, W. C., Neal, D. E., Buckmaster, C. L., Cheng, M. Y., Hyde, S. A., Lyons, D. M., Parker, K. J. 2011; 7 (4): 584-587

  Abstract

  Oxytocin is widely believed to be present and structurally identical in all placental mammals. Here, we report that multiple species of New World monkeys possess a novel form of oxytocin, [P8] oxytocin. This mutation arises from a substitution of a leucine to a proline in amino acid position 8. Further analysis of this mutation in Saimiri sciureus (squirrel monkey) indicates that [P8] oxytocin is transcribed and translated properly. This mutation is specific to oxytocin, as the peptide sequence for arginine vasopressin, a structurally related nonapeptide, is unaltered. These findings dispel the notion that all placental mammals possess a 'universal' oxytocin sequence, and highlight the need for research on the functional significance of this novel nonapeptide in New World monkeys.

  View details for DOI 10.1098/rsbl.2011.0107

  View details for PubMedID 21411453

• Resilience and adaptive aspects of stress in neurobehavioral development NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS Lyons, D. M., Macri, S. 2011; 35 (7): 1451-1451

  View details for DOI 10.1016/j.neubiorev.2010.09.004

  View details for Web of Science ID 000292428200001

  View details for PubMedID 20851144

• Somatic and neuroendocrine responses to standard and biologically salient acoustic startle stimuli in monkeys PSYCHONEUROENDOCRINOLOGY Parker, K. J., Hyde, S. A., Buckmaster, C. L., Tanaka, S. M., Brewster, K. K., Schatzberg, A. F., Lyons, D. M., Woodward, S. H. 2011; 36 (4): 547-556

  Abstract

  The startle response, a simple defensive response to a sudden stimulus signaling proximal threat, has been well studied in rodents and humans, but has been rarely examined in monkeys. The first goal of the present studies was to develop a minimally immobilizing startle measurement paradigm and validate its usefulness by testing two core features of the startle response (habituation and graded responsivity) in squirrel monkey subjects. Two different types of startle stimuli were used: standard broad-band noise bursts, and species-specific alarm vocalizations ("yaps") which are elicited in response to threat in both wild and captive animals. The second goal of the present studies was to test whether yaps produce enhanced startle responsivity due to their increased biological salience compared to simple, non-biologically relevant noise bursts. The third goal of the present studies was to evaluate the hypothalamic-pituitary-adrenal (HPA) axis response to startle stimuli, as little is known about the stress-activating role of startle stimuli in any species. These experiments determined that the whole-body startle response in relatively unrestrained squirrel monkeys habituates across repeated stimulus presentations and is proportional to stimulus intensity. In addition, differential habituation was observed across biologically salient vs. standard acoustic startle stimuli. Responses to "yaps" were larger initially but attenuated more rapidly over trials. Responses to "yaps" were also larger in the early subepochs of the response window but then achieved a lower level than responses to noise bursts in the later subepochs. Finally, adrenocorticotropic hormone and cortisol concentrations were significantly elevated above baseline after startle stimuli presentation, though monkeys did not exhibit differential HPA axis responses to the two types of startle stimuli. The development of monkey startle methodology may further enhance the utility of this paradigm in translational studies of human stress-related psychiatric disorders.

  View details for DOI 10.1016/j.psyneuen.2010.08.009

  View details for Web of Science ID 000288922300013

  View details for PubMedID 20869176

  View details for PubMedCentralID PMC3020232

• [F-18]FTC-146 for imaging sigma-1 receptors in squirrel monkey brain using PET/MRI James, M. L., Shen, B., Nielsen, C. H., Buckmaster, C. L., Berganos, R. A., Zavaleta, C., Lyons, D., McCurdy, C. R., Gambhir, S. S., Chin, F. T. WILEY-BLACKWELL. 2011: S317–S317

  View details for Web of Science ID 000295901600317

• Animal Models of Early Life Stress: Implications for Understanding Resilience DEVELOPMENTAL PSYCHOBIOLOGY Lyons, D. M., Parker, K. J., Schatzberg, A. F. 2010; 52 (7): 616-624

  Abstract

  In the mid-1950s, Levine and his colleagues reported that brief intermittent exposure to early life stress diminished indications of subsequent emotionality in rats. Here we review ongoing studies of a similar process in squirrel monkeys. Results from these animal models suggest that brief intermittent exposure to stress promotes the development of arousal regulation and resilience. Implications for programs designed to enhance resilience in human development are discussed.

  View details for DOI 10.1002/dev.20500

  View details for Web of Science ID 000283570400002

  View details for PubMedID 20957724

• Stress coping stimulates hippocampal neurogenesis in adult monkeys PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Lyons, D. M., Buckmaster, P. S., Lee, A. G., Wu, C., Mitra, R., Duffey, L. M., Buckmaster, C. L., Her, S., Patel, P. D., Schatzberg, A. F. 2010; 107 (33): 14823-14827

  Abstract

  Coping with intermittent social stress is an essential aspect of living in complex social environments. Coping tends to counteract the deleterious effects of stress and is thought to induce neuroadaptations in corticolimbic brain systems. Here we test this hypothesis in adult squirrel monkey males exposed to intermittent social separations and new pair formations. These manipulations simulate conditions that typically occur in male social associations because of competition for limited access to residency in mixed-sex groups. As evidence of coping, we previously confirmed that cortisol levels initially increase and then are restored to prestress levels within several days of each separation and new pair formation. Follow-up studies with exogenous cortisol further established that feedback regulation of the hypothalamic-pituitary-adrenal axis is not impaired. Now we report that exposure to intermittent social separations and new pair formations increased hippocampal neurogenesis in squirrel monkey males. Hippocampal neurogenesis in rodents contributes to spatial learning performance, and in monkeys we found that spatial learning was enhanced in conditions that increased hippocampal neurogenesis. Corresponding changes were discerned in the expression of genes involved in survival and integration of adult-born granule cells into hippocampal neural circuits. These findings support recent indications that stress coping stimulates hippocampal neurogenesis in adult rodents. Psychotherapies designed to promote stress coping potentially have similar effects in humans with major depression.

  View details for DOI 10.1073/pnas.0914568107

  View details for Web of Science ID 000281287600055

  View details for PubMedID 20675584

  View details for PubMedCentralID PMC2930418

• Modafinil and gamma-hydroxybutyrate have sleep state-specific pharmacological actions on hypocretin-1 physiology in a primate model of human sleep BEHAVIOURAL PHARMACOLOGY Zeitzer, J. M., Buckmaster, C. L., Landoltd, H., Lyons, D. M., Mignot, E. 2009; 20 (7): 643-652

  Abstract

  Hypocretin-1 is a hypothalamic neuropeptide that is important in the regulation of wake and the lack of which results in the sleep disorder narcolepsy. Using a monkey that has consolidated wake akin to humans, we examined pharmacological manipulation of sleep and wake and its effects on hypocretin physiology. Monkeys were given the sleep-inducing γ-hydroxybutyrate (GHB) and the wake-inducing modafinil both in the morning and in the evening. Cerebrospinal fluid hypocretin-1 concentrations changed significantly in response to the drugs only when accompanied by a behavioral change (GHB-induced sleep in the morning or modafinil-induced wake in the evening). We also found that there was a large (180-fold) interindividual variation in GHB pharmacokinetics that explains variability in sleep induction in response to the drug. Our data indicate that the neurochemical concomitants of sleep and wake are capable of changing the physiological output of hypocretin neurons. Sleep independent of circadian timing is capable of decreasing cerebrospinal fluid hypocretin-1 concentrations. Furthermore, hypocretin neurons do not seem to respond to an 'effort' to remain awake, but rather keep track of time spent awake as a wake-promoting counterbalance to extended wakefulness.

  View details for DOI 10.1097/FBP.0b013e328331b9db

  View details for Web of Science ID 000270483300010

  View details for PubMedID 19752724

  View details for PubMedCentralID PMC2939929

• Developmental cascades linking stress inoculation, arousal regulation, and resilience FRONTIERS IN BEHAVIORAL NEUROSCIENCE Lyons, D. M., Parker, K. J., Katz, M., Schatzberg, A. F. 2009; 3

  Abstract

  Stressful experiences that are challenging but not overwhelming appear to promote the development of arousal regulation and resilience. Variously described in studies of humans as inoculating, steeling, or toughening, the notion that coping with early life stress enhances arousal regulation and resilience is further supported by longitudinal studies of squirrel monkey development. Exposure to early life stress inoculation diminishes subsequent indications of anxiety, increases exploration of novel situations, and decreases stress-levels of cortisol compared to age-matched monkeys raised in undisturbed social groups. Stress inoculation also enhances prefrontal-dependent cognitive control of behavior and increases ventromedial prefrontal cortical volumes. Larger volumes do not reflect increased cortical thickness but instead represent surface area expansion of ventromedial prefrontal cortex. Expansion of ventromedial prefrontal cortex coincides with increased white matter myelination inferred from diffusion tensor magnetic resonance imaging. These findings suggest that early life stress inoculation triggers developmental cascades across multiple domains of adaptive functioning. Prefrontal myelination and cortical expansion induced by the process of coping with stress support broad and enduring trait-like transformations in cognitive, motivational, and emotional aspects of behavior. Implications for programs designed to promote resilience in humans are discussed.

  View details for DOI 10.3389/neuro.08.032.2009

  View details for Web of Science ID 000208031500032

  View details for PubMedID 19826626

  View details for PubMedCentralID PMC2759374

• Animal Models AMERICAN PSYCHIATRIC PUBLISHING TEXTBOOK OF PSYCHOPHARMACOLOGY, 4TH EDITION Lyons, D. M., Schatzberg, A. F., Nemeroff, C. B. 2009: 153–60

  View details for Web of Science ID 000310050700007

• Prefrontal Plasticity and Stress Inoculation-Induced Resilience DEVELOPMENTAL NEUROSCIENCE Katz, M., Liu, C., Schaer, M., Parker, K. J., Ottet, M., Epps, A., Buckmaster, C. L., Bammer, R., Moseley, M. E., Schatzberg, A. F., Eliez, S., Lyons, D. M. 2009; 31 (4): 293-299

  Abstract

  Coping with mild early life stress tends to make subsequent coping efforts more effective and therefore more likely to be used as a means of arousal regulation and resilience. Here we show that this developmental learning-like process of stress inoculation increases ventromedial prefrontal cortical volumes in peripubertal monkeys. Larger volumes do not reflect increased cortical thickness but instead represent surface area expansion of ventromedial prefrontal cortex. Expansion of ventromedial prefrontal cortex coincides with increased white matter myelination inferred from diffusion tensor magnetic resonance imaging. These findings suggest that the process of coping with early life stress increases prefrontal myelination and expands a region of cortex that broadly controls arousal regulation and resilience.

  View details for DOI 10.1159/000216540

  View details for PubMedID 19546566

• Stress-induced changes in corticosteroid receptor expression in primate hippocampus and prefrontal cortex PSYCHONEUROENDOCRINOLOGY Patel, P. D., Katz, M., Karssen, A. M., Lyons, D. M. 2008; 33 (3): 360-367

  Abstract

  Neurobiological studies of stress often focus on the hippocampus where cortisol binds with different affinities to two types of corticosteroid receptors, i.e., mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). The hippocampus is involved in learning and memory, and regulates the neuroendocrine stress response, but other brain regions also play a role, especially prefrontal cortex. Here, we examine MR and GR expression in adult squirrel monkey prefrontal cortex and hippocampus after exposure to social stress in infancy or adulthood. In situ hybridization histochemistry with (35)S-labeled squirrel monkey riboprobes and quantitative film autoradiography were used to measure the relative distributions of MR and GR mRNA. Distinct cortical cell layer-specific patterns of MR expression differed from GR expression in three prefrontal regions. The relative distributions of MR and GR also differed in hippocampal Cornu Ammonis (CA) regions. In monkeys exposed to adult social stress compared to the no-stress control, GR expression was diminished in hippocampal CA1 (P=0.021), whereas MR was diminished in cell layer III of ventrolateral prefrontal cortex (P=0.049). In contrast, exposure to early life stress diminished GR but not MR expression in cell layers I and II of dorsolateral prefrontal cortex (P's<0.048). Similar reductions likewise occurred in ventrolateral prefrontal cortex, but the effects of early life stress on GR expression in this region were marginally not significant (P=0.053). These results provide new information on regional differences and the long-term effects of stress on MR and GR distributions in corticolimbic regions that control cognitive and neuroendocrine functions.

  View details for DOI 10.1016/j.psyneuen.2007.12.003

  View details for Web of Science ID 000254568400011

  View details for PubMedID 18222612

  View details for PubMedCentralID PMC2386086

• Stress-induced changes in primate prefrontal profiles of gene expression MOLECULAR PSYCHIATRY Karssen, A. M., Her, S., Li, J. Z., Patel, P. D., Meng, F., Bunney, W. E., Jones, E. G., Watson, S. J., Akil, H., Myers, R. M., Schatzberg, A. F., Lyons, D. M. 2007; 12 (12): 1089-1102

  Abstract

  Stressful experiences that consistently increase cortisol levels appear to alter the expression of hundreds of genes in prefrontal limbic brain regions. Here, we investigate this hypothesis in monkeys exposed to intermittent social stress-induced episodes of hypercortisolism or a no-stress control condition. Prefrontal profiles of gene expression compiled from Affymetrix microarray data for monkeys randomized to the no-stress condition were consistent with microarray results published for healthy humans. In monkeys exposed to intermittent social stress, more genes than expected by chance appeared to be differentially expressed in ventromedial prefrontal cortex compared to monkeys not exposed to adult social stress. Most of these stress responsive candidate genes were modestly downregulated, including ubiquitin conjugation enzymes and ligases involved in synaptic plasticity, cell cycle progression and nuclear receptor signaling. Social stress did not affect gene expression beyond that expected by chance in dorsolateral prefrontal cortex or prefrontal white matter. Thirty four of 48 comparisons chosen for verification by quantitative real-time polymerase chain reaction (qPCR) were consistent with the microarray-predicted result. Furthermore, qPCR and microarray data were highly correlated. These results provide new insights on the regulation of gene expression in a prefrontal corticolimbic region involved in the pathophysiology of stress and major depression. Comparisons between these data from monkeys and those for ventromedial prefrontal cortex in humans with a history of major depression may help to distinguish the molecular signature of stress from other confounding factors in human postmortem brain research.

  View details for DOI 10.1038/sj.mp.4002095

  View details for Web of Science ID 000251265200007

  View details for PubMedID 17893703

• Preliminary evidence that hippocampal volumes in monkeys predict stress levels of adrenocorticotropic hormone BIOLOGICAL PSYCHIATRY Lyons, D. M., Parker, K. J., Zeitzer, J. M., Buckmaster, C. L., Schatzberg, A. F. 2007; 62 (10): 1171-1174

  Abstract

  Hippocampal volumes previously determined in monkeys by magnetic resonance imaging are used to test the hypothesis that small hippocampi predict increased stress levels of adrenocorticotropic hormone (ACTH).Plasma ACTH levels were measured after restraint stress in 19 male monkeys pretreated with saline or hydrocortisone. Monkeys were then randomized to an undisturbed control condition or intermittent social separations followed by new pair formations. After 17 months of exposure to the intermittent social manipulations, restraint stress tests were repeated to determine test/retest correlations.Individual differences in postrestraint stress ACTH levels over the 17-month test/retest interval were remarkably consistent for the saline (r(s) = .82, p = .0004) and hydrocortisone (r(s) = .78, p = .001) pretreatments. Social manipulations did not affect postrestraint stress ACTH levels, but monkeys with smaller hippocampal volumes responded to restraint after saline pretreatment with greater increases in ACTH levels with total brain volume variation controlled as a statistical covariate (beta = -.58, p = .031). Monkeys with smaller hippocampal volumes also responded with diminished sensitivity to glucocorticoid feedback determined by greater postrestraint ACTH levels after pretreatment with hydrocortisone (beta = -.68, p = .010).These findings support clinical reports that small hippocampi may be a risk factor for impaired regulation of the hypothalamic-pituitary-adrenal axis in humans with stress-related psychiatric disorders.

  View details for DOI 10.1016/i.biopsych.2007.03.012

  View details for Web of Science ID 000250905800015

  View details for PubMedID 17573043

  View details for PubMedCentralID PMC2129091

• Increasing length of wakefulness and modulation of hypocretin-1 in the wake-consolidated squirrel monkey AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Zeitzer, J. M., Buckmaster, C. L., Lyons, D. M., Mignot, E. 2007; 293 (4): R1736-R1742

  Abstract

  The neuropeptides hypocretins (orexins), the loss of which results in the sleep disorder narcolepsy, are hypothesized to be involved in the consolidation of wakefulness and have been proposed to be part of the circadian-driven alertness signal. To elucidate the role of hypocretins in the consolidation of human wakefulness we examined the effect of wake extension on hypocretin-1 in squirrel monkeys, primates that consolidate wakefulness during the daytime as do humans. Wake was extended up to 7 h with hypocretin-1, cortisol, ghrelin, leptin, locomotion, and feeding, all being assayed. Hypocretin-1 (P < 0.01), cortisol (P < 0.001), and locomotion (P < 0.005) all increased with sleep deprivation, while ghrelin (P = 0.79) and leptin (P = 1.00) did not change with sleep deprivation. Using cross-correlation and multivariate modeling of these potential covariates along with homeostatic pressure (a measure of time awake/asleep), we found that time of day and homeostatic pressure together explained 44% of the variance in the hypocretin-1 data (P < 0.001), while cortisol did not significantly contribute to the overall hypocretin-1 variance. Locomotion during the daytime, but not during the nighttime, helped explain < 5% of the hypocretin-1 variance (P < 0.05). These data are consistent with earlier evidence indicating that in the squirrel monkey hypocretin-1 is mainly regulated by circadian inputs and homeostatic sleep pressure. Concomitants of wakefulness that affect hypocretin-1 in polyphasic species, such as locomotion, food intake, and food deprivation, likely have a more minor role in monophasic species, such as humans.

  View details for DOI 10.1152/ajpregu.00460.2007

  View details for Web of Science ID 000250088000033

  View details for PubMedID 17686881

• Early life stress and novelty seeking behavior in adolescent monkeys PSYCHONEUROENDOCRINOLOGY Parker, K. J., Rainwater, K. L., Buckmaster, C. L., Schatzberg, A. F., Lindley, S. E., Lyons, D. M. 2007; 32 (7): 785-792

  Abstract

  Recent evidence suggests that early exposure to mild stress promotes the development of novelty seeking behavior. Here we test this hypothesis in squirrel monkeys and investigate whether novelty seeking behavior is associated with differences in cerebrospinal fluid (CSF) levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5HIAA), the dopamine metabolite homovanillic acid (HVA), the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), and the neuropeptide corticotrophin-releasing factor (CRF). Monkeys were randomized early in life to either mild intermittent stress (IS) or no stress (NS) conditions, and subsequently presented with opportunities to interact with a familiar or novel object in a test box that was connected to each monkey's home cage. To further minimize the potentially stressful nature of the test situation, monkeys were acclimated to the test procedures prior to study initiation. Post-test plasma levels of cortisol in IS and NS monkeys did not differ significantly from baseline levels measured in undisturbed conditions. During testing, more IS than NS monkeys voluntarily left the home cage, and IS monkeys spent more time in the test box compared to NS monkeys. More IS than NS monkeys engaged in object exploration in the test box, and IS monkeys preferred to interact with the novel vs. familiar object. Novelty seeking was not associated with differences in 5HIAA, HVA, MHPG, or CRF, but correlated with differences in object exploration observed in a different test situation at an earlier age. These trait-like differences in novelty seeking appear to reflect mild early stress-induced adaptations that enhance curiosity and resilience.

  View details for DOI 10.1016/j.psyneuen.2007.05.008

  View details for Web of Science ID 000249510200003

  View details for PubMedID 17604913

  View details for PubMedCentralID PMC2716798

• Stress inoculatio n-induced indications of resilience in monkeys 22nd Annual Meeting of the International-Society-for-Traumatic-Stress-Studies Lyons, D. M., Parker, K. J. JOHN WILEY & SONS INC. 2007: 423–33

  Abstract

  The negative consequences of stress are well-recognized in mental health research. Exposure to early life stressors, for example, increases the risk for the development of mood, anger, anxiety, and substance abuse disorders. Interestingly, however, early life stressors have also been linked to the subsequent development of resilience. Variously described as inoculating, immunizing, steeling, toughening, or thriving, the hypothesis that early life stressors provide a challenge that, when overcome, induces adaptations that enhance emotional processing, cognitive control, curiosity, and neuroendocrine regulation is examined in this review of squirrel monkey research.

  View details for DOI 10.1002/jts.20265

  View details for Web of Science ID 000249183400006

  View details for PubMedID 17721972

• Social stress-related behavior affects hippocampal cell proliferation in mice PHYSIOLOGY & BEHAVIOR Mitra, R., Sundlass, K., Parker, K. J., Schatzberg, A. F., Lyons, D. M. 2006; 89 (2): 123-127

  Abstract

  Although social stress inhibits neurogenesis in the adult hippocampus, the extent to which individual differences in stress-related behavior affect hippocampal cell proliferation is not well understood. Based on results from resident-intruder stress tests administered to adult male mice, here we report that individual differences in hippocampal cell proliferation are related to the frequency of defensive behavior, and not the amount of aggression received or the frequency of fleeing. In contrast, access to voluntary wheel-running exercise did not affect hippocampal cell proliferation in either stressed or non-stressed mice. Social stress-induced inhibition of cell proliferation was restricted to the hippocampus, as neither stress nor access to wheel-running exercise altered cell proliferation in the amygdala. These findings indicate that individual differences in stress-related behavior influence cell proliferation in the mouse hippocampus, and may have important implications for understanding structural and functional hippocampal impairments in human psychiatric patients.

  View details for DOI 10.1016/j.physbeh.2006.05.047

  View details for Web of Science ID 000240414300001

  View details for PubMedID 16837015

• Social stress-induced changes in gene expression profiles in primate prefrontal cortex 61st Annual Convention of the Society-of-Biological-Psychiatry Lyons, D. M., Karssen, A. M., Li, J. Z., Her, S., Patel, P. D., Bunney, W. E., Jones, E. G., Watson, S. J., Akil, H., Meyers, R. M., Schatzberg, A. F. ELSEVIER SCIENCE INC. 2006: 194S–194S

  View details for Web of Science ID 000236767301205

• Early experience and later resilience of the HPA axis in monkeys Lyons, D. M. ELSEVIER SCIENCE INC. 2006: 90S

  View details for Web of Science ID 000236767300292

• Application of microarray technology in primate behavioral neuroscience research METHODS Karssen, A. M., Li, J. Z., Her, S., Patel, P. D., Meng, F., Evans, S. J., Vawter, M. P., Tomita, H., Choudary, P. V., Bunney, W. E., Jones, E. G., Watson, S. J., Akil, H., Myers, R. M., Schatzberg, A. F., Lyons, D. M. 2006; 38 (3): 227-234

  Abstract

  Gene expression profiling of brain tissue samples applied to DNA microarrays promises to provide novel insights into the neurobiological bases of primate behavior. The strength of the microarray technology lies in the ability to simultaneously measure the expression levels of all genes in defined brain regions that are known to mediate behavior. The application of microarrays presents, however, various limitations and challenges for primate neuroscience research. Low RNA abundance, modest changes in gene expression, heterogeneous distribution of mRNA among cell subpopulations, and individual differences in behavior all mandate great care in the collection, processing, and analysis of brain tissue. A unique problem for nonhuman primate research is the limited availability of species-specific arrays. Arrays designed for humans are often used, but expression level differences are inevitably confounded by gene sequence differences in all cross-species array applications. Tools to deal with this problem are currently being developed. Here we review these methodological issues, and provide examples from our experiences using human arrays to examine brain tissue samples from squirrel monkeys. Until species-specific microarrays become more widely available, great caution must be taken in the assessment and interpretation of microarray data from nonhuman primates. Nevertheless, the application of human microarrays in nonhuman primate neuroscience research recovers useful information from thousands of genes, and represents an important new strategy for understanding the molecular complexity of behavior and mental health.

  View details for DOI 10.1016/j.ymeth.2005.09.017

  View details for PubMedID 16469505

• Maternal mediation, stress inoculation, and the development of neuroendocrine stress resistance in primates PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Parker, K. J., Buckmaster, C. L., Sundlass, K., Schatzberg, A. F., Lyons, D. M. 2006; 103 (8): 3000-3005

  Abstract

  The stress inoculation hypothesis presupposes that brief intermittent stress exposure early in life induces the development of subsequent stress resistance in human and nonhuman primates. Rodent studies, however, suggest a role for maternal care rather than stress exposure per se (i.e., the maternal mediation hypothesis). To investigate these two hypotheses, we examined maternal care and the development of stress resistance after exposure to brief intermittent infant stress (IS), mother-infant stress (MIS), or no stress (NS) protocols administered to 30 monkeys between postnatal weeks 17 and 27. Unlike rodents, the IS condition did not permanently increase primate maternal care, nor did measures of total maternal care predict subsequent offspring hypothalamic-pituitary-adrenal-axis responsivity. Although MIS infants received less maternal care than IS and NS infants, both IS and MIS monkeys developed subsequent stress resistance. These findings indicate that rearing differences in the development of stress resistance are more closely related to differences in prior stress exposure than to differences in maternal care. A second experiment confirmed this conclusion in a different cohort of 25 monkeys exposed as infants to high foraging-demand (HFD) or low foraging-demand (LFD) conditions. HFD infants exhibited intermittent elevations in cortisol levels and received less maternal care than LFD infants. In keeping with a key prediction of the stress inoculation hypothesis, HFD males responded to stress in adulthood with diminished hypothalamic-pituitary-adrenal-axis activation compared with LFD males. Results from both experiments demonstrate that stress inoculation, rather than high levels of maternal care, promotes the development of primate stress resistance.

  View details for DOI 10.1073/pnas.0506571103

  View details for Web of Science ID 000235554900093

  View details for PubMedID 16473950

  View details for PubMedCentralID PMC1413772

• Neural substrates of stress inoculation determined in vivo by brain imaging in monkeys 44th Annual Meeting of the American-College-Neuropsychopharmacology Lyons, D. M., Parker, K. J., Katz, M., Buckmaster, C. L., Schatzberg, A. F. NATURE PUBLISHING GROUP. 2005: S59–S60

  View details for Web of Science ID 000233442100165

• Intranasal oxytocin administration attenuates the ACTH stress response in monkeys PSYCHONEUROENDOCRINOLOGY Parker, K. J., Buckmaster, C. L., Schatzberg, A. F., Lyons, D. M. 2005; 30 (9): 924-929

  Abstract

  Social relationships protect against the development of stress-related psychiatric disorders, yet little is known about the neurobiology that regulates this phenomenon. Recent evidence suggests that oxytocin (OT), a neuropeptide involved in social bond formation, may play a role. This experiment investigated the effects of chronic intranasal OT administration on acute stress-induced hypothalamic-pituitary-adrenal (HPA) axis activation in adult female squirrel monkeys. Subjects were randomized to one of two experimental conditions. Monkeys were intranasally administered either 50 microg oxytocin (N = 6 monkeys) or 0 microg oxytocin (N = 6 monkeys)/300 microl saline once a day for eight consecutive days. Immediately after drug administration on the eighth day, all monkeys were exposed to acute social isolation. Blood samples for determinations of adrenocorticotropic hormone (ACTH) and cortisol concentrations were collected after 30 and 90 min of stress exposure. Consistent with an anti-stress effect, OT-treated monkeys exhibited lower ACTH concentrations compared to saline-treated monkeys after 90 min of social isolation (F(1,7) = 6.891; P = 0.034). No drug-related differences in cortisol levels were observed, indicating that OT does not directly attenuate the adrenal stress response. Intranasal peptide administration has been shown to penetrate the central nervous system, and research must determine whether intranasally delivered OT exerts its effect(s) at a pituitary and/or brain level. This primate model offers critical opportunities to improve our understanding of the anti-stress effects of OT and may lead to novel pharmacological treatments for stress-related psychiatric disorders.

  View details for DOI 10.1016/j.psyneuen.2005.04.002

  View details for Web of Science ID 000231003800012

  View details for PubMedID 15946803

• Mild early life stress enhances prefrontal-dependent response inhibition in monkeys BIOLOGICAL PSYCHIATRY Parker, K. J., Buckmaster, C. L., Justus, K. R., Schatzberg, A. F., Lyons, D. M. 2005; 57 (8): 848-855

  Abstract

  Severely stressful early experiences have been implicated in the pathophysiology of psychiatric disorders. In contrast, exposure to mild early life stress (i.e., stress inoculation) strengthens emotional and neuroendocrine resistance to subsequent stressors. Herein we extend this research to examine the effects of mild early life stress on cognition.Squirrel monkeys were randomized to a mild intermittent stress (IS; n = 11) or nonstress (NS; n = 9) condition from 17 to 27 weeks postpartum. At 1.5 years of age, monkeys were assessed for response inhibition on a test previously shown to reflect prefrontal-dependent cognitive function.IS monkeys demonstrated fewer response inhibition errors compared with NS monkeys. There were no rearing-related differences in aspects of performance that did not require inhibitory control. Compared with NS monkeys, IS monkeys had lower basal plasma pituitary-adrenal stress hormone levels. No rearing-related differences on neuroendocrine measures obtained 15 minutes after testing were found.Results from this experiment provide the first evidence that exposure to mildly stressful early experiences improves prefrontal-dependent response inhibition in primates. Combined with our previous data, findings from this animal model suggest that exposure to mild early life stress may enhance the development of brain systems that regulate emotional, neuroendocrine, and cognitive control.

  View details for Web of Science ID 000228280700004

  View details for PubMedID 15820705

• Mutations in squirrel monkey glucocorticoid receptor impair nuclear translocation JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY Her, S., Patel, P. D., Schatzberg, A. F., Lyons, D. M. 2005; 94 (4): 319-326

  Abstract

  To identify the determinants of impaired glucocorticoid receptor (GR) signaling in a model of glucocorticoid resistance, cloned GR from Guyanese squirrel monkeys (gsmGR) was tagged with enhanced green fluorescent protein, and nuclear translocation was examined in transfected COS1 cells. In keeping with evidence that gsmGR transactivational competence is impaired, we found that nuclear translocation is likewise diminished in gsmGR relative to human GR (hGR). Experiments with GR chimeras revealed that replacement of the gsmGR ligand binding domain (LBD) with that from hGR increased translocation. Truncated gsmGR constructs lacking the LDB after amino acid 552 also showed increased translocation even in the absence of cortisol. Three back-mutations of gsmGR to hGR (Thr551Ser, Ala616Ser, and Ser618Ala) in the LBD confirmed that these amino acids play a role in diminished translocation.

  View details for DOI 10.1016/j.jsbmb.2004.11.010

  View details for Web of Science ID 000229445800005

  View details for PubMedID 15857751

• Prospective investigation of stress inoculation in young monkeys ARCHIVES OF GENERAL PSYCHIATRY Parker, K. J., Buckmaster, C. L., Schatzberg, A. F., Lyons, D. M. 2004; 61 (9): 933-941

  Abstract

  Retrospective studies in humans have identified characteristics that promote stress resistance, including childhood exposure to moderately stressful events (ie, stress inoculation).Because of limited opportunities for prospective studies in children, we tested whether exposure to moderate stress early in life produces later stress resistance in a primate model.Twenty squirrel monkeys were randomized to intermittent stress inoculation (IS; n = 11) or a nonstress control condition (NS; n = 9) from postnatal weeks 17 to 27. At postnatal week 35, each mother-offspring dyad underwent testing in a moderately stressful novel environment for inferential measures of offspring anxiety (ie, maternal clinging, mother-offspring interactions, object exploration, and food consumption) and stress hormone concentrations (corticotropin [ACTH] and cortisol). At postnatal week 50, after acclimation to an initially stressful wire-mesh box attached to the home cage, independent young monkeys underwent testing for inferential measures of anxiety (ie, voluntary exploration and play) in the box.In the novel environment test, IS compared with NS offspring demonstrated diminished anxiety as measured by decreased maternal clinging (P =.02), enhanced exploratory behavior (P =.005), and increased food consumption (P =.02). Mothers of IS offspring accommodated offspring-initiated exploration (P =.009) and served as a secure base more often compared with NS mothers (P =.047). Compared with NS offspring, IS offspring had lower basal plasma ACTH (P =.001) and cortisol (P =.001) concentrations and lower corticotropin (P =.04) and cortisol (P =.03) concentrations after stress. In the subsequent home-cage wire-box test, IS offspring demonstrated enhanced exploratory (P<.001) and play (P =.008) behaviors compared with NS offspring.These results provide the first prospective evidence that moderately stressful early experiences strengthen socioemotional and neuroendocrine resistance to subsequent stressors. This preclinical model offers essential opportunities to improve our understanding and enhance prevention of human stress-related psychiatric disorders by elucidating the etiology and neurobiology of stress resistance.

  View details for Web of Science ID 000223726200009

  View details for PubMedID 15351772

• Locomotor-dependent and -independent components to hypocretin-1 (orexinA) regulation in sleep-wake consolidating monkeys JOURNAL OF PHYSIOLOGY-LONDON Zeitzer, J. M., Buckmaster, C. L., Lyons, D. M., Mignot, E. 2004; 557 (3): 1045-1053

  Abstract

  The hypocretin system is involved in the integration of hypothalamic functions with sleep and wake. Hypocretin-1 release peaks at the end of the active period in both diurnal and nocturnal species. A role for hypocretin-1 in the generation of locomotor activity has been suggested by electrophysiological and neurochemical studies in rodents, dogs and cats. These species, however, do not consolidate wake into a single, daily bout and manipulations of locomotion elicit changes in wakefulness, making it difficult to parse the relative contribution of these two factors. We have examined the relationship between locomotion and hypocretin-1 in a wake-consolidating animal, the squirrel monkey (Saimiri sciureus). Strikingly, we found that restricting locomotion to 17% of usual activity had no significant effect on the normal diurnal rise in cerebrospinal fluid (CSF) hypocretin-1, despite an associated increase in CSF cortisol. Increasing locomotion to greater than baseline activity did not significantly increase CSF hypocretin-1 concentrations, but did appear to have a positive modulatory effect on CSF hypocretin-1. In this wake-consolidating animal, locomotion is not necessary for CSF hypocretin-1 to increase throughout the daytime, but high levels of locomotion are likely to provide a small positive feedback onto the hypocretin system.

  View details for DOI 10.1113/jphysiol.2004.061606

  View details for Web of Science ID 000222403700029

  View details for PubMedID 15107479

  View details for PubMedCentralID PMC1665142

• Cognitive correlates of white matter growth and stress hormones in female squirrel monkey adults JOURNAL OF NEUROSCIENCE Lyons, D. M., Yang, C., Eliez, S., Reiss, A. L., Schatzberg, A. F. 2004; 24 (14): 3655-3662

  Abstract

  Neurobiological studies of stress and cognitive aging seldom consider white matter despite indications that complex brain processes depend on networks and white matter interconnections. Frontal and temporal lobe white matter volumes increase throughout midlife adulthood in humans, and this aspect of aging is thought to enhance distributed brain functions. Here, we examine spatial learning and memory, neuroendocrine responses to psychological stress, and regional volumes of gray and white matter determined by magnetic resonance imaging in 31 female squirrel monkeys between the ages of 5 and 17 years. This period of lifespan development corresponds to the years 18-60 in humans. Older adults responded to stress with greater increases in plasma levels of adrenocorticotropic hormone and modest reductions in glucocorticoid feedback sensitivity relative to young adults. Learning and memory did not differ with age during the initial cognitive test sessions, but older adults more often failed to inhibit the initial learned response after subsequent spatial reversals. Impaired cognitive response inhibition correlated with the expansion of white matter volume statistically controlling for age, stress hormones, gray matter, and CSF volumes. These results indicate that instead of enhancing cognitive control during midlife adulthood, white matter volume expansion contributes to aspects of cognitive decline. Cellular and molecular research combined with brain imaging is needed to determine the basis of white matter growth in adults, elucidate its functions during lifespan development, and provide potential new targets for therapies aimed at maintaining in humans cognitive vitality with aging.

  View details for DOI 10.1523/JNEUROSCI.0324-04.2004

  View details for Web of Science ID 000220715400022

  View details for PubMedID 15071114

• Early maternal availability and prefrontal correlates of reward-related memory NEUROBIOLOGY OF LEARNING AND MEMORY Lyons, D. M., Schatzberg, A. F. 2003; 80 (2): 97-104

  Abstract

  Early emotional experiences affect developing brain systems that subsequently mediate adult learning and memory in rodents. Here we test for similar effects in squirrel monkeys (Saimiri sciureus) four years after disruptions in early maternal availability. These conditions were previously shown to generate differences in emotional behavior, hypothalamic-pituitary-adrenal stress physiology, and right ventral medial prefrontal volumes determined in adulthood by magnetic resonance imaging. This report identifies in the same monkeys variability in reward-related memory on tests with a spatial reversal. Adult monkeys that more often selected locations repeatedly rewarded before each reversal had larger right ventral medial prefrontal volumes, but not hippocampal nor dorsolateral prefrontal volumes on the left or right brain side. Differences in performance were also discerned after each spatial reversal. These findings indicate that maternal availability alters developing ventral medial prefrontal brain regions involved in reward-related memory.

  View details for DOI 10.1016/S1074-7427(03)00044-3

  View details for Web of Science ID 000185048500001

  View details for PubMedID 12932424

• Functional brain imaging of olfactory processing in monkeys NEUROIMAGE Boyett-Anderson, J. M., Lyons, D. M., Reiss, A. L., Schatzberg, A. F., Menon, V. 2003; 20 (1): 257-264

  Abstract

  As a step toward bridging the gap between human and animal studies of olfactory brain systems, we report results from an fMRI study of olfaction in squirrel monkeys. High-resolution fMRI images at 3 T with 1.25 x 1.25 x 1.2 mm(3) voxels were obtained covering the whole brain using an 8-cm-diameter birdcage coil and a gradient-echo spiral pulse sequence. Data were acquired from six sedated adult males using a standard block design. All fMRI data were spatially normalized to a common template and analyzed at the individual and group levels with statistical parametric and nonparametric methods. Robust odorant-induced activations were detected in several brain regions previously implicated in conscious human olfactory processing, including the orbitofrontal cortex, cerebellum, and piriform cortex. Consistent with human data, no stimulus intensity effects were observed in any of these regions. Average signal changes in these regions exceeded 0.6%, more than three times the expected signal change based on human fMRI studies of olfaction adjusting for differences in voxel size. These results demonstrate the feasibility of studying olfaction in sedated monkeys with imaging techniques commonly used at 3 T in humans and help promote direct comparisons between humans and nonhuman primates. Our findings, for example, provide novel support for the hypothesis that the cerebellum is involved in sensory acquisition. More broadly, this study suggests that olfactory processing in sedated monkeys and nonsedated humans shares similar neural substrates both within and beyond the primary olfactory system.

  View details for DOI 10.1016/S1053-8119(03)00288-X

  View details for Web of Science ID 000185746400022

  View details for PubMedID 14527586

• Circadian and homeostatic regulation of hypocretin in a primate model: Implications for the consolidation of wakefulness JOURNAL OF NEUROSCIENCE Zeitzer, J. M., Buckmaster, C. L., Parker, K. J., Hauck, C. M., Lyons, D. M., Mignot, E. 2003; 23 (8): 3555-3560

  Abstract

  In humans, consolidation of wakefulness into a single episode can be modeled as the interaction of two processes, a homeostatic "hour-glass" wake signal that declines throughout the daytime and a circadian wake-promoting signal that peaks in the evening. Hypocretins, novel hypothalamic neuropeptides that are dysfunctional in the sleep disorder narcolepsy, may be involved in the expression of the circadian wake-promoting signal. Hypocretins (orexins) are wake-promoting peptides, but their role in normal human sleep physiology has yet to be determined. We examined the daily temporal pattern of hypocretin-1 in the cisternal CSF of the squirrel monkey, a New World primate with a pattern of wake similar to that of humans. Hypocretin-1 levels peaked in the latter third of the day, consistent with the premise that hypocretin-1 is involved in wake regulation. When we lengthened the wake period by 4 hr, hypocretin-1 concentrations remained elevated, indicating a circadian-independent component to hypocretin-1 regulation. Changes in the stress hormone cortisol were not correlated with hypocretin-1 changes. Although hypocretin-1 is at least partially activated by a reactive homeostatic mechanism, it is likely also regulated by the circadian pacemaker. In the squirrel monkey, hypocretin-1 works in opposition to the accumulating sleep drive during the day to maintain a constant level of wake.

  View details for Web of Science ID 000182475200052

  View details for PubMedID 12716965

• Euroendocrine aspects of hyperportisolism in major depression HORMONES AND BEHAVIOR Parker, K. J., Schatzberg, A. F., Lyons, D. M. 2003; 43 (1): 60-66

  Abstract

  A consistent finding in biological psychiatry is that hypothalamic-pituitary-adrenal (HPA) axis physiology is altered in humans with major depression. These findings include hypersecretion of cortisol at baseline and on the dexamethasone suppression test. In this review, we present a process-oriented model for HPA axis regulation in major depression. Specifically, we suggest that acute depressions are characterized by hypersecretion of hypothalamic corticotropin-releasing factor, pituitary adrenocorticotropic hormone (ACTH), and adrenal cortisol. In chronic depressions, however, enhanced adrenal responsiveness to ACTH and glucocorticoid negative feedback work in complementary fashion so that cortisol levels remain elevated while ACTH levels are reduced. In considering the evidence for hypercortisolism in humans, studies of nonhuman primates are presented and their utility and limitations as comparative models of human depression are discussed.

  View details for DOI 10.1016/S0018-506X(02)00016-8

  View details for Web of Science ID 000182658400009

  View details for PubMedID 12614635

• Experience-dependent asymmetric variation in primate prefrontal morphology BEHAVIOURAL BRAIN RESEARCH Lyons, D. M., Afarian, H., Schatzberg, A. F., Sawyer-Glover, A., Moseley, M. E. 2002; 136 (1): 51-59

  Abstract

  Theories of human development suggest that experiences embedded in social relationships alter prefrontal brain systems that mediate emotional self-regulation. This study tests for experience-dependent effects on prefrontal gray and white matter volumes determined in 39 young adult monkeys (Saimiri sciureus) 4 years after conditions that modified early maternal availability. These conditions were previously shown to alter subsequent measures of emotional behavior, social propensities, and hypothalamic-pituitary-adrenal axis stress physiology. Here we identify significant differences in right but not left adult prefrontal volumes, with experience-dependent asymmetric variation most clearly expressed in ventral medial cortex measured in vivo by magnetic resonance imaging (MRI). Follow-up studies now need to determine whether maternal availability directly affects or interacts with subsequent experiences to alter prefrontal substrates of emotional processing and sensitivity to stress.

  View details for Web of Science ID 000178776300005

  View details for PubMedID 12385789

• Stress, depression, and inherited variation in primate hippocampal and prefrontal brain development. Psychopharmacology bulletin Lyons, D. M. 2002; 36 (1): 27-43

  Abstract

  The search for genetic and environmental risk factors that alter brain growth and emotional development is limited in humans with affective disorders that are triggered or aggravated by stress. Animal models are particularly well suited for the investigation of genetic variation in carefully controlled environments. Here, we illustrate this preclinical approach with a series of studies on early life stress and inherited variation in squirrel monkey hippocampal and prefrontal volumes determined in vivo with magnetic resonance imaging.

  View details for PubMedID 12397846

• Effects of Emotion on Oxytocin, Prolactin, and ACTH in Women STRESS-THE INTERNATIONAL JOURNAL ON THE BIOLOGY OF STRESS Turner, R. A., Altemus, M., Yip, D. N., Kupferman, E., Fletcher, D., Bostrom, A., Lyons, D. M., Amico, J. A. 2002; 5 (4): 269-276

  Abstract

  Research on both non-human mammals and humans has raised interest in the role that oxytocin may play in human attachment and attachment-related emotions. This study examined changes in plasma oxytocin, prolactin, and ACTH concentrations in response to laboratory-induced positive and negative emotions related to close, interpersonal relationships. Participants were 32 female volunteers recruited from university communities. During positive emotion induction, oxytocin decreased over time (F(1,3) = 4.41, p < 0.007), prolactin increased (F(1,3) = 4.80, p < 0.004) and ACTH remained constant. During negative emotion induction, prolactin levels increased (F(1,3) = 2.81, p < 0.05), ACTH decreased only after the induction terminated (F(1,3) = 4.02, p < 0.01) and oxytocin remained constant. While oxytocin decreased during positive emotion, this finding contrasted previous research that showed decreases in response to negative emotion. In conclusion, plasma oxytocin levels were not reliably altered by positive or negative emotion induction. While prolactin and ACTH were expected to decrease over time due to diurnal variation, they instead either increased or remained level during emotion induction, or decreased only after the induction. Overall, the degree of change in circulating hormones in response to happy and sad emotions was very small and possibly not functionally significant.

  View details for Web of Science ID 000208090500005

  View details for PubMedID 12475731

• Early life stress and inherited variation in monkey hippocampal volumes ARCHIVES OF GENERAL PSYCHIATRY Lyons, D. M., Yang, C., Sawyer-Glover, A. M., Moseley, M. E., Schatzberg, A. F. 2001; 58 (12): 1145-1151

  Abstract

  Opportunities for research on the causes and consequences of stress-related hippocampal atrophy are limited in human psychiatric disorders. Therefore, this longitudinal study investigated early life stress and inherited variation in monkey hippocampal volumes.Paternal half-siblings raised apart from one another by different mothers in the absence of fathers were randomized to 1 of 3 postnatal conditions that disrupted diverse aspects of early maternal care (n = 13 monkeys per condition). These conditions were previously shown to produce differences in social behavior, emotional reactivity, and neuroendocrine stress physiology. Hippocampal volumes were subsequently determined in adulthood by high-resolution magnetic resonance imaging.Adult hippocampal volumes did not differ with respect to the stressful postnatal conditions. Based on paternal half-sibling effects, the estimated proportion of genetic variance, ie, heritability, was 54% for hippocampal size. Paternal half-siblings with small adult hippocampal volumes responded to the removal of all mothers after weaning with initially larger relative increases in cortisol levels. Plasma cortisol levels 3 and 7 days later, and measures of cortisol-negative feedback in adulthood were not, however, correlated with hippocampal size.In humans with mood and anxiety disorders, small hippocampal volumes have been taken as evidence that excessive stress levels of cortisol induce hippocampal volume loss. Results from this study of monkeys suggest that small hippocampi also reflect an inherited characteristic of the brain. Genetically informed clinical studies should assess whether inherited variation in hippocampal morphology contributes to excessive stress levels of cortisol through diminished neuroendocrine regulation.

  View details for Web of Science ID 000172586000006

  View details for PubMedID 11735843

• Frustrative nonreward and pituitary-adrenal activity in squirrel monkeys PHYSIOLOGY & BEHAVIOR Lyons, D. M., Fong, K. D., Schrieken, N., LEVINE, S. 2000; 71 (5): 559-563

  Abstract

  Little is known about frustration-induced changes in stress physiology in humans and nonhuman primates. Here we assess in two experiments with squirrel monkeys plasma levels of pituitary-adrenal stress hormones in conditions designed to provoke frustrative nonreward. In the first experiment 18 prepubertal monkeys were trained to feed from one of eight sites, and then tested without food at any of the sites. These monkeys responded with significant increases in cortisol and adrenocorticotropic hormone (ACTH). In the second experiment 18 adult monkeys were trained to feed from one of eight sites, and then tested after food was moved to a different foraging site. Nine monkeys found food at the relocated site, discontinued foraging at the previously baited site, and responded with decreases in cortisol. The other nine monkeys failed to find the relocated site, initially increased their visits to the previously baited site, and responded with elevations in cortisol and ACTH. In keeping with comparable findings in rats, our observations indicate that frustrative nonreward elicits ACTH-stimulated secretion of cortisol in primates.

  View details for Web of Science ID 000166100800016

  View details for PubMedID 11239675

• Glucocorticoid and mineralocorticoid receptor mRNA expression in squirrel monkey brain JOURNAL OF PSYCHIATRIC RESEARCH Patel, P. D., Lopez, J. F., Lyons, D. M., Burke, S., Wallace, M., Schatzberg, A. F. 2000; 34 (6): 383-392

  Abstract

  Corticosteroids have been implicated in hippocampal atrophy in patients with severe psychiatric disorders, but little is known about receptor expression for corticosteroids in human or nonhuman primate brain. Both the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) were surveyed in this study of squirrel monkey brain using in situ hybridization histochemistry. Regions of high GR mRNA levels included CA1 and CA2 of hippocampus, dentate gyrus, paraventricular hypothalamus, lateral geniculate, lateral>medial amygdala, and cerebellum. Western analysis confirmed that GR immunoreactivity in squirrel monkey brain tissue most likely reflects the alpha isoform. Regions of high MR mRNA levels included all hippocampal pyramidal cell fields, dentate gyrus granule cell layer, lateral septum, medial>lateral amygdala, and to a lesser extent, cerebellum. Low levels of MR were also expressed in caudate and putamen. Receptor expression for corticosteroids in deep brain structures and the hippocampal formation was similar to that previously reported in rodents, but GR and MR mRNA were expressed at higher levels in squirrel monkey cerebral cortex. GR expression was evident in all cortical layers, particularly the pyramidal cell-rich layers II/III and V. MR expression was restricted to the more superficial cortical layers, and was only moderately represented in layer V. Laminar patterns were apparent in all regions of cortex for GR expression in squirrel monkeys, but low MR mRNA levels were found in dorsomedial prefrontal cortex (PFC). Different subregional distributions and distinctive laminar patterns suggest specialized functions or coordinated interactions between GR and MR mediated functions in primate PFC.

  View details for Web of Science ID 000167473400002

  View details for PubMedID 11165305

• Stress-level cortisol treatment impairs inhibitory control of behavior in monkeys JOURNAL OF NEUROSCIENCE Lyons, D. M., Lopez, J. M., Yang, C., Schatzberg, A. F. 2000; 20 (20): 7816-7821

  Abstract

  Most studies of cortisol-induced cognitive impairments have focused on hippocampal-dependent memory. This study investigates a different aspect of cognition in a randomized placebo-controlled experiment with monkeys that were treated with cortisol according to a protocol that simulates a prolonged stress response. Young adult and older adult monkeys were assigned randomly to placebo or chronic treatment with cortisol in a 2 x 2 factorial design (n = 8 monkeys per condition). Inhibitory control of behavior was assessed with a test shown previously in primates to reflect prefrontal cortical dysfunction. Failure to inhibit a specific goal-directed response was evident more often in older adults. Treatment with cortisol increased this propensity in both older and young adult monkeys. Age-related differences in response inhibition were consistent across blocks of repeated test trials, but the treatment effects were clearly expressed only after prolonged exposure to cortisol. Aspects of performance that did not require inhibition were not altered by age or treatment with cortisol, which concurs with effects on response inhibition rather than nonspecific changes in behavior. These findings lend support to related reports that cortisol-induced disruptions in prefrontal dopamine neurotransmission may contribute to deficits in response inhibition and play a role in cognitive impairments associated with endogenous hypercortisolism in humans.

  View details for Web of Science ID 000089753300043

  View details for PubMedID 11027246

• Mammary adenocarcinoma in a male squirrel monkey (Saimiri sciureus) VETERINARY PATHOLOGY Waggie, K. S., Tolwani, R. J., Lyons, D. M. 2000; 37 (5): 505-507

  Abstract

  A nodule was identified within the right mammary gland of a 16-year-old male squirrel monkey (Saimiri sciureus). The mass was excised and diagnosed as a mammary adenocarcinoma. The monkey developed congestive heart failure 1.5 years later and was euthanatized. At necropsy, a subcutaneous mass was found in the right axillary region. Histologically, the mass was identified as a lymph node whose architecture was effaced by neoplastic cells resembling those of the mammary tumor. Metastasis to internal organs was not observed. This is the first reported case of a mammary tumor in a New World primate and the only known case of mammary cancer in a male nonhuman primate.

  View details for Web of Science ID 000089871500025

  View details for PubMedID 11055884

• Early environmental regulation of glucocorticoid feedback sensitivity in young adult monkeys JOURNAL OF NEUROENDOCRINOLOGY Lyons, D. M., Yang, C., Mobley, B. W., Nickerson, J. T., Schatzberg, A. F. 2000; 12 (8): 723-728

  Abstract

  Variations in maternal care induce in neonatal rodents life-long changes in glucocorticoid feedback regulation of the hypothalamic-pituitary-adrenal axis. This aspect of plasticity in neuroendocrine development has not been established in primates. We assessed, in young adult squirrel monkeys, postnatal rearing effects on cortisol-induced suppression of corticotropin-releasing factor (CRF) stimulated secretion of adrenocorticotropic hormone (ACTH). Offspring of randomly bred monkeys were periodically removed from natal groups between 13 and 21 weeks of age. In two other postnatal rearing conditions, systematic differences in maternal availability were produced by manipulating the effort required of lactating mothers to successfully find food. All offspring were subsequently administered, 3-5 years later on two occasions, an intravenous ovine CRF injection preceded 60 min earlier by placebo or cortisol pretreatment. The difference between CRF-stimulated time-integrated secretion of ACTH following placebo vs cortisol pretreatment served as an index of glucocorticoid negative feedback. Difference scores were greatest in monkeys previously separated from natal groups. This finding was not attributable to significant rearing condition differences in plasma cortisol levels achieved following pretreatment with exogenous cortisol, nor plasma ACTH levels produced when the CRF injection was preceded by pretreatment with placebo. The results suggest that postnatal experiences altered glucocorticoid feedback in monkeys at least through early adulthood. This conclusion supports retrospective reports indicating that, for humans with major mood and anxiety disorders, systematic differences in glucocorticoid feedback may reflect neural mechanisms in development linking early life stress with psychopathology in adulthood.

  View details for Web of Science ID 000088302600004

  View details for PubMedID 10929083

• Impaired transactivation of the glucocorticoid receptor cloned from the Guyanese squirrel monkey JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY Patel, P. D., Lyons, D. M., Zhang, Z. M., Ngo, H., Schatzberg, A. F. 2000; 72 (3-4): 115-123

  Abstract

  Squirrel monkeys are among a diverse group of New World primates that demonstrate unusually high levels of circulating corticosteroids and glucocorticoid receptor (GR) insensitivity. Recent evidence suggests that overexpression of an immunophilin impairs dexamethasone binding to GR in the Bolivian squirrel monkey (Saimiri boliviensis). Here we describe the cloning, expression, and functional characterization of GR from the closely related Guyanese squirrel monkey (S. sciureus). The cloned Guyanese squirrel monkey GR (gsmGR) cDNA closely resembles human GR (hGR) cDNA, and yields a high affinity dexamethasone binding receptor when expressed in COS-1 cells. Transactivation analysis of hGR and gsmGR expressed in CV-1 cells and cultured squirrel monkey kidney (SMK) cells indicates that: (1) SMK cells elaborate a functional high activity GR from human GR cDNA; (2) gsmGR is an order of magnitude less efficient than hGR at transactivation in CV-1 and SMK cells; and (3) maximal transactivation by gsmGR is attenuated in both cell lines. Glucocorticoid resistance in S. sciureus is at least partly attributable to a naturally occurring mutation in the GR gene that results in impaired GR transactivation.

  View details for Web of Science ID 000086821400003

  View details for PubMedID 10775802

• Dilative cardiomyopathy leading to congestive heart failure in a male squirrel monkey (Saimiri sciureus) JOURNAL OF MEDICAL PRIMATOLOGY Tolwani, R. J., Waggie, K. S., GREEN, S. L., Tolwani, A. J., Lyons, D. M., Schatzberg, A. F. 2000; 29 (1): 42-45

  Abstract

  A 17-year-old, 1-kg, colony-housed, male squirrel monkey (Samiri sciureus) developed clinical signs of congestive heart failure. The monkey presented with lethargy, increased heart and respiratory rates, and mild abdominal distention. The clinical history, laboratory analysis, and radiographic findings were consistent with heart failure due to dilative cardiomyopathy. Gross and microscopic examination of the heart confirmed a dilative cardiomyopathy. This is the first report describing congestive heart failure caused by dilative cardiomyopathy in a squirrel monkey. Spontaneous dilative cardiomyopathy may be infrequently observed in the squirrel monkeys because they are not routinely housed in the research environment during their advancing years.

  View details for Web of Science ID 000087265900006

  View details for PubMedID 10870674

• Postnatal experiences and genetic effects on squirrel monkey social affinities and emotional distress HORMONES AND BEHAVIOR Lyons, D. M., Martel, F. L., LEVINE, S., Risch, N. J., Schatzberg, A. F. 1999; 36 (3): 266-275

  Abstract

  Most nonhuman primate research on risk factors underlying vulnerability to stress has focused on early psychosocial experiences in various species of macaques. To test for genetic and experiential effects on emotional vulnerability in randomly bred squirrel monkeys, here we combined a paternal half-sibling analysis with three postnatal rearing protocols that altered aspects of maternal availability. In one condition offspring were periodically removed from natal groups, whereas differences in maternal availability were produced in two other conditions by manipulating the effort required of lactating mothers to successfully locate food. After completion of these protocols at 21 weeks of age, social affinities, maternal separation induced peep-calls, and plasma levels of cortisol were assessed from 29 to 37 weeks of age. Significant postnatal rearing effects and the lowest heritabilities were detected in peak elevations of cortisol measured 1 day after the removal of mothers from otherwise undisturbed groups. Individual differences in cortisol 3-7 days later revealed negligible postnatal rearing effects and the highest heritabilities (h(2) approximately. 70), as offspring sired by certain fathers failed to return to the preseparation level found in undisturbed natal groups. Paternal half-siblings that responded with long lasting increases in cortisol spent more time near their mother in undisturbed groups and exhibited long-lasting increases in separation induced peep-calls. These findings concur with human twin studies that suggest genetic and experiential factors contribute to individual differences in vulnerability to emotional distress.

  View details for Web of Science ID 000084740500007

  View details for PubMedID 10603290

• Separation induced changes in squirrel monkey hypothalamic-pituitary-adrenal physiology resemble aspects of hypercortisolism in humans PSYCHONEUROENDOCRINOLOGY Lyons, D. M., Wang, O. J., Lindley, S. E., LEVINE, S., Kalin, N. H., Schatzberg, A. F. 1999; 24 (2): 131-142

  Abstract

  When separated from groups, squirrel monkeys respond with significant increases in plasma cortisol and adrenocorticotropic hormone (ACTH). While cortisol remains elevated above pre-separation levels, significant reductions occur in ACTH. Monkeys that respond with greater increases in cortisol subsequently exhibit greater reductions in ACTH, which suggests that reductions in ACTH are mediated by corticosteroid feedback. Monkeys that respond with greater increases in cortisol also tend to exhibit greater cerebrospinal fluid levels of the dopamine metabolite HVA, but not the norepinephrine metabolite MHPG, or corticotropin-releasing factor (CRF). Attenuation of corticosteroid feedback with metyrapone results in significant increases in circulating ACTH, and in older monkeys increases plasma HVA. Similar findings in humans have been reported in clinical studies of hypercortisolism and major depression.

  View details for Web of Science ID 000078796300001

  View details for PubMedID 10101722

• Salivary cortisol levels in socially phobic adolescent girls DEPRESSION AND ANXIETY Martel, F. L., Hayward, C., Lyons, D. M., Sanborn, K., Varady, S., Schatzberg, A. F. 1999; 10 (1): 25-27

  Abstract

  Anxiety disorders such as social phobia (SP) often have their onset during adolescence and frequently precede the onset of major depression. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is well-documented in major depression. Consequently, there is considerable interest in HPA function in anxiety disorders. We examined salivary cortisol levels in 27 SP adolescent girls and 21 matched controls during normal daily activities, and immediately before and after a modified Trier Social Stress Test (TSST). Both SP subjects and controls showed significant elevations in cortisol levels prior to the TSST, and prior to attending school. These results suggest that salivary cortisol is a sensitive measure of anticipatory anxiety, but we failed to find significant differences between SP subjects and controls.

  View details for Web of Science ID 000085271400004

  View details for PubMedID 10499186

• Annual physiological changes in individually housed squirrel monkeys (Saimiri sciureus) AMERICAN JOURNAL OF PRIMATOLOGY Schiml, P., Mendoza, S. P., Saltzman, W., Lyons, D. M., Mason, W. A. 1999; 47 (2): 93-103

  Abstract

  This study investigated whether annual changes in physiology occur in individually housed squirrel monkeys (Saimiri sciureus). Physiological measures were monitored for 20 months. Over the course of the study, all individually housed males and females exhibited clear annual changes in gonadal and adrenal hormone levels, and males exhibited species-typical changes in body weight. Females exhibited a typical pattern of hormonal changes, with elevations in gonadal steroids occurring during the same months as elevations in cortisol. Males, however, exhibited an atypical pattern, as elevations in hormone levels were not synchronized with each other; rather, elevations in testosterone occurred out of phase with changes in cortisol and body weight. The timing of annual events in individually housed subjects was compared to that in nearby social groups, in which the timing of the breeding season from year to year was determined by social group formations and was outside the naturally occurring breeding season. Elevations of ovarian and adrenocortical hormones in individually housed females were synchronized with indices of breeding in heterosexual social groups. Similarly, weight gain in males was associated with elevations in cortisol and, as with socially housed males, tended to precede seasonal breeding in the social groups. In contrast, annual testosterone elevations for individually housed males were not synchronized with breeding in nearby social groups. We conclude that direct physical interaction is not required for the annual expression of breeding readiness. Synchrony of seasonality among squirrel monkeys may be accomplished by distant social cues in females, but males may require physical interaction for complete synchrony of annual physiological changes.

  View details for Web of Science ID 000078244300001

  View details for PubMedID 9973264

• Postnatal foraging demands alter adrenocortical activity and psychosocial development DEVELOPMENTAL PSYCHOBIOLOGY Lyons, D. M., Kim, S., Schatzberg, A. F., LEVINE, S. 1998; 32 (4): 285-291

  Abstract

  Mother squirrel monkeys stop carrying infants at earlier ages in high-demand (HD) conditions where food is difficult to find relative to low-demand (LD) conditions. To characterize these transitions in psychosocial development, from 10- to 21-weeks postpartum we collected measures of behavior, adrenocortical activity, and social transactions coded for initiator (mother or infant), goal (make-contact or break-contact), and outcome (success or failure). Make-contact attempts were most often initiated by HD infants, but mothers often opposed these attempts and less than 50% were successful. Break-contact attempts were most often initiated by LD infants, but mothers often opposed these attempts and fewer LD than HD infant break-contact attempts were successful. Plasma levels of cortisol were significantly higher in HD than LD mothers, but differences in adrenocortical activity were less consistent in their infants. HD and LD infants also spent similar amounts of time nursing on their mothers and feeding on solid foods. By rescheduling some transitions in development (carry-->self-transport), and not others (nursing-->self-feeding), mothers may have partially protected infants from the immediate impact of an otherwise stressful foraging task.

  View details for Web of Science ID 000073477300003

  View details for PubMedID 9589217

• Reactions of adult and immature squirrel monkeys to intergroup exposure ZOO BIOLOGY Aruguete, M. S., Lyons, D. M., Mason, W. A., Mendoza, S. P. 1998; 17 (6): 519-524

  View details for Web of Science ID 000078143600005

• Psychobiological consequences of social relationships Conference of the New-York-Academy-of-Sciences on the Integrative Neurobiology of Affiliation LEVINE, S., Lyons, D. M., Schatzberg, A. F. NEW YORK ACAD SCIENCES. 1997: 210–218

  Abstract

  Social separations can induce long-lasting increases in cortisol, whereas companionship can result in social buffering. Preliminary evidence from studies of squirrel monkeys suggests that social separation-induced hypersecretion of cortisol is initially driven by hypersecretion of ACTH. From 1-21 days postseparation, however, cortisol remains elevated above pre-separation controls, while ACTH levels are consistently reduced. Hypercortisolism is maintained despite reductions in ACTH, because adrenal responsiveness to ACTH is enhanced. Low circulating ACTH, in turn, is maintained by robust feedback mechanisms that apparently inhibit biosynthesis or release of pituitary ACTH. These findings are consistent with neuroendocrine interactions known or hypothesized to occur during major depressive disorders in humans and raise unique possibilities for comparative research in human and nonhuman primates.

  View details for Web of Science ID A1997BJ17S00013

  View details for PubMedID 9071353

• Seasonality in squirrel monkeys (Saimiri sciureus), social facilitation by females PHYSIOLOGY & BEHAVIOR Schiml, P. A., Mendoza, S. P., Saltzman, W., Lyons, D. M., Mason, W. A. 1996; 60 (4): 1105-1113

  Abstract

  The extent to which social living arrangements influenced seasonal changes in physiology and behavior was examined in adult squirrel monkeys (Saimiri sciureus). Data were collected over 20 months (encompassing two breeding seasons) from animals that were housed in three mixed-sex social configurations that varied in the number of heterosexual and isosexual social partners. For both sexes, the presence of multiple females was found to facilitate reproduction. Females housed with other females were more likely to exhibit seasonal ovarian cyclicity and tended to have higher conception rates. Social facilitation of reproduction was particularly prominent for subordinate females. The presence of same-sex companions also resulted in reduced adrenocortical output in females during the first nonbreeding season. In males, the availability of multiple females increased plasma testosterone levels, except in the presence of more dominant males. Seasonal increases in male weight coincided with increased cortisol levels and were most prominent in social groups containing multiple females. The influence of multiple females on male seasonality occurred despite the finding that male-female interactions were infrequent and, in fact, occurred less frequently when isosexual partners were available. Unexpectedly, affiliative social interactions between same-sex and opposite-sex partners occurred less frequently during the breeding season. As expected, behaviors associated with sex tended to increase during the breeding season. Very little agonism was observed during the course of the study and there was no evidence of interanimal competition for mates.

  View details for Web of Science ID A1996VJ16800011

  View details for PubMedID 8884940

• SOCIAL EFFECTS AND CIRCADIAN-RHYTHMS IN SQUIRREL-MONKEY PITUITARY-ADRENAL ACTIVITY HORMONES AND BEHAVIOR Lyons, D. M., HA, C. M., LEVINE, S. 1995; 29 (2): 177-190

  Abstract

  Simultaneous measures of plasma cortisol and ACTH were collected at the morning peak (AM) and evening nadir (PM) of the circadian rhythm in group-housed and individually housed squirrel monkeys (Saimiri sciureus). Pronounced AM-PM differences in cortisol were evident in both conditions, but morning measures of cortisol in monkeys housed without companions were 32% higher than baseline control values observed when the same monkeys were sampled in groups. Consistent AM-PM differences in cortisol were not associated with consistent AM-PM differences in ACTH, and for monkeys housed without companions, plasma ACTH concentrations were consistently and significantly reduced (23% lower in the morning, 42% lower in the evening). All monkeys were subsequently pretreated overnight when dexamethasone to temporarily suppress the secretion of endogenous ACTH and then challenged the following morning with a bolus injection of synthetic ACTH. Monkeys housed without companions responded to the challenge with greater, more prolonged elevations in cortisol relative to monkeys housed in groups. These observations together suggest that squirrel monkeys housed without companions hypersecrete cortisol at the morning peak of the rhythm because adrenal responsiveness to ACTH is enhanced. Low circulating ACTH levels in turn are maintained by robust glucocorticoid feedback mechanisms that inhibit the synthesis or release of pituitary ACTH.

  View details for Web of Science ID A1995RE69400005

  View details for PubMedID 7557921

• SOCIOREGULATORY EFFECTS ON SQUIRREL-MONKEY PITUITARY-ADRENAL ACTIVITY - A LONGITUDINAL ANALYSIS OF CORTISOL AND ACTH PSYCHONEUROENDOCRINOLOGY Lyons, D. M., LEVINE, S. 1994; 19 (3): 283-291

  Abstract

  Squirrel monkeys show unusually prolonged elevations in plasma cortisol when separated from like-sex social companions. To determine whether this hypersecretion of cortisol reflects a deficiency in feedback mechanisms that normally inhibit the prolonged activation of the pituitary-adrenal axis, we simultaneously measured plasma cortisol and corticotropin (ACTH) in 30 juvenile monkeys housed in established groups, individual cages, and newly formed groups. As found in recent longitudinal studies of adults, when juveniles were living without companions, mean cortisol titers were consistently higher than those observed when the same juveniles were living in like-sex social groups. When cortisol was elevated, however, ACTH titers were significantly and chronically reduced. These results suggest that elevated cortisol does inhibit ACTH synthesis or release, and that hypercortisolism in squirrel monkeys living without companions is not a consequence of chronic elevations in ACTH. Similar peculiarities in pituitary-adrenal activity are evident in a number of affective disorders in human beings.

  View details for Web of Science ID A1994NA88000003

  View details for PubMedID 8202576

• PSYCHOSOCIAL AND HORMONAL ASPECTS OF HIERARCHY FORMATION IN GROUPS OF MALE SQUIRREL-MONKEYS AMERICAN JOURNAL OF PRIMATOLOGY Lyons, D. M., Mendoza, S. P., Mason, W. A. 1994; 32 (2): 109-122

  View details for Web of Science ID A1994MT28400003

• SOCIAL GROUPING TENDENCIES AND SEPARATION-INDUCED DISTRESS IN JUVENILE SHEEP AND GOATS DEVELOPMENTAL PSYCHOBIOLOGY LYONS, D. M., PRICE, E. O., MOBERG, G. P. 1993; 26 (5): 251–59

  Abstract

  Social affinities in juvenile sheep and goats were compared by measuring grouping tendencies and separation-induced distress during experimental encounters with a person in either the presence or the absence of juvenile pen-mates. When tested with pen-mates, sheep spent more time near penmates than did goats. When separated from pen-mates, locomotor activity and plasma corticosteroid titers were higher in sheep, whereas vocal rates were higher in goats. Proximity to pen-mate scores were not correlated with either vocal rates, r = 0.20, or locomotion scores, r = 0.21, recorded when juveniles were tested alone. Proximity to pen-mate scores were correlated with posttest corticosteroid titers, r = 0.70; juvenile sheep spent more time near pen-mates and showed greater adrenocortical responses when temporarily separated from juvenile pen-mates. These findings support the possibility that interspecies differences in emotional reactivity contribute to the differences in grouping tendencies these ungulates display in natural or relatively unrestricted social groups.

  View details for DOI 10.1002/dev.420260503

  View details for Web of Science ID A1993LJ71400002

  View details for PubMedID 8339864

• SEXUAL SEGREGATION IN SQUIRREL-MONKEYS (SAIMIRI-SCIUREUS) - A TRANSACTIONAL-ANALYSIS OF ADULT SOCIAL DYNAMICS JOURNAL OF COMPARATIVE PSYCHOLOGY Lyons, D. M., Mendoza, S. P., Mason, W. A. 1992; 106 (4): 323-330

  Abstract

  Female agonism against males and male interventions in social transactions between the sexes are 2 explanations for the low rates of social engagement observed between male and female squirrel monkeys (Saimiri sciureus). These possibilities were evaluated by comparing the frequency, structure, and content of transactions between the sexes in 3 experimental social units: male-female pairs, single-male-multifemale groups, and multimale-multifemale groups. Affiliative transactions between the sexes occurred 3-5 times less often in multimale-multifemale groups than in male-female pairs and in single-male-multifemale groups. Intermale agonism in the multimale-multifemale groups often coincided with ongoing transactions between the sexes, whereas female agonism against males was rather uncommon in all social units. The results failed to support the female agonism hypothesis and indicate a need for more detailed studies of intermale social dynamics.

  View details for Web of Science ID A1992JY56500001

  View details for PubMedID 1451415

• DISTINCT IMMEDIATE AND PROLONGED EFFECTS OF SEPARATION ON PLASMA-CORTISOL IN ADULT FEMALE SQUIRREL-MONKEYS PSYCHOBIOLOGY Mendoza, S. P., Hennessy, M. B., Lyons, D. M. 1992; 20 (4): 300-306

  View details for Web of Science ID A1992KC06200008

• SOCIOPHYSIOLOGY OF SQUIRREL-MONKEYS AMERICAN JOURNAL OF PRIMATOLOGY Mendoza, S. P., Lyons, D. M., Saltzman, W. 1991; 23 (1): 37-54

  View details for Web of Science ID A1991EP47400004