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Journal ArticleDOI

Sex differences in the effects of social defeat on brain and behavior in the California mouse: Insights from a monogamous rodent

TL;DR: Intranasal OT administration was shown to mimic the effects of defeat-induced increases in endogenous OT activity, causing social withdrawal in undefeated females, suggesting that inhibition of OT activity could reduce the impact of stress on behavior in females.
About: This article is published in Seminars in Cell & Developmental Biology.The article was published on 2017-01-01 and is currently open access. It has received 39 citations till now. The article focuses on the topics: Social defeat & Social stress.

Summary (2 min read)

1. Introduction

  • The genus Peromyscus consists of a diverse group of species that vary in their physiology, ecology, and behavior [14] .
  • There is a wealth of natural history and social organization data for different species of Peromyscus [15] , which allows one to select a species that is optimal for the question to be studied.
  • The California mouse (P. californicus) in particular has proven valuable for examining the effects of social defeat stress in both males and females.
  • The California mouse is a monogamous species and both males and females defend territories [16] .
  • Here the authors will discuss how studies using these protocols have provided insights into sex differences in the neuroendocrine responses to social stress.

2. The social defeat model of mood and anxiety disorders

  • An important weakness has been the difficulty in applying this approach to females.
  • Other species have proved to be more conducive to studying females.
  • For example female Syrian hamsters are actually more aggressive than males [36] .
  • Here the intense aggression of females may actually blunt the behavioral effects of defeat stress which are weaker and more short-lived compared to those observed in males [37, 38] .
  • In contrast, both male and female California mice exposed to defeat show long lasting changes in behavior and brain function.

3. California mouse model of social defeat

  • For females, social defeat has robust effects on behavior in the social interaction test.
  • In this test the focal mouse has an opportunity to approach an unfamiliar "target" mouse of the same sex confined to a wire cage.
  • In male mice and rats, defeat stress can reduce social interaction behavior and chronic (but not acute) antidepressant treatment can reverse this effect.
  • Indirect evidence suggests that gonadal steroids may act early in life to organize sex differences in the circuitry that mediates social withdrawal in stressed females.
  • Mice raised on corncob bedding also had reduced estrogen receptor expression across several brain regions.

4. Short term effects of defeat on OT and AVP: similarities between the sexes

  • In general the activity of OT and AVP neurons within the paraventricular nucleus (PVN) showed similar responses in males and females when assessed with fluorescent immunohistochemistry [49, 46] .
  • While it is not clear that this sex difference has short-term impacts on behavior, more consistent responses of OT neurons during defeat in males might impact responses of the hypothalamic-pituitaryadrenal (HPA) axis.
  • Oxytocin can inhibit glucocorticoid responses to stressors [82, 83] .
  • After a third episode of social defeat, female California mouse corticosterone levels were significantly higher than controls whereas this response was blunted in males [42] .

5. Long term effects of defeat on OT and AVP: sex differences

  • The BNST is as an important nucleus mediating threat detection and psychopathology [91] , and this population of OT neurons within the medioventral bed nucleus stria terminalis is evolutionarily conserved across rodent [92, 93] and primate [94, 95] species.
  • Defeated females displayed an increase in the percentage of OT/cfos colocalizations in both social and nonsocial contexts [49] .
  • This effect differs from the rostral PVN in which increases in OT/c-fos colocalizations were only observed in social contexts.
  • The effect on OT cell number was observed in animals at both two and ten weeks following defeat, while the mRNA effect was examined only in animals at the two-week time point.
  • This might appear counterintuitive, because stressed females had reduced social interaction behavior.

6. Sex-specific effects of intranasal OT on social behavior

  • To understand how experience can alter these parameters, which should provide perspective on the context-dependent effects of OT [108] .
  • Familiarity with the environmental context is an important factor influencing the effects of OT on behavior and cognition.
  • For males, OT was anxiolytic in the home cage but not in an unfamiliar environment.
  • These results are consistent with how defeat affects behavior, because defeat affects female but not male behavior in the social interaction test.
  • These results support the hypothesis the mechanisms of susceptibility and resilience to stress-induced psychiatric disorders have important differences between males and females [111] .

7. Conclusions

  • The social defeat model has contributed greatly to the fields of neuroscience and psychiatry by providing insight into the physiological and behavioral effects of social stress across many broad groups of animals.
  • The examination of nonapeptide system responses of California mice to social defeat has revealed that distinct but closely related neural circuits show sex-specific responses.
  • Most of these changes interact with environmental and social contexts to affect behavior.
  • The development of new tools such as a California mouse brain atlas (brainmaps.org) and brain transcriptomes should facilitate further mechanistic studies to complement ongoing innovative work using more conventional mouse and rat models.
  • Together, these research programs have the potential to provide novel insights in to the neurobiological mechanisms that mediate the effects of stress on behavior.

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Citations
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Journal ArticleDOI
TL;DR: This review provides an update on the current state of research of the neurobiological mechanisms of stress resilience, and proposes viewing resilience as a process that requires the integration of multiple central and peripheral systems that will ultimately lead to novel therapeutic options.

152 citations

Journal ArticleDOI
TL;DR: Evidence for neural circuits mediating the effects of OT in appetitive and aversive social contexts is reviewed and it is proposed that distinct but potentially overlapping circuits mediate OT-dependent social approach or social avoidance.

68 citations

Journal ArticleDOI
Jaanus Harro1
TL;DR: It is argued that if anything is wrong with animal models, including those for depression, it is not about the principle of modelling complex human disorder in animals but in the way the tests are selected, conducted and interpreted.
Abstract: Animal models of depression are certainly needed but the question in the title has been raised owing to the controversies in the interpretation of the readout in a number of tests, to the perceived lack of progress in the development of novel treatments and to the expressed doubts in whether animal models can offer anything to make a true breakthrough in understanding the neurobiology of depression and producing novel drugs against depression. Herewith, it is argued that if anything is wrong with animal models, including those for depression, it is not about the principle of modelling complex human disorder in animals but in the way the tests are selected, conducted and interpreted. Further progress in the study of depression and in developing new treatments, will be supported by animal models of depression if these were more critically targeted to drug screening vs. studies of underlying neurobiology, clearly stratified to vulnerability and pathogenetic models, focused on well-defined endophenotypes and validated for each setting while bearing the existing limits to validation in mind. Animal models of depression need not to rely merely on behavioural readouts but increasingly incorporate neurobiological measures as the understanding of depression as human brain disorder advances. Further developments would be fostered by cross-fertilizinga translational approach that is bidirectional, research on humans making more use of neurobiological findings in animals.

57 citations

Journal ArticleDOI
TL;DR: It is shown that female mice subjected to RSD with the male DREADD aggressor developed anxiety-like behavior and social avoidance, and these findings validate that RSD is a relevant model to study stress responses in female mice.
Abstract: Anxiety and mood disorders affect both men and women. The majority of experimental models of stress, however, are completed using only male animals. For repeated social defeat (RSD), a rodent model, this is due to the inherent difficulty in eliciting male aggression toward female mice. To address this limitation, a recent study showed that a DREADD-based activation of the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl) was effective in inducing aggressive behavior in male mice towards females in a social defeat paradigm. Therefore, the goal of this study was to determine if this modified version of RSD in females elicited behavioral, physiological, and immune responses similar to those reported in males. Here, we show that female mice subjected to RSD with the male DREADD aggressor developed anxiety-like behavior and social avoidance. These behavioral alterations coincided with enhanced neuronal and microglial activation in threat-appraisal regions of the brain. Moreover, stressed female mice had an enhanced peripheral immune response characterized by increased myelopoiesis, release of myeloid cells into circulation, and monocyte accumulation in the spleen and brain. These results are consistent with previously reported findings that male mice exposed to RSD exhibited increased fear and threat appraisal responses, enhanced myelopoiesis, myeloid cell release and trafficking, and anxiety-like behavior. These findings validate that RSD is a relevant model to study stress responses in female mice.

44 citations

Journal ArticleDOI
TL;DR: This paper highlights topics covered in a recent Cold Spring Harbor Laboratory meeting charged with examining the status of animal models for mental illness, finding that despite the difficulties inherent with modeling brain disorders in animals, when used judiciously-fully cognizant that models of specific behavioral or biological aspects cannot completely recapitulate the human disorder-animal research is crucial for advancing the understanding of neuropsychiatric disease.

34 citations

References
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Journal ArticleDOI
TL;DR: The regulation by gonadal and adrenal steroids is one of the most remarkable features of the OT system and is, unfortunately, the least understood.
Abstract: The neurohypophysial peptide oxytocin (OT) and OT-like hormones facilitate reproduction in all vertebrates at several levels. The major site of OT gene expression is the magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei. In response to a variety of stimuli such as suckling, parturition, or certain kinds of stress, the processed OT peptide is released from the posterior pituitary into the systemic circulation. Such stimuli also lead to an intranuclear release of OT. Moreover, oxytocinergic neurons display widespread projections throughout the central nervous system. However, OT is also synthesized in peripheral tissues, e.g., uterus, placenta, amnion, corpus luteum, testis, and heart. The OT receptor is a typical class I G protein-coupled receptor that is primarily coupled via Gq proteins to phospholipase C-β. The high-affinity receptor state requires both Mg2+ and cholesterol, which probably function as allosteric modulators. The agonist-binding region of the receptor has bee...

2,691 citations

Journal ArticleDOI
TL;DR: This paper summarizes the current views on coping styles as a useful concept in understanding individual adaptive capacity and vulnerability to stress-related disease and indicates the existence of a proactive and a reactive coping style in feral populations.

2,555 citations

Journal ArticleDOI
TL;DR: Age of onset analysis shows that this sex difference begins in early adolescence and persists through the mid-50s and means that the higher prevalence of 12-month depression among women than men is largely due to women having a higher risk of first onset.

2,113 citations

Journal ArticleDOI
10 Feb 2006-Science
TL;DR: It is shown that viral-mediated, mesolimbic dopamine pathway–specific knockdown of brain-derived neurotrophic factor is required for the development of experience-dependent social aversion in mice experiencing repeated aggression.
Abstract: Mice experiencing repeated aggression develop a long-lasting aversion to social contact, which can be normalized by chronic, but not acute, administration of antidepressant. Using viral-mediated, mesolimbic dopamine pathway-specific knockdown of brain-derived neurotrophic factor (BDNF), we showed that BDNF is required for the development of this experience-dependent social aversion. Gene profiling in the nucleus accumbens indicates that local knockdown of BDNF obliterates most of the effects of repeated aggression on gene expression within this circuit, with similar effects being produced by chronic treatment with antidepressant. These results establish an essential role for BDNF in mediating long-term neural and behavioral plasticity in response to aversive social experiences.

1,873 citations


"Sex differences in the effects of s..." refers background in this paper

  • ...An important aspect of the behavioral changes induced by defeat stress is that they can be reversed by chronic but not acute administration of antidepressant treatments [24,25]....

    [...]

  • ...Interestingly, the social withdrawal response to social defeat is evolutionarily conserved and has been reported in one form or another in birds [29], rodents [25,30,31], tree shrews [32,33] and primates [34]....

    [...]

  • ...Under these conditions, ten days of defeat are usually performed to generate behavioral responses such anhedonia [23,24] and social avoidance [23,25,26]....

    [...]

Journal ArticleDOI
19 Oct 2007-Cell
TL;DR: It is shown that molecular recapitulations of three prototypical adaptations associated with the unsusceptible phenotype are each sufficient to promote resistant behavior and validate a multidisciplinary approach to examine the neurobiological mechanisms of variations in stress resistance.

1,863 citations


"Sex differences in the effects of s..." refers background in this paper

  • ...Under these conditions, ten days of defeat are usually performed to generate behavioral responses such anhedonia [23,24] and social avoidance [23,25,26]....

    [...]

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Frequently Asked Questions (1)
Q1. What are the contributions in "Sex differences in the effects of social defeat on brain and behavior in the california mouse: insights from a monogamous rodent" ?

This allows defeat to be studied in both sexes. This suggests that inhibition of OT activity could reduce the impact of stress on behavior in females.