Dr. Parker is an Associate Professor of Psychiatry and Behavioral Sciences at Stanford University where she directs the Social Neurosciences Research Program. Dr. Parker's research expertise is the biology of social functioning, with a particular interest in oxytocin and vasopressin signaling pathways. Her preclinical research program focuses on developing novel monkey models of social impairments; her clinical research program encompasses biomarker discovery and therapeutic testing in autism and other brain disorders.
Dr. Parker received her undergraduate and graduate degrees from the University of Michigan and completed postdoctoral training at Stanford University. Dr. Parker joined the Stanford faculty in 2007. She is an Affiliate Scientist at the California National Primate Research Center, a Member of the American College of Neuropsychopharmacology, and a Kavli Fellow of the US National Academy of Sciences.
Dr. Parker’s research program has been supported by multiple funding agencies including the NIH, the Simons Foundation, NARSAD, and the Weston Havens Foundation. Dr. Parker serves on the Editorial Board of Psychoneuroendocrinology, the scientific advisory board for the Stanford Autism Center at Packard Children’s Hospital, and on various national (e.g., NIH and NSF) and international (e.g., Medical Research Council) grant review committees. She has also participated as an invited expert at NIH workshops focused on neurodevelopmental disorders.
Dr. Parker was born in Boulder, CO and grew up in suburban Chicago, IL. She lives in the San Francisco Bay Area with her husband (a high-tech executive), her three children, and two Australian shepherds.
Affiliate Scientist, California National Primate Research Center (2012 - Present)
Honors & Awards
George A. Miller Award, American Psychological Association
Kavli Fellow, U.S. National Academy of Sciences
Young Investigator Award, NARSAD
Distinguished Dissertation Award recipient, University of Michigan
Boards, Advisory Committees, Professional Organizations
Member of BRLE Grant Review Panel, National Institutes of Health (2012 - Present)
Editorial Board Member, Psychoneuroendocrinology (2013 - Present)
Scientific Advisory Board Member, Stanford Autism Center at Packard Children’s Hospital (2016 - Present)
Member, American College of Neuropsychopharmacology (2018 - Present)
Postdoctoral, Stanford University, Psychiatry Neuroscience
Ph.D., University of Michigan, Biological Psychology
A.B., University of Michigan, Psychology
Current Research and Scholarly Interests
The principal goal of the Parker Lab Social Neurosciences Research Program at Stanford University is to better understand the biology of social functioning using an integrative, translational approach. Our behavioral research spans studies of individual differences in rhesus monkey social development to studies of social cognition impairments in various clinical populations (e.g., in children with autism; in survivors of pediatric hypothalamic-pituitary tumors; in adults with posttraumatic stress disorder). We are also developing several innovative monkey models of social impairments, including studies of rhesus monkeys that naturally exhibit social cognition deficits and common marmoset monkeys which are engineered to do so. Our biological studies employ epigenetic, gene expression, and neurotransmitter-based approaches to identify biomarkers of impaired social functioning, and we also conduct treatment trials to test the efficacy of novel pharmacotherapies to improve social abilities in low-social monkeys and in children with autism. Our lab is particularly interested in testing whether “social” neuropeptide (e.g., oxytocin and arginine vasopressin) signaling pathways are implicated in human and non-human primate social behavior, and whether these neuropeptide pathways are robust biomarkers of, and treatment targets for, social impairments in clinical populations.
Intranasal Vasopressin Treatment in Children With Autism
This purposed of this clinical trial is to investigate the effectiveness of vasopressin nasal spray for treating symptoms associated with autism. Vasopressin is a hormone that is produced naturally within the body and has been implicated in regulating social behaviors. It has been proposed that administration of the hormone may also help improve social functioning in individuals with autism.
The Role of Vasopressin in the Social Deficits of Autism
Researchers at the Stanford University School of Medicine are seeking participants for a study examining the effectiveness of vasopressin, a neuropeptide, in treating children with autism spectrum disorder. Difficulty with social interactions is characteristic of people with autism, who often have problems interpreting facial expressions or maintaining eye contact while talking with someone. There are currently no effective medicines available to treat social problems in individuals with autism. Neuropeptides, such as vasopressin and oxytocin, are molecules used by neurons in the brain to communicate with one another. Vasopressin is closely related to oxytocin, which is currently being tested as a treatment for autism, and has been shown to enhance social functioning in animals. Animal studies have shown that when the proper functioning of vasopressin is experimentally altered, animals develop a variety of social deficits, including impaired memory for peers and a reduced interest in social interaction. Researchers found that when vasopressin was administered to mice with a genetically induced form of autism, their social functioning improved. Vasopressin is already approved by the Food and Drug Administration for use in humans, and has proved to be a successful treatment for some common pediatric conditions, including bedwetting. Similar to oxytocin, it also has been shown to improve social cognition and memory in people who do not have autism. The researchers will test the effects of vasopressin on social impairments in 50 boys and girls with autism, ages 6 to 12 years old. The study will last four weeks for each participant. Participants will receive either vasopressin or a placebo nasal spray. At the end of this phase of the study, those who received the placebo will have the option of participating in a four-week trial during which they will be given vasopressin. Stanford is the only site for the study. Participants do not need to live locally but will need to come to the Stanford University Department of Psychiatry and Behavioral Sciences for study visits.
Intranasal Oxytocin Treatment for Social Deficits in Children With Autism
Autism is a pervasive developmental disorder characterized by core deficits in social behavior and communication, and the presence of repetitive or stereotyped behaviors. It is one of three recognized disorders in the autism spectrum which affects an estimated 1 in 88 children in the United States. At present, pharmacotherapies target only associated features of autism, with no effective drug treatments for the social impairments. Several lines of evidence now suggest that the neuropeptide oxytocin (OT) may be an effective treatment for the core social deficits in autism. Here we will test the effects of twice daily intranasal OT (24 IU) over a 4-week period for enhancing social deficits in male and female children aged 6-12 years with autism. This research has high potential to lead to the development of more effective treatments and earlier interventions for children with autism.
Stanford is currently not accepting patients for this trial. For more information, please contact Robin Libove, BS, (650) 736-1235.
See Lab website for current projects: http://med.stanford.edu/parkerlab.html, Stanford University
Stanford University; California National Primate Research Center; Caribbean Primate Research Center
- Antonio Hardan, Professor, Stanford
- Joseph Garner, Associate Professor of Comparative Medicine and, by courtesy, of Psychiatry and Behavioral Sciences, School of Medicine
- Alan Schatzberg, Professor, School of Medicine
- Jennifer Phillips, Clinical Associate Professor, School of Medicine
- Joshua Elias, Assistant Professor, Chemical and Systems Biology, School of Medicine
- Rachel Manber, Professor, School of Medicine
- Sonia Partap, Clinical Associate Professor, Neurology & Neurological Sciences
- David Lyons, Professor (Research) of Psychiatry & Behavioral Sciences, School of Medicine
Independent Studies (9)
- Directed Reading in Neurosciences
NEPR 299 (Aut, Win, Spr, Sum)
- Directed Reading in Psychiatry
PSYC 299 (Aut, Win, Spr, Sum)
- Graduate Research
NEPR 399 (Aut, Win, Spr, Sum)
- Graduate Research
PSYC 399 (Aut, Win, Spr, Sum)
HUMBIO 194 (Aut, Win)
- Medical Scholars Research
PSYC 370 (Aut, Win, Spr, Sum)
- Out-of-Department Graduate Research
BIO 300X (Aut)
- Teaching in Psychiatry
PSYC 290 (Aut, Win, Spr, Sum)
- Undergraduate Research
PSYC 199 (Aut, Win, Spr, Sum)
- Directed Reading in Neurosciences
Postdoctoral Research Mentor
Graduate and Fellowship Programs
Biology (School of Humanities and Sciences) (Phd Program)
Child Psychiatry (Fellowship Program)
Biomarker discovery for disease status and symptom severity in children with autism.
2017; 89: 39–45
Autism spectrum disorder (ASD) is characterized by social impairments and repetitive behaviors, and affects 1 in 68 US children. Despite ASD's societal impact, its disease mechanisms remain poorly understood. Recent preclinical ASD biomarker discovery research has implicated the neuropeptides oxytocin (OXT) and arginine vasopressin (AVP), and their receptors, OXTR and AVPR1A, in animal models. Efforts to translate these findings to individuals with ASD have typically involved evaluating single neuropeptide measures as biomarkers of ASD and/or behavioral functioning. Given that ASD is a heterogeneous disorder, and unidimensional ASD biomarker studies have been challenging to reproduce, here we employed a multidimensional neuropeptide biomarker analysis to more powerfully interrogate disease status and symptom severity in a well characterized child cohort comprised of ASD patients and neurotypical controls. These blood-based neuropeptide measures, considered as a whole, correctly predicted disease status for 57 out of 68 (i.e., 84%) participants. Further analysis revealed that a composite measure of OXTR and AVPR1A gene expression was the key driver of group classification, and that children with ASD had lower neuropeptide receptor mRNA levels compared to controls. Lower neuropeptide receptor mRNA levels also predicted greater symptom severity for core ASD features (i.e., social impairments and stereotyped behaviors), but were unrelated to intellectual impairment, an associated feature of ASD. Findings from this research highlight the value of assessing multiple related biological measures, and their relative contributions, in the same study, and suggest that low blood neuropeptide receptor availability may be a promising biomarker of disease presence and symptom severity in ASD.
View details for DOI 10.1016/j.psyneuen.2017.12.022
View details for PubMedID 29309996
Intranasal oxytocin treatment for social deficits and biomarkers of response in children with autism.
Proceedings of the National Academy of Sciences
2017; 114 (30): 8119-8124
View details for DOI 10.1073/pnas.1705521114
Preference for novel faces in male infant monkeys predicts cerebrospinal fluid oxytocin concentrations later in life.
View details for DOI 10.1038/s41598-017-13109-5
Vigilance for threat accounts for inter-individual variation in physiological responses to adversity in rhesus macaques: A cognition × environment approach.
View details for DOI 10.1002/dev.21572
Effects of early life adversity on cortisol/salivary alpha-amylase symmetry in free-ranging juvenile rhesus macaques
HORMONES AND BEHAVIOR
2016; 86: 78-84
Early life adversity (ELA) affects physiological and behavioral development. One key component is the relationship between the developing Hypothalamic-Pituitary-Adrenal (HPA) axis and the Sympathetic Nervous System (SNS). Recent studies suggest a relationship between early life adversity and asymmetry in cortisol (a measure of HPA activation) and salivary alpha-amylase (sAA: a correlate of SNS activation) responses to stress among human children, but to our knowledge there have been no comparable studies in nonhumans. Here, we investigate the responses of these two analytes in "low stress" and "high stress" situations in free-ranging juvenile rhesus macaques (Macaca mulatta) on Cayo Santiago, Puerto Rico. Behavioral data on maternal maltreatment were collected during the first 3months of life to determine individual rates of ELA, and saliva samples were collected from subjects noninvasively during juvenility. Irrespective of ELA, salivary alpha-amylase levels were lower in low stress situations and higher in high stress situations. For cortisol however, high ELA subjects exhibited higher low stress concentrations and blunted acute responses during high stress situations compared to moderate and low ELA subjects. Cortisol and sAA values were positively correlated among low ELA subjects, suggesting symmetry, but were uncorrelated or negatively correlated among moderate and high ELA subjects, suggesting asymmetry in these individuals. These findings indicate dysregulation of the stress response among juveniles maltreated during infancy: specifically, attenuated cortisol reactivity coupled with typical sAA reactivity characterize the stress response profiles of juveniles exposed to higher rates of ELA during the first 3months of life.
View details for DOI 10.1016/j.yhbeh.2016.05.004
View details for Web of Science ID 000388056600010
View details for PubMedID 27170429
Early Predictors of Impaired Social Functioning in Male Rhesus Macaques (Macaca mulatta).
2016; 11 (10)
Autism spectrum disorder (ASD) is characterized by social cognition impairments but its basic disease mechanisms remain poorly understood. Progress has been impeded by the absence of animal models that manifest behavioral phenotypes relevant to ASD. Rhesus monkeys are an ideal model organism to address this barrier to progress. Like humans, rhesus monkeys are highly social, possess complex social cognition abilities, and exhibit pronounced individual differences in social functioning. Moreover, we have previously shown that Low-Social (LS) vs. High-Social (HS) adult male monkeys exhibit lower social motivation and poorer social skills. It is not known, however, when these social deficits first emerge. The goals of this study were to test whether juvenile LS and HS monkeys differed as infants in their ability to process social information, and whether infant social abilities predicted later social classification (i.e., LS vs. HS), in order to facilitate earlier identification of monkeys at risk for poor social outcomes. Social classification was determined for N = 25 LS and N = 25 HS male monkeys that were 1-4 years of age. As part of a colony-wide assessment, these monkeys had previously undergone, as infants, tests of face recognition memory and the ability to respond appropriately to conspecific social signals. Monkeys later identified as LS vs. HS showed impairments in recognizing familiar vs. novel faces and in the species-typical adaptive ability to gaze avert to scenes of conspecific aggression. Additionally, multivariate logistic regression using infant social ability measures perfectly predicted later social classification of all N = 50 monkeys. These findings suggest that an early capacity to process important social information may account for differences in rhesus monkeys' motivation and competence to establish and maintain social relationships later in life. Further development of this model will facilitate identification of novel biological targets for intervention to improve social outcomes in at-risk young monkeys.
View details for DOI 10.1371/journal.pone.0165401
View details for PubMedID 27788195
View details for PubMedCentralID PMC5082922
Endocannabinoid signaling in social functioning: an RDoC perspective.
View details for DOI 10.1038/tp.2016.169
Cup tool use by squirrel monkeys
AMERICAN JOURNAL OF PRIMATOLOGY
2015; 77 (12): 1323-1332
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
Dopamine D4 receptor genotype variation in free-ranging rhesus macaques and its association with juvenile behavior.
Behavioural brain research
2015; 292: 50-55
A polymorphism in the dopamine receptor D4 (DRD4) gene has been associated with significant variation in behavioral impulsivity, novelty-seeking, and risk-taking in humans and other animals. Rhesus macaques are an excellent animal model for research on the genetic basis of behavior using the candidate gene approach. Little is known, however, about allelic variation in DRD4 in large free-ranging populations of rhesus macaques and how this allelic variation relates to emotion regulation and behavior. In this study, we genotyped for the DRD4 polymorphism 178 individuals of different age and sex categories in the free-ranging rhesus macaque population on the island of Cayo Santiago, PR. Moreover, we examined the possible association between DRD4 allelic variation and three measures of juvenile behavior (time spent in proximity to the mother, avoidance of other individuals, and behavioral restlessness). Five different DRD4 alleles (5R, 5.5R, 6R, 6.5R, and 7R) were identified in the subject population. The most common allele was the 5R allele (78.5%), followed by the 7R allele (16.1%). Juveniles carrying the long form of the DRD4 allele (7R) spent less time in proximity to their mothers, avoided other individuals more often, and scored higher on behavioral restlessness than juveniles carrying the shorter alleles. Behavioral restlessness was also influenced by maternal DRD4 genotype. These results highlight both similarities and differences in the relative occurrence of DRD4 alleles and their association with behavior in this rhesus macaque population, other nonhuman primate species or populations, and humans.
View details for DOI 10.1016/j.bbr.2015.06.014
View details for PubMedID 26073765
Cerebrospinal fluid and plasma oxytocin concentrations are positively correlated and negatively predict anxiety in children
2015; 20 (9): 1085-1090
The neuropeptide oxytocin (OXT) exerts anxiolytic and prosocial effects in the central nervous system of rodents. A number of recent studies have attempted to translate these findings by investigating the relationships between peripheral (e.g., blood, urinary and salivary) OXT concentrations and behavioral functioning in humans. Although peripheral samples are easy to obtain in humans, whether peripheral OXT measures are functionally related to central OXT activity remains unclear. To investigate a possible relationship, we quantified OXT concentrations in concomitantly collected cerebrospinal fluid (CSF) and blood samples from child and adult patients undergoing clinically indicated lumbar punctures or other CSF-related procedures. Anxiety scores were obtained in a subset of child participants whose parents completed psychometric assessments. Findings from this study indicate that plasma OXT concentrations significantly and positively predict CSF OXT concentrations (r=0.56, P=0.0064, N=27). Moreover, both plasma (r=-0.92, P=0.0262, N=10) and CSF (r=-0.91, P=0.0335, N=10) OXT concentrations significantly and negatively predicted trait anxiety scores, consistent with the preclinical literature. Importantly, plasma OXT concentrations significantly and positively (r=0.96, P=0.0115, N=10) predicted CSF OXT concentrations in the subset of child participants who provided behavioral data. This study provides the first empirical support for the use of blood measures of OXT as a surrogate for central OXT activity, validated in the context of behavioral functioning. These preliminary findings also suggest that impaired OXT signaling may be a biomarker of anxiety in humans, and a potential target for therapeutic development in individuals with anxiety disorders.Molecular Psychiatry advance online publication, 4 November 2014; doi:10.1038/mp.2014.132.
View details for DOI 10.1038/mp.2014.132
View details for Web of Science ID 000360175500009
- Arginine Vasopressin Is a Blood-Based Biomarker of Social Functioning in Children with Autism PLOS ONE 2015; 10 (7)
- Plasma vasopressin concentrations positively predict cerebrospinal fluid vasopressin concentrations in human neonates PEPTIDES 2014; 61: 12-16
- Early Experience Affects the Strength of Vigilance for Threat in Rhesus Monkey Infants PSYCHOLOGICAL SCIENCE 2014; 25 (10): 1893-1902
Plasma oxytocin concentrations and OXTR polymorphisms predict social impairments in children with and without autism spectrum disorder
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2014; 111 (33): 12258-12263
The neuropeptide oxytocin (OXT) and its receptor (OXTR) regulate social functioning in animals and humans. Initial clinical research suggests that dysregulated plasma OXT concentrations and/or OXTR SNPs may be biomarkers of social impairments in autism spectrum disorder (ASD). We do not know, however, whether OXT dysregulation is unique to ASD or whether OXT biology influences social functioning more generally, thus contributing to, but not causing, ASD phenotypes. To distinguish between these possibilities, we tested in a child ASD cohort, which included unaffected siblings and unrelated neurotypical controls (ages 3-12 y; n = 193), whether plasma OXT concentrations and OXTR SNPs (i) interact to produce ASD phenotypes, (ii) exert differential phenotypic effects in ASD vs. non-ASD children, or (iii) have similar phenotypic effects independent of disease status. In the largest cohort tested to date, we found no evidence to support the OXT deficit hypothesis of ASD. Rather, OXT concentrations strongly and positively predicted theory of mind and social communication performance in all groups. Furthermore, OXT concentrations showed significant heritability between ASD-discordant siblings (h(2) = 85.5%); a heritability estimate on par with that of height in humans. Finally, carriers of the "G" allele of rs53576 showed impaired affect recognition performance and carriers of the "A" allele of rs2254298 exhibited greater global social impairments in all groups. These findings indicate that OXT biology is not uniquely associated with ASD, but instead exerts independent, additive, and highly heritable influences on individual differences in human social functioning, including the severe social impairments which characterize ASD.
View details for DOI 10.1073/pnas.1402236111
View details for Web of Science ID 000340438800080
View details for PubMedID 25092315
Emotion dysregulation and the core features of autism spectrum disorder.
Journal of autism and developmental disorders
2014; 44 (7): 1766-1772
The aim of this study was to examine the relationship between emotion dysregulation and the core features of Autism Spectrum Disorder (ASD), which include social/communication deficits, restricted/repetitive behaviors, and sensory abnormalities. An 18-item Emotion Dysregulation Index was developed on the basis of expert ratings of the Child Behavior Checklist. Compared to typically developing controls, children and adolescents with ASD showed more emotion dysregulation and had significantly greater symptom severity on all scales. Within ASD participants, emotion dysregulation was related to all core features of the disorder, but the strongest association was with repetitive behaviors. These findings may facilitate the development of more effective therapeutic strategies targeting emotion dysregulation in order to optimize long-term outcomes for individuals with ASD.
View details for DOI 10.1007/s10803-013-2022-5
View details for PubMedID 24362795
Plasma oxytocin concentrations are lower in depressed vs. healthy control women and are independent of cortisol.
Journal of psychiatric research
2014; 51: 30-36
The neuropeptide oxytocin (OT) promotes social behavior and attenuates stress responsivity in mammals. Recent clinical evidence suggests OT concentrations may be dysregulated in major depression. This study extends previous research by testing whether: 1) OT concentrations vary systematically in depressive disorders with and without hypercortisolemia, 2) gender differences in OT concentrations are observed in depressed vs. healthy control participants, and 3) OT concentrations are predictive of clinical phenotypes. Plasma OT concentrations of psychotic major depressive (PMD; n = 14: 10 female, 4 male), non-psychotic major depressive (NPMD; n = 17: 12 female, 5 male), and non-depressed, healthy control (n = 19: 11 female, 8 male) participants were assayed at 2000, 2400, 0400, and 0800 h. Plasma cortisol concentrations were quantified at 2300 h, and clinical phenotypes were determined. As expected, PMD participants, compared to NPMD and healthy control participants, showed higher plasma cortisol concentrations. Although both depressed groups showed similar OT concentrations, a significant interaction effect between group and gender was observed. Specifically, depressed females exhibited lower mean OT concentrations than depressed males. Further, depressed vs. healthy control female participants exhibited lower mean OT concentrations, whereas depressed vs. healthy control male participants showed a trend in the opposite direction. OT concentrations were also predictive of desirability, drug dependence, and compulsivity scores as measured by the Million Clinical Multiaxial Inventory-III. All findings were independent of cortisol. These data suggest that OT signaling may provide a mechanism by which to better understand female-biased risk to develop depressive disorders and that plasma OT concentrations may be a useful biomarker of certain clinical phenotypes.
View details for DOI 10.1016/j.jpsychires.2013.12.012
View details for PubMedID 24405552
Physiological and behavioural responses to weaning conflict in free-ranging primate infants.
2014; 97: 241–47
Weaning, characterized by maternal reduction of resources, is both psychologically and energetically stressful to mammalian offspring. Despite the importance of physiology in this process, previous studies have reported only indirect measures of weaning stress from infants, because of the difficulties of collecting physiological measures from free-ranging mammalian infants. Here we present some of the first data on the relationship between weaning and energetic and psychological stress in infant mammals. We collected data on 47 free-ranging rhesus macaque infants on Cayo Santiago, Puerto Rico, showing that faecal glucocorticoid metabolite (fGCM) concentrations were directly related to the frequency of maternal rejection, with fGCM concentrations increasing as rates of rejection increased. Infants with higher fGCM concentrations also engaged in higher rates of mother following, and mother following was associated with increased time on the nipple, suggesting that infants that experienced greater weaning-related stress increased their efforts to maintain proximity and contact with their mothers. Infants experiencing more frequent rejection uttered more distress vocalizations when being rejected; however, there was no relationship between rates of distress vocalizations and fGCM concentrations, suggesting a disassociation between behavioural and physiological stress responses to weaning. Elevated glucocorticoid concentrations during weaning may function to mobilize energy reserves and prepare the infant for continued maternal rejection and shortage of energetic resources.
View details for DOI 10.1016/j.anbehav.2014.09.016
View details for PubMedID 25431499
View details for PubMedCentralID PMC4242433
The three-hit concept of vulnerability and resilience: Toward understanding adaptation to early-life adversity outcome
2013; 38 (9): 1858-1873
Stressful experiences during early-life can modulate the genetic programming of specific brain circuits underlying emotional and cognitive aspects of behavioral adaptation to stressful experiences later in life. Although this programming effect exerted by experience-related factors is an important determinant of mental health, its outcome depends on cognitive inputs and hence the valence an individual assigns to a given environmental context. From this perspective we will highlight, with studies in rodents, non-human primates and humans, the three-hit concept of vulnerability and resilience to stress-related mental disorders, which is based on gene-environment interactions during critical phases of perinatal and juvenile brain development. The three-hit (i.e., hit-1: genetic predisposition, hit-2: early-life environment, and hit-3: later-life environment) concept accommodates the cumulative stress hypothesis stating that in a given context vulnerability is enhanced when failure to cope with adversity accumulates. Alternatively, the concept also points to the individual's predictive adaptive capacity, which underlies the stress inoculation and match/mismatch hypotheses. The latter hypotheses propose that the experience of relatively mild early-life adversity prepares for the future and promotes resilience to similar challenges in later-life; when a mismatch occurs between early and later-life experience, coping is compromised and vulnerability is enhanced. The three-hit concept is fundamental for understanding how individuals can either be prepared for coping with life to come and remain resilient or are unable to do so and succumb to a stress-related mental disorder, under seemingly identical circumstances.
View details for DOI 10.1016/j.psyneuen.2013.06.008
View details for Web of Science ID 000325188300045
View details for PubMedID 23838101
View details for PubMedCentralID PMC3773020
Neonatal CSF oxytocin levels are associated with parent report of infant soothability and sociability.
2013; 38 (7): 1208-1212
Oxytocin (OT) has been linked to social behavior in rodents, non-human primates, and adult humans, but almost nothing is known about brain OT activity in human newborns or its impact on social development. To better understand the role of OT biology in human social functioning, a multi-disciplinary, longitudinal study was conducted. Cerebral spinal fluid (CSF) OT levels from 18 human neonates were evaluated and examined in relationship to social-seeking behavior at term, at 3 months, and at 6 months of age. Higher neonatal CSF OT levels were consistently associated with solicitation of parental soothing and interest in social engagement with others. This is the first study to link CSF OT levels to normative human social functioning. Research is now required to test whether early OT levels serve as a biomarker for subsequent social abnormalities.
View details for DOI 10.1016/j.psyneuen.2012.10.017
View details for PubMedID 23507187
Distinct Plasma Profile of Polar Neutral Amino Acids, Leucine, and Glutamate in Children with Autism Spectrum Disorders
JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS
2012; 42 (5): 827-836
The goal of this investigation was to examine plasma amino acid (AA) levels in children with Autism Spectrum Disorders (ASD, N = 27) and neuro-typically developing controls (N = 20). We observed reduced plasma levels of most polar neutral AA and leucine in children with ASD. This AA profile conferred significant post hoc power for discriminating children with ASD from healthy children. Furthermore, statistical correlations suggested the lack of a typical decrease of glutamate and aspartate with age, and a non-typical increase of isoleucine and lysine with age in the ASD group. Findings from this limited prospective study warrant further examination of plasma AA levels in larger cross-sectional and longitudinal cohorts to adequately assess for relationships with developmental and clinical features of ASD.
View details for DOI 10.1007/s10803-011-1314-x
View details for Web of Science ID 000302771500017
View details for PubMedID 21713591
Effects of intranasal oxytocin on social anxiety in males with fragile X syndrome
2012; 37 (4): 509-518
Fragile X syndrome (FXS) is a rare inherited genetic disorder causing severe intellectual disability and autistic-like symptoms. Individuals with FXS, males in particular, often exhibit extreme eye gaze avoidance and hyperarousal when they encounter stressful social situations. We investigated whether oxytocin (OT), a hormone with prosocial and anxiolytic effects, could alleviate symptoms of social anxiety in this population. A randomized double-blind placebo-controlled single-dose trial was performed with intranasal administration of placebo, 24 IU OT and 48 IU OT. Measures of eye gaze frequency, heart rate, respiratory sinus arrhythmia (RSA), heart rate variability (HRV) and salivary cortisol were obtained during a structured social challenge conducted 50 min following OT administration. Ten low-functioning males with FXS (aged 13-28 years) traveled to Stanford for the initial visit: 8 completed the study. Eye gaze frequency improved significantly in response to the 24 IU OT dose and salivary cortisol levels decreased significantly in response to the 48 IU OT dose. There was no effect of OT on heart rate, RSA or HRV although individual plots of the heart rate data suggested that OT increased heart rate in some participants and decreased heart rate in others. These findings suggest that intranasal administration of OT may ameliorate some symptoms of social anxiety in patients with FXS. Further double-blind placebo-controlled studies of OT, conducted in combination with behavioral treatment programs, may be warranted.
View details for DOI 10.1016/j.psyneuen.2011.07.020
View details for Web of Science ID 000302044800007
View details for PubMedID 21862226
View details for PubMedCentralID PMC3353652
- Hypothalamic-pituitary-adrenal axis physiology and cognitive control of behavior in stress inoculated monkeys 2nd Herzliyah Symposium on Developmental Psychopathology SAGE PUBLICATIONS LTD. 2012: 45–52
Psychological Stress in Childhood and Susceptibility to the Chronic Diseases of Aging: Moving Toward a Model of Behavioral and Biological Mechanisms
2011; 137 (6): 959-997
Among people exposed to major psychological stressors in early life, there are elevated rates of morbidity and mortality from chronic diseases of aging. The most compelling data come from studies of children raised in poverty or maltreated by their parents, who show heightened vulnerability to vascular disease, autoimmune disorders, and premature mortality. These findings raise challenging theoretical questions. How does childhood stress get under the skin, at the molecular level, to affect risk for later diseases? And how does it incubate there, giving rise to diseases several decades later? Here we present a biological embedding model, which attempts to address these questions by synthesizing knowledge across several behavioral and biomedical literatures. This model maintains that childhood stress gets "programmed" into macrophages through epigenetic markings, posttranslational modifications, and tissue remodeling. As a consequence these cells are endowed with proinflammatory tendencies, manifest in exaggerated cytokine responses to challenge and decreased sensitivity to inhibitory hormonal signals. The model goes on to propose that over the life course, these proinflammatory tendencies are exacerbated by behavioral proclivities and hormonal dysregulation, themselves the products of exposure to early stress. Behaviorally, the model posits that childhood stress gives rise to excessive threat vigilance, mistrust of others, poor social relationships, impaired self-regulation, and unhealthy lifestyle choices. Hormonally, early stress confers altered patterns of endocrine and autonomic discharge. This milieu amplifies the proinflammatory environment already instantiated by macrophages. Acting in concert with other exposures and genetic liabilities, the resulting inflammation drives forward pathogenic mechanisms that ultimately foster chronic disease.
View details for DOI 10.1037/a0024768
View details for Web of Science ID 000296471000004
View details for PubMedID 21787044
A novel form of oxytocin in New World monkeys
2011; 7 (4): 584-587
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 Web of Science ID 000292639100031
View details for PubMedID 21411453
View details for PubMedCentralID PMC3130245
Identifying key features of early stressful experiences that produce stress vulnerability and resilience in primates
NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS
2011; 35 (7): 1466-1483
This article examines the complex role of early stressful experiences in producing both vulnerability and resilience to later stress-related psychopathology in a variety of primate models of human development. Two types of models are reviewed: Parental Separation Models (e.g., isolate-rearing, peer-rearing, parental separations, and stress inoculation) and Maternal Behavior Models (e.g., foraging demands, variation in maternal style, and maternal abuse). Based on empirical evidence, it is argued that early life stress exposure does not increase adult vulnerability to stress-related psychopathology as a linear function, as is generally believed, but instead reflects a quadratic function. Features of early stress exposure including the type, duration, frequency, ecological validity, sensory modality, and developmental timing, within and between species, are identified to better understand how early stressful experiences alter neurobiological systems to produce such diverse developmental outcomes. This article concludes by identifying gaps in our current knowledge, providing directions for future research, and discussing the translational implications of these primate models for human development and psychopathology.
View details for DOI 10.1016/j.neubiorev.2010.09.003
View details for Web of Science ID 000292428200003
View details for PubMedID 20851145
View details for PubMedCentralID PMC3023826
Somatic and neuroendocrine responses to standard and biologically salient acoustic startle stimuli in monkeys
2011; 36 (4): 547-556
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
Mu-opioid Receptor (OPRM1) Variation, Oxytocin Levels and Maternal Attachment in Free-Ranging Rhesus Macaques Macaca mulatta
2011; 125 (2): 131-136
Understanding the genetic and neuroendocrine basis of the mother-infant bond is critical to understanding mammalian affiliation and attachment. Functionally similar nonsynonymous mu-opioid receptor (OPRM1) SNPs have arisen and been maintained in humans (A118G) and rhesus macaques Macaca mulatta (C77G). In rhesus macaques, variation in OPRM1 predicts individual differences in infant affiliation for mothers. Specifically, infants carrying the G allele show increased distress on separation from their mothers, and spend more time with them upon reunion, than individuals homozygous for the C allele. In humans, individuals possessing the G allele report higher perceptions of emotional pain on receiving rejection by social partners. We studied maternal behavior over the course of a year among free-ranging female rhesus macaques on Cayo Santiago, Puerto Rico. We then trapped females and collected blood samples from which we assessed OPRM1 genotype; we also collected cerebrospinal fluid samples from which we measured oxytocin (OT) levels. We show that females possessing the G allele restrain their infants more (i.e., prevent infants from separating from them by pulling them back) than females homozygous for the C allele. Females possessing the G allele also show higher OT levels when lactating, and lower OT levels when neither lactating nor pregnant, than females homozygous for the C allele. This is the first study to demonstrate an association between OPRM1 genotype and maternal attachment for infants, and is one of the first studies of any free-ranging primate population to link functional genetic variation to behavior via potentially related neuroendocrine mechanisms.
View details for DOI 10.1037/a0022695
View details for Web of Science ID 000289182000001
View details for PubMedID 21463018
Oxytocin receptor gene polymorphism (rs2254298) interacts with familial risk for psychopathology to predict symptoms of depression and anxiety in adolescent girls
2011; 36 (1): 144-147
The nonapeptide oxytocin and its receptor have been implicated in the regulation of mammalian social behavior and stress physiology. Evidence is accumulating that the quality of the parental environment is associated with oxytocin biology in children. The present study was designed to examine the interaction of the single nucleotide polymorphism (SNP) rs2254298 within the oxytocin receptor (OXTR) gene and quality of parental environment in predicting children's psychosocial functioning. More specifically, in a sample of 92 Caucasian adolescent girls (9-14 years old), we examined whether adverse parental environment, operationalized as mothers' history of recurrent major depressive disorder, interacts with the rs2254298 SNP on the OXTR gene to predict daughters' symptoms of depression and anxiety. Caucasian girls who both were heterozygous for the OXTR rs2254298 polymorphism and had high early adversity reported the highest levels of symptoms of depression, physical anxiety, and social anxiety. These findings highlight the potential importance of this OXTR gene polymorphism in the etiology of depression and anxiety disorders.
View details for DOI 10.1016/j.psyneuen.2010.07.003
View details for Web of Science ID 000286299100016
View details for PubMedID 20708845
View details for PubMedCentralID PMC2997902
Animal Models of Early Life Stress: Implications for Understanding Resilience
2010; 52 (7): 616-624
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
Preliminary evidence that plasma oxytocin levels are elevated in major depression
2010; 178 (2): 359-362
It is well established that the neuropeptide oxytocin (OT) is involved in regulating social behavior, anxiety, and hypothalamic-pituitary-adrenal (HPA) axis physiology in mammals. Because individuals with major depression often exhibit functional irregularities in these measures, we test in this pilot study whether depressed subjects (n=11) exhibit dysregulated OT biology compared to healthy control subjects (n=19). Subjects were hospitalized overnight and blood samples were collected hourly between 1800 and 0900h. Plasma levels of OT, the closely related neuropeptide argine-vasopressin (AVP), and cortisol were quantified. Results indicated that depressed subjects exhibit increased OT levels compared to healthy control subjects, and this difference is most apparent during the nocturnal peak. No depression-related differences in AVP or cortisol levels were discerned. This depression-related elevation in plasma OT levels is consistent with reports of increased hypothalamic OT-expressing neurons and OT mRNA in depressed patients. This present finding is likewise consistent with the hypothesis that dysregulated OT biology may be a biomarker of the emotional distress and impaired social relationships which characterize major depression. Additional research is required to elucidate the role of OT in the pathophysiology of this psychiatric disorder.
View details for DOI 10.1016/j.psychres.2009.09.017
View details for Web of Science ID 000279988900025
View details for PubMedID 20494448
View details for PubMedCentralID PMC2902664
Effects of Age on Cerebrospinal Fluid Oxytocin Levels in Free-Ranging Adult Female and Infant Rhesus Macaques
2010; 124 (3): 428-433
There is growing interest in examining oxytocin and social functioning in human and non-human primates. Studies of human oxytocin biology are typically restricted to peripheral assessments because opportunities to collect cerebrospinal fluid (CSF) are rare. Several studies have examined CSF oxytocin levels in captive adult primates, but none to our knowledge have been conducted under free-ranging conditions and inclusive of infants. The main goal of this study was to establish feasibility of quantifying CSF oxytocin levels in free-ranging adult female and infant rhesus monkeys living on Cayo Santiago, PR. CSF oxytocin levels were examined in relation to individuals' demographic and reproductive characteristics as well as plasma cortisol levels. CSF oxytocin concentrations ranged from 36.02 to 134.41 pg/ml in adult females (ages 7-26 years; N = 31) and 35.94 to 77.3 pg/ml in infants (ages 38-134 days; N = 17). CSF oxytocin levels were positively correlated with adult female age and negatively correlated with infant age. The former correlation was driven by reproductive status. CSF oxytocin levels were unrelated to dominance rank or plasma cortisol levels. In contrast to a previous study of plasma oxytocin concentrations in this population, CSF oxytocin levels did not differ significantly between lactating and non-lactating females. These findings: 1) provide feasibility data for examining CSF oxytocin levels in free-ranging non-human primates and 2) indicate that CSF oxytocin levels may be a biomarker of age-related central nervous system changes across lifespan development. Research is now required to examine CSF oxytocin levels in the context of social functioning in free-ranging rhesus monkeys.
View details for DOI 10.1037/a0019576
View details for Web of Science ID 000278466000015
View details for PubMedID 20528088
FOR BETTER OR WORSE? STRESS INOCULATION EFFECTS FOR IMPLICIT BUT NOT EXPLICIT ANXIETY
DEPRESSION AND ANXIETY
2009; 26 (9): 831-837
Severe early life stress (ELS) is associated with negative outcomes. It is not clear, however, what impact moderate ELS has. A growing stress inoculation literature suggests that moderate (vs. low or high) ELS is associated with diminished behavioral and physiological anxiety responses. At the same time, studies of trait anxiety suggest that moderate (vs. low) ELS is associated with greater self-reported anxiety. This study tested the hypothesis that stress inoculation effects are evident for implicit (nonconscious) but not explicit (conscious) aspects of anxiety.Ninety-seven healthy women were assessed for ELS and explicit anxiety using questionnaires and assessed for implicit anxiety using a version of the Implicit Association Test.Results indicated a quadratic relation between ELS and implicit anxiety, such that moderate ELS was associated with lower implicit anxiety levels than low or high ELS. By contrast, the relation between ELS and explicit anxiety was linear.These findings support the stress inoculation hypothesis and suggest that stress inoculation applies for implicit but not explicit aspects of anxiety.
View details for DOI 10.1002/da.20592
View details for Web of Science ID 000269685500008
View details for PubMedID 19569055
View details for PubMedCentralID PMC3364103
Prefrontal Plasticity and Stress Inoculation-Induced Resilience
2009; 31 (4): 293-299
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 Web of Science ID 000267787200006
View details for PubMedID 19546566
View details for PubMedCentralID PMC2820579
Developmental cascades linking stress inoculation, arousal regulation, and resilience
FRONTIERS IN BEHAVIORAL NEUROSCIENCE
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
Preliminary evidence that hippocampal volumes in monkeys predict stress levels of adrenocorticotropic hormone
2007; 62 (10): 1171-1174
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
Early life stress and novelty seeking behavior in adolescent monkeys
2007; 32 (7): 785-792
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
JOHN WILEY & SONS INC. 2007: 423–33
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
2006; 89 (2): 123-127
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
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
2006; 103 (8): 3000-3005
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
Intranasal oxytocin administration attenuates the ACTH stress response in monkeys
2005; 30 (9): 924-929
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
2005; 57 (8): 848-855
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
Prospective investigation of stress inoculation in young monkeys
ARCHIVES OF GENERAL PSYCHIATRY
2004; 61 (9): 933-941
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
Female meadow voles (Microtus pennsylvanicus) demonstrate same-sex partner preferences
JOURNAL OF COMPARATIVE PSYCHOLOGY
2003; 117 (3): 283-289
Female meadow voles (Microtus pennsylvanicus) are territorial during warm months but demonstrate social tolerance under low temperatures. In spring, females nest together and some pairs participate in communal nursing and rearing of young. Because communal nursing involves significant cooperation, selective pair-bonds may develop between 2 nestmates. Using a choice apparatus, the authors determined that (a) captive females demonstrated partner preferences for a nestmate; (b) partner preferences were enduring and persisted after dyadic separation; and (c) following the loss of a nestmate, females did not develop preferences for a new nestmate, even after extended cohabitation. Data support the hypothesis that captive meadow voles develop selective and enduring same-sex social bonds that may, under free-living conditions, facilitate communal nesting and cooperative rearing of young.
View details for DOI 10.1037/0735-7036.117.3.283
View details for Web of Science ID 000185458600006
View details for PubMedID 14498804
Circadian and homeostatic regulation of hypocretin in a primate model: Implications for the consolidation of wakefulness
JOURNAL OF NEUROSCIENCE
2003; 23 (8): 3555-3560
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
2003; 43 (1): 60-66
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
Interaction of photoperiod and testes development is associated with paternal care in Microtus pennsylvanicus (meadow voles)
PHYSIOLOGY & BEHAVIOR
2002; 75 (1-2): 91-95
During the summer breeding season, free-living meadow voles do not engage in paternal care. However, in fall when female territoriality declines, social nesting and breeding activity may overlap and adult males nest with females and young. In the laboratory, meadow voles housed under short day (SD) lengths exhibit more and better quality paternal care than those housed under long day (LD) lengths. This observation is commensurate with the hypothesis that SD paternal care may increase fitness by decreasing pup mortality during colder months. However, SD males also demonstrate variability in paternal care. We hypothesize that this variability may be due to male fertility status; SD infertile males, incapable of siring offspring, should be less likely to care for pups than fertile males, for whom paternal care may confer fitness benefits. The goal of this experiment was to determine whether paternal behavior differed between fertile LD males, fertile SD males (i.e. males that were gonadally photoperiod-unresponsive to SD lengths), and infertile SD males (i.e. males that were gonadally photoperiod-responsive to SD lengths), as indexed by paired testes weights and behavioral evaluation. Fertile SD males exhibited proportionally more paternal behavior than infertile SD males or fertile LD males, which did not differ from each other. Fertile SD males also exhibited paternal behavior faster, spent more time in contact with pups, and engaged in longer and more frequent bouts of pup-directed grooming and huddling than either infertile SD males or fertile LD males. Collectively, these data suggest that photoperiod and fertility status may interact to exert both inhibitory and permissive control over the expression of paternal behavior in adult meadow voles.
View details for Web of Science ID 000175195300012
View details for PubMedID 11890957
Social and environmental factors influence the suppression of pup-directed aggression and development of paternal behavior in captive meadow voles (Microtus pennsylvanicus)
JOURNAL OF COMPARATIVE PSYCHOLOGY
2001; 115 (4): 331-336
During summer, female meadow voles (Microtus pennsylvanicus) maintain territories and males do not engage in paternal care. As day length shortens, territories dissolve and males nest with females and young. Because paternal behavior has never been studied in free-living meadow voles during colder months or in the laboratory under short photoperiods, the authors examined whether males housed in short day (SD) lengths exhibited more frequent or better quality paternal behavior than males housed in long day (LD) lengths. Sexually and parentally inexperienced (naive) SD males exhibited proportionally more and qualitatively better paternal care than naive LD males. SD males were more responsive than LD males to classic social cues associated with prepartum aggression inhibition and paternal onset. SD sires also displayed qualitatively better paternal behavior than LD sires. These data suggest that meadow vole paternal state is regulated by specific social and environmental cues that may contain reliable information about ecological conditions that favor paternal care.
View details for DOI 10.1037//0735-7036.115.4.331
View details for Web of Science ID 000173402200001
View details for PubMedID 11824895
Day length and sociosexual cohabitation alter central oxytocin receptor binding in female meadow voles (Microtus pennsylvanicus)
2001; 115 (6): 1349-1356
In voles (Microtus), central oxytocin (OT) receptor patterns are associated with interspecific social organization. Social, monogamous voles have more OT receptors in the extended amygdala than asocial, nonmonogamous voles. Nonmonogamous meadow voles (Microtus pennsylvanicus), which exhibit seasonal changes in social organization (long day [LD] females are territorial, short day [SD] females live socially), provide a model for examining whether OT receptor patterns are associated with seasonal changes in intraspecific social behaviors. The authors examined whether sexually inexperienced (naive) SD females had more OT receptor binding than naive LD females. Naive SD females had greater OT receptor binding in the lateral septum (LS), lateral amygdala (LatAmyg), and central amygdala (CenAmyg) than less social, naive LD females. Because both SD and LD females acquire partner preferences, the authors assessed whether OT receptor binding was associated with partner preference onset. For LD females, partner preference onset corresponded with greater OT receptor binding in the anterior olfactory nucleus, LS, and bed nucleus of the stria terminalis, compared with naive LD females. In contrast, naive SD females and those exhibiting partner preferences did not differ. However, SD females that failed to acquire partner preferences showed less OT binding in the LatAmyg and CenAmyg. This study is the first to show that central OT receptor patterns are associated with seasonal changes in intraspecific social organization and partner preference onset in a nonmonogamous rodent.
View details for Web of Science ID 000172687600018
View details for PubMedID 11770065
Paternal behavior is associated with central neurohormone receptor binding patterns in meadow voles (Microtus pennsylvanicus)
2001; 115 (6): 1341-1348
Paternal and nonpaternal voles (microtus) have different arginine-vasopressin (AVP) and oxytocin (OT) receptor patterns in the extended amygdala, a neural pathway associated with parental behavior. Using receptor autoradiography, the authors examined whether AVP and OT receptor patterns were associated with facultative paternal behavior in either sexually and parentally inexperienced or experienced meadow voles (Microtus pennsylvanicus). Experienced, in contrast to inexperienced, males had less AVP binding in the lateral septum (LS), more AVP binding in the anterior olfactory nucleus (AON), and more OT binding in the AON, bed nucleus of the stria terminalis, LS, and lateral amygdala. Thus, specific AVP receptor patterns, which co-occur with paternal care in consistently paternal voles, also may be associated with paternal care (when present) in typically nonpaternal species. This study also demonstrated a possible relationship between OT receptor patterns and paternal state in male mammals.
View details for Web of Science ID 000172687600017
View details for PubMedID 11770064
Central vasopressin administration regulates the onset of facultative paternal behavior in Microtus pennsylvanicus (Meadow voles)
HORMONES AND BEHAVIOR
2001; 39 (4): 285-294
Pharmacological experiments have implicated a role for central arginine vasopressin (AVP) in regulating paternal behavior in monogamous prairie voles. Although nonmonogamous meadow voles exhibit appreciable paternal care when housed under winter, short day lengths (SD), no research has examined whether the same neurobiological systems are involved in regulating paternal behavior in a nonmonogamous species when it behaves paternally. The goal of these experiments was to determine whether central administration of AVP, but not cerebrospinal fluid (CSF), affected the suppression of pup-directed aggression and/or the onset of paternal behavior in meadow voles. Data from experiment 1 implicated a role for AVP in facilitating changes in male behavior: central administration of 1 ng of AVP (but not 3 ng or CSF) inhibited pup-directed aggression in previously pup-aggressive males, and 3 ng of AVP (but not 1 ng or CSF) induced paternal behavior in previously nonpaternal males. In contrast, AVP (1 and 3 ng) did not enhance paternal behavior in already paternal males. Experiment 2 tested the specificity of AVP. Previous research indicated that 24 h of unmated cohabitation with a female reliably induced paternal behavior in SD males. Hence, experiment 2 examined whether administration of a V(1a) AVP antagonist (AVPA), but not CSF, prior to 24 h of unmated cohabitation would block the onset of paternal behavior. Males that received CSF displayed paternal behavior faster and engaged in more investigatory and paternal behaviors than males that received AVPA. Thus, pharmacological experiments support the hypothesis that AVP likely regulates paternal behavior in both facultatively and consistently paternal vole species.
View details for DOI 10.1006/hbeh.2001.1655
View details for Web of Science ID 000169257100005
View details for PubMedID 11374914
- Development of selective partner preferences in captive male and female Microtus pennsylvanicus (meadow voles) Animal Behaviour 2001; 61 (6): 1217-1226