Review Article | Published:

Stress and the social brain: behavioural effects and neurobiological mechanisms

Nature Reviews Neuroscience volume 16, pages 290304 (2015) | Download Citation

Abstract

Stress often affects our social lives. When undergoing high-level or persistent stress, individuals frequently retract from social interactions and become irritable and hostile. Predisposition to antisocial behaviours — including social detachment and violence — is also modulated by early life adversity; however, the effects of early life stress depend on the timing of exposure and genetic factors. Research in animals and humans has revealed some of the structural, functional and molecular changes in the brain that underlie the effects of stress on social behaviour. Findings in this emerging field will have implications both for the clinic and for society.

Key points

  • The effects of stress on social behaviour depend on the timing, the duration and the type of stress exposure.

  • Social withdrawal and aggression are a typical consequence of experiencing, or having experienced, high and persistent stress levels.

  • From a developmental perspective, early stressors impose an increasing pattern of dysfunctional social behaviour, progressing from asociality (elicited by prenatal stressors) to hostility (by postnatal stressors) and to antisociality (by stressors during juvenility).

  • In humans, stress can also elicit prosocial behaviours, particularly towards ingroup members.

  • Individual differences in the effect of stress in social behaviours are partly explained by certain gene polymorphisms (for example, the monoamine oxidase A (MAOA) gene).

  • Glucocorticoids mediate, at least in part, the effects of stress on social behaviours.

  • Monoamines, social neuropeptides, the corticotropin-releasing hormone (CRH) system, cell adhesion molecules and epigenetic mechanisms are implicated in the translation of stress effects in social behaviours.

  • Positive social interactions can protect individuals from the adverse effects of stress.

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References

  1. 1.

    , & Stress and the brain: from adaptation to disease. Nature Rev. Neurosci. 6, 463–475 (2005).

  2. 2.

    & The neuro-symphony of stress. Nature Rev. Neurosci. 10, 459–466 (2009).

  3. 3.

    & Neural regulation of endocrine and autonomic stress responses. Nature Rev. Neurosci. 10, 397–409 (2009).

  4. 4.

    , , & Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nature Rev. Neurosci. 10, 434–445 (2009). This is an excellent account of the effects of stress suffered across the lifespan and its impact on brain development, function and the emergence of psychiatric vulnerabilities. In some respects, this is the 'non-social counterpart' of this Review.

  5. 5.

    The ever-changing brain: cellular and molecular mechanisms for the effects of stressful experiences. Dev. Neurobiol. 72, 878–890 (2012).

  6. 6.

    Bodily Changes in Pain, Hunger, Fear and Rage: an Account of Recent Researches into the Function of Emotional Excitement. (D. Appleton and Co., 1915).

  7. 7.

    , , & Task Force for Pediatric Emergency Mass Critical Care. The reality of pediatric emergency mass critical care in the developing world. Pediatr. Crit. Care Med. 12, S169–S179 (2011).

  8. 8.

    Why is violence more common where inequality is greater? Ann. NY Acad. Sci. 1036, 1–12 (2004).

  9. 9.

    & The neurobiology of depression: inroads to treatment and new drug discovery. J. Clin. Psychiatry 66 (Suppl. 7), 5–13 (2005).

  10. 10.

    & The social brain in psychiatric and neurological disorders. Trends Cogn. Sci. 16, 559–572 (2012).

  11. 11.

    & Aggression escalated by social instigation or by discontinuation of reinforcement (“frustration”) in mice: inhibition by anpirtoline: a 5HT1B receptor agonist. Neuropsychopharmacology 27, 171–181 (2002).

  12. 12.

    et al. Behavioral characterization of escalated aggression induced by GABAB receptor activation in the dorsal raphe nucleus. Psychopharmacol. 224, 155–166 (2012).

  13. 13.

    et al. Impaired hippocampal neuroligin-2 function by chronic stress or synthetic peptide treatment is linked to social deficits and increased aggression. Neuropsychopharmacology 39, 1148–1158 (2014).

  14. 14.

    et al. Role for MMP9 in stress-induced downregulation of nectin-3 in hippocampal CA1 and associated behavioural alterations. Nature Commun. 5, 4995 (2014). This study implicates a new molecular cascade in the hippocampus that mediates the effects of chronic stress on sociability and cognition.

  15. 15.

    , , & Acute and chronic restraint stress alter the incidence of social conflict in male rats. Horm. Behav. 43, 205–213 (2003).

  16. 16.

    et al. Personality traits in rats predict vulnerability and resilience to developing stress-induced depression-like behaviors, HPA axis hyper-reactivity and brain changes in pERK1/2 activity. Psychoneuroendocrinology 37, 1209–1223 (2012).

  17. 17.

    et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311, 864–868 (2006).

  18. 18.

    et al. Isolation changes the incentive value of sucrose and social behaviour in juvenile and adult rats. Behav. Brain Res. 106, 133–142 (1999).

  19. 19.

    , , & Chronic variable stress in fathers alters paternal and social behavior but not pup development in the biparental California mouse (Peromyscus californicus). Horm. Behav. 64, 799–811 (2013).

  20. 20.

    , , & Agonistic behavior and unpredictable chronic mild stress in mice. Behav. Genet. 33, 513–519 (2003).

  21. 21.

    , & Aggression is suppressed by acute stress but induced by chronic stress: immobilization effects on aggression, hormones, and cortical 5HT1B/ striatal dopamine D2 receptor density. Cogn. Affect Behav. Neurosci. 12, 446–459 (2012).

  22. 22.

    The pharmacology of isolation-induced aggressive behavior in mice. Curr. Dev. Psychopharmacol. 5, 1–27 (1979).

  23. 23.

    , , , & Chronic stress in dogs subjected to social and spatial restriction. I. Behavioral responses. Physiol. Behav. 66, 233–242 (1999).

  24. 24.

    et al. Visible burrow system as a model of chronic social stress — behavioral and neuroendocrine correlates. Psychoneuroendocrinology 20, 117–134 (1995).

  25. 25.

    , & Modulation of aggressive behaviour by fighting experience: mechanisms and contest outcomes. Biol. Rev. Camb. Philos. Soc. 81, 33–74 (2006).

  26. 26.

    et al. Conditioned defeat in male and female Syrian hamsters. Horm. Behav. 44, 293–299 (2003).

  27. 27.

    , , & Conditioned defeat in the Syrian golden hamster (Mesocricetus auratus). Behav. Neural Biol. 60, 93–102 (1993).

  28. 28.

    & Effects of chronic social stress during lactation on maternal behavior and growth in rats. Stress 14, 677–684 (2011).

  29. 29.

    , & Excessive aggression as model of violence: a critical evaluation of current preclinical methods. Psychopharmacology 226, 445–458 (2013). This study updates the criteria by which antisocial features can be differentiated in animals, presents in detail three such models and evaluates their translational value for understanding human violence.

  30. 30.

    et al. Prenatal stress produces social behavior deficits and alters the number of oxytocin and vasopressin neurons in adult rats. Neurochem. Res. 38, 1479–1489 (2013).

  31. 31.

    , , , & Influence of early stress on social abilities and serotonergic functions across generations in mice. PLoS ONE 6, e21842 (2011). This is the first study to show that early life stress can change social behaviour in individuals across generations.

  32. 32.

    et al. Early social deprivation impairs pair bonding and alters serum corticosterone and the NAcc dopamine system in mandarin voles. Psychoneuroendocrinology 38, 3128–3138 (2013).

  33. 33.

    , & Nocturnal hyperactivity, increased social novelty preference and delayed extinction of fear responses in post-weaning socially isolated mice. Brain Res. Bull. 85, 354–362 (2011).

  34. 34.

    , & Male Wistar rats are more susceptible to lasting social anxiety than wild-type Groningen rats following social defeat stress during adolescence. Behav. Processes 88, 76–80 (2011).

  35. 35.

    et al. Peripuberty stress leads to abnormal aggression, altered amygdala and orbitofrontal reactivity and increased prefrontal MAOA gene expression. Transl. Psychiatry 3, e216 (2013). This study presents strong evidence for a role of neurobiological mechanisms in the link from early adversity to antisocial behaviours, and shows that animal models recapitulate changes in brain function that resemble those of individuals with borderline personality disorder.

  36. 36.

    et al. Neonatal tactile stimulation alleviates the negative effects of neonatal isolation on novel object recognition, sociability and neuroendocrine levels in male adult mandarin voles (Microtus mandarinus). Physiol. Behav. 112–113, 14–22 (2013).

  37. 37.

    , , , & Effects of neonatal paternal deprivation or early deprivation on anxiety and social behaviors of the adults in mandarin voles. Behav. Processes 82, 271–278 (2009).

  38. 38.

    , , , & Post-weaning environmental enrichment alters affective responses and interacts with behavioral testing to alter nNOS immunoreactivity. Pharmacol. Biochem. Behav. 100, 25–32 (2011).

  39. 39.

    , , & Behavioural and neuroendocrine adaptations to repeated stress during puberty in male golden hamsters. J. Neuroendocrinol. 16, 767–775 (2004).

  40. 40.

    , , & Effects of isolation-rearing on the development of social behaviors in male Mongolian gerbils (Meriones unguiculatus). Physiol. Behav. 94, 491–500 (2008).

  41. 41.

    , , & Effects of prenatal stress on anxiety and social interactions in adult rats. Brain Res. Dev. Brain Res. 160, 265–274 (2005).

  42. 42.

    , & Opposite effects of maternal separation on intermale and maternal aggression in C57BL/6 mice: link to hypothalamic vasopressin and oxytocin immunoreactivity. Psychoneuroendocrinology 32, 437–450 (2007).

  43. 43.

    , , , & Effects of early life stress on adult male aggression and hypothalamic vasopressin and serotonin. Eur. J. Neurosci. 24, 1711–1720 (2006). This study was the first to show that early life adversity in rodents can lead to increased aggression, and identified changes in social neuropeptides and serotonin as potential mediators.

  44. 44.

    , , & Early social deprivation and the ontogeny of unrestricted social behavior in the laboratory rat. Dev. Psychobiol. 15, 47–59 (1982).

  45. 45.

    & Prepubertal social subjugation and anabolic androgenic steroid-induced aggression in male rats. J. Neuroendocrinol. 20, 997–1005 (2008).

  46. 46.

    , & Adolescent social instability stress increases aggression in a food competition task in adult male Long-Evans rats. Dev. Psychobiol. 56, 1575–1588 (2014).

  47. 47.

    , , , & Early social deprivation induces disturbed social communication and violent aggression in adulthood. Behav. Neurosci. 122, 849–854 (2008).

  48. 48.

    et al. Evidence for biological roots in the transgenerational transmission of intimate partner violence. Transl. Psychiatry 2, e106 (2012).

  49. 49.

    , & Behavioral and neurobiological consequences of social subjugation during puberty in golden hamsters. J. Neurosci. 18, 2667–2672 (1998).

  50. 50.

    , , & Repeated exposure to social stress alters the development of agonistic behavior in male golden hamsters. Hormones Behav. 43, 229–236 (2003).

  51. 51.

    , & The consequences of adolescent chronic unpredictable stress exposure on brain and behavior. Neuroscience 249, 232–241 (2013).

  52. 52.

    & Comparison of two rodent models of maternal separation on juvenile social behavior. Front. Psychiatry 2, 39 (2011).

  53. 53.

    , , , & Social competence is reduced in socially deprived rhesus monkeys (Macaca mulatta). J. Comp. Psychol. 122, 62–67 (2008).

  54. 54.

    , & Early life events and their consequences for later disease: A life history and evolutionary perspective. Am. J. Hum. Biol. 19, 1–19 (2007).

  55. 55.

    & The effects of early life stress on the epigenome: From the womb to adulthood and even before. Exp. Neurol. (2014).

  56. 56.

    , , & Transgenerational effects of social stress on social behavior, corticosterone, oxytocin, and prolactin in rats. Horm. Behav. 65, 386–393 (2014).

  57. 57.

    , , & Early life epigenetic programming and transmission of stress-induced traits in mammals: how and when can environmental factors influence traits and their transgenerational inheritance? Bioessays 36, 491–502 (2014).

  58. 58.

    , & Corticosteroid hormones in the central stress response: Quick-and-slow. Front. Neuroendocrinol. 29, 268–272 (2008).

  59. 59.

    , & The effects of non-genomic glucocorticoid mechanisms on bodily functions and the central neural system. A critical evaluation of findings. Front. Neuroendocrinol. 29, 273–291 (2008).

  60. 60.

    , , & Mineralocorticoid and glucocorticoid receptors at the neuronal membrane, regulators of nongenomic corticosteroid signalling. Mol. Cell Endocrinol. 350, 299–309 (2012).

  61. 61.

    & Non-genomic effects of glucocorticoids in the neural system - Evidence, mechanisms and implications. Progress Neurobiol. 65, 367–390 (2001).

  62. 62.

    et al. Early environmental regulation of forebrain glucocorticoid receptor gene expression: Implications for adrenocortical responses to stress. Dev. Neurosci. 18, 49–72 (1996).

  63. 63.

    & Prenatal stress, glucocorticoids and the programming of the brain. J. Neuroendocrinol. 13, 113–128 (2001).

  64. 64.

    , & Early deprivation, but not maternal separation, attenuates rise in corticosterone levels after exposure to a novel environment in both juvenile and adult female rats. Behav. Brain Res. 175, 383–391 (2006). This study is important because it showed for the first time that apparently minor technical details of stress exposure have substantial effects on the long-term consequences of stressors. In particular, the authors directly compared the maternal separation and early deprivation models (neonatal separation from the dam and from both the dam and cage-mates, respectively).

  65. 65.

    , , , & Post-weaning social isolation induces abnormal forms of aggression in conjunction with increased glucocorticoid and autonomic stress responses. Hormones Behav. 60, 28–36 (2011).

  66. 66.

    & Neonatal corticosterone treatment increases submissiveness in adulthood in mice. Physiol. Behav. 19, 163–165 (1977).

  67. 67.

    , & Increased corticosterone in peripubertal rats leads to long-lasting alterations in social exploration and aggression. Front Behav. Neurosci. 7, 26 (2013).

  68. 68.

    , , & Social deficits induced by peripubertal stress in rats are reversed by resveratrol. J. Psychiatr. Res. 57, 157–164 (2014).

  69. 69.

    , , & Peripubertal stress-induced behavioral changes are associated with altered expression of genes involved in excitation and inhibition in the amygdala. Transl. Psychiatry 4, e410 (2014).

  70. 70.

    et al. Long-term behavioral programming induced by peripuberty stress in rats is accompanied by GABAergic-related alterations in the amygdala. PLoS ONE 9, e94666 (2014).

  71. 71.

    , & Genomic and non-genomic effects of glucocorticoids on aggressive behavior in male rats. Psychoneuroendocrinology 29, 618–635 (2004).

  72. 72.

    & Normal and abnormal aggression: human disorders and novel laboratory models. Neurosci. Biobehavioral Rev. 30, 292–303 (2006).

  73. 73.

    , & Corticosterone — an anxiogenic or an anxiolytic agent? J. Pharm. Pharmacol. 31, 300–305 (1979).

  74. 74.

    , & Deviant forms of aggression in glucocorticoid hyporeactive rats: a model for 'pathological' aggression? J. Neuroendocrinol. 13, 102–107 (2001). This was the first study to demonstrate that the inhibition of glucocorticoid production induces qualitative changes in aggressive behaviour, to propose that these changes were abnormal and to model aspects of human violence. It was also the first to propose criteria for differentiating normal and abnormal forms of attack in rodents.

  75. 75.

    et al. Chronic stress triggers social aversion via glucocorticoid receptor in dopaminoceptive neurons. Science 339, 332–335 (2013).

  76. 76.

    et al. Interaction between FKBP5 and childhood trauma and risk of aggressive behavior. Arch. Gen. Psychiatry 69, 62–70 (2012).

  77. 77.

    et al. Moderating role of FKBP5 genotype in the impact of childhood adversity on cortisol stress response during adulthood. Eur. Neuropsychopharmacol 24, 837–845 (2014).

  78. 78.

    et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nature Neurosci. 16, 33–41 (2013).

  79. 79.

    & How the brain processes social information: searching for the social brain. Annu. Rev. Neurosci. 27, 697–722 (2004). This is the first review to explicitly focus on the concept of the social brain. It analyses socially relevant neural systems from animals to humans, and encompasses all aspects of social behaviour from perception to action.

  80. 80.

    , , & Advancing the discovery of medications for autism spectrum disorder using new technologies to reveal social brain circuitry in rodents. Psychopharmacology 231, 1147–1165 (2014).

  81. 81.

    , , & Neuropharmacology of brain-stimulation-evoked aggression. Neurosci. Biobehav. Rev. 23, 359–389 (1999).

  82. 82.

    , , , & The neural signature of escalating frustration in humans. Cortex 54, 165–178 (2014).

  83. 83.

    , , & Punishing unfairness: rewarding or the organization of a reactively aggressive response? Hum. Brain Mapp. 35, 2137–2147 (2014).

  84. 84.

    & Neurocriminology: implications for the punishment, prediction and prevention of criminal behaviour. Nature Rev. Neurosci. 15, 54–63 (2014).

  85. 85.

    et al. Increased cortical thickness in a frontoparietal network in social anxiety disorder. Hum. Brain Mapp. 35, 2966–2977 (2014).

  86. 86.

    Dysfunctions of medial and lateral orbitofrontal cortex in psychopathy. Ann. NY Acad. Sci. 1121, 461–479 (2007).

  87. 87.

    & Epigenetic influence of stress and the social environment. ILAR J. 53, 279–288 (2012).

  88. 88.

    , & Mapping functional brain development: building a social brain through interactive specialization. Dev. Psychol. 45, 151–159 (2009).

  89. 89.

    Allostasis and allostatic load: implications for neuropsychopharmacology. Neuropsychopharmacology 22, 108–124 (2000).

  90. 90.

    , , , & High pregnancy anxiety during mid-gestation is associated with decreased gray matter density in 6-9-year-old children. Psychoneuroendocrinology 35, 141–153 (2010).

  91. 91.

    & Neurobehavioral risk is associated with gestational exposure to stress hormones. Expert Rev. Endocrinol. Metab. 7, 445–459 (2012).

  92. 92.

    et al. Effects of repeated maternal stress on FOS expression in the hypothalamic paraventricular nucleus of fetal rats. Neuroscience 134, 387–395 (2005).

  93. 93.

    et al. The effects of prenatal stress on the development of hypothalamic paraventricular neurons in fetal rats. Neuroscience 92, 1079–1088 (1999).

  94. 94.

    , & Prenatal bystander stress induces neuroanatomical changes in the prefrontal cortex and hippocampus of developing rat offspring. Brain Res. 1412, 55–62 (2011).

  95. 95.

    et al. Perinatal dexamethasone-induced alterations in apoptosis within the hippocampus and paraventricular nucleus of the hypothalamus are influenced by age and sex. J. Neurosci. Res. 90, 1403–1412 (2012).

  96. 96.

    Stress, sex, and neural adaptation to a changing environment: mechanisms of neuronal remodeling. Ann. NY Acad. Sci. 1204, E38–E59 (2010).

  97. 97.

    Stress and plasticity in the limbic system. Neurochem. Res. 28, 1735–1742 (2003).

  98. 98.

    Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration. J. Neurobiol. 49, 245–253 (2001).

  99. 99.

    et al. Maternal deprivation induces deficits in temporal memory and cognitive flexibility and exaggerates synaptic plasticity in the rat medial prefrontal cortex. Neurobiol. Learn. Mem. 98, 207–214 (2012).

  100. 100.

    , & Early life adversity alters the developmental profiles of addiction-related prefrontal cortex circuitry. Brain Sci. 3, 143–158 (2013).

  101. 101.

    et al. Early-life stress affects the structural and functional plasticity of the medial prefrontal cortex in adolescent rats. Eur. J. Neurosci. 38, 2089–2107 (2013).

  102. 102.

    , & Post-weaning social isolation of male rats reduces the volume of the medial amygdala and leads to deficits in adult sexual behavior. Behav. Brain Res. 117, 107–113 (2000).

  103. 103.

    , , , & Effects of social isolation rearing on the limbic brain: a combined behavioral and magnetic resonance imaging volumetry study in rats. Neuroscience 159, 21–30 (2009).

  104. 104.

    et al. Chronic social stress in puberty alters appetitive male sexual behavior and neural metabolic activity. Horm. Behav. 66, 220–227 (2014).

  105. 105.

    , , & Adolescent social stress does not necessarily lead to a compromised adaptive capacity during adulthood: a study on the consequences of social stress in rats. Neuroscience 249, 258–270 (2013).

  106. 106.

    , & Social experience induces sex-specific fos expression in the amygdala of the juvenile rat. Horm. Behav. 62, 154–161 (2012).

  107. 107.

    , , & Neonatal maternal separation upregulates protein signalling for cell survival in rat hypothalamus. Stress 17, 275–284 (2014). Most studies focus on brain dysfunctions that develop in the prefrontal cortex and amygdala, whereas this interesting report reveals that early stressors promote cell survival, suppress cell death and increase cell density in the hypothalamus, an important locus of control of aggressiveness. It suggests that disrupted sociality can not only ensue from deficits in brain circuits that control cognitive and emotional functions but also from structural gains in areas that are involved in the execution of behavioural acts.

  108. 108.

    & Prenatal nicotine and maternal deprivation stress deregulate the development of CA1, CA3, and dentate gyrus neurons in hippocampus of infant rats. PLoS ONE 8, e65517 (2013).

  109. 109.

    The neurobiology of abnormal manifestations of aggression—a review of hypothalamic mechanisms in cats, rodents, and humans. Brain Res. Bull. 93, 97–109 (2013).

  110. 110.

    , , , & Sexually dimorphic effects of maternal separation stress on corticotrophin-releasing factor and vasopressin systems in the adult rat brain. Int. J. Dev. Neurosci. 26, 259–268 (2008).

  111. 111.

    , & Paucity of cfos expression in the medial preoptic area of prenatally stressed male rats following exposure to sexually receptive females. Brain Res. Bull. 37, 363–368 (1995).

  112. 112.

    et al. Mesolimbic dopaminergic activity responding to acute stress is blunted in adolescent rats that experienced neonatal maternal separation. Neuroscience 171, 144–152 (2010).

  113. 113.

    , & cfos expression, behavioural, endocrine and autonomic responses to acute social stress in male rats after chronic restraint: modulation by serotonin. Neuroscience 95, 453–463 (2000).

  114. 114.

    , , & Differential expression of cfos mRNA within neurocircuits of male hamsters exposed to acute or chronic defeat. J. Neuroendocrinol. 11, 547–559 (1999).

  115. 115.

    , & Adaptation in patterns of cfos expression in the brain associated with exposure to either single or repeated social stress in male rats. Eur. J. Neurosci. 10, 20–33 (1998).

  116. 116.

    et al. Early life stress modulates amygdala-prefrontal functional connectivity: implications for oxytocin effects. Hum. Brain Mapp. 35, 5328–5339 (2014).

  117. 117.

    et al. Neural mechanisms of genetic risk for impulsivity and violence in humans. Proc. Natl Acad. Sci. USA 103, 6269–6274 (2006).

  118. 118.

    et al. 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nature Neurosci. 8, 828–834 (2005).

  119. 119.

    et al. The neural background of hyper-emotional aggression induced by post-weaning social isolation. Behav. Brain Res. 233, 120–129 (2012).

  120. 120.

    et al. Aberrant social and cerebral responding in a competitive reaction time paradigm in criminal psychopaths. Neuroimage 49, 3365–3372 (2010).

  121. 121.

    et al. Brain mechanisms involved in predatory aggression are activated in a laboratory model of violent intra-specific aggression. Eur. J. Neurosci. 32, 1744–1753 (2010).

  122. 122.

    et al. Neural mechanisms of predatory aggression in rats — implications for abnormal intraspecific aggression. Behav. Brain Res. 283, 108–115 (2015).

  123. 123.

    , , , & Subtyping aggression in children and adolescents. J. Neuropsychiatry Clin. Neurosci. 2, 189–192 (1990).

  124. 124.

    et al. Serotonin transporter expression is predicted by early life stress and is associated with disinhibited behavior in infant rhesus macaques. Genes Brain Behav. 9, 45–52 (2010).

  125. 125.

    et al. Cerebrospinal fluid monoamine and adrenal correlates of aggression in free-ranging rhesus monkeys. Arch. Gen. Psychiatry 49, 436–441 (1992).

  126. 126.

    et al. Mesolimbic dopamine neurons in the brain reward circuit mediate susceptibility to social defeat and antidepressant action. J. Neurosci. 30, 16453–16458 (2010).

  127. 127.

    & The brain reward circuitry in mood disorders. Nature Rev. Neurosci. 14, 609–625 (2013).

  128. 128.

    , , & Aggression and defeat: persistent effects on cocaine self-administration and gene expression in peptidergic and aminergic mesocorticolimbic circuits. Neurosci. Biobehav Rev. 27, 787–802 (2004).

  129. 129.

    et al. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature 493, 532–536 (2013).

  130. 130.

    et al. Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress. Biol. Psychiatry 77 212–222 (2015).

  131. 131.

    Stress responses and the mesolimbic dopamine system: social contexts and sex differences. Horm. Behav. 60, 457–469 (2011).

  132. 132.

    , , , & Sex differences in effects of dopamine D1 receptors on social withdrawal. Neuropharmacology 77, 208–216 (2014).

  133. 133.

    & The mesoaccumbens dopamine in coping with stress. Neurosci. Biobehav Rev. 36, 79–89 (2012).

  134. 134.

    et al. Repeated exposure to social stress has long-term effects on indirect markers of dopaminergic activity in brain regions associated with motivated behavior. Neuroscience 124, 449–457 (2004).

  135. 135.

    et al. Role of genotype in the cycle of violence in maltreated children. Science 297, 851–854 (2002). A landmark study showing that early life stress interacts with specific gene polymorphisms (in this case the MAOA gene), increasing the risk of developing violent behaviours.

  136. 136.

    et al. Gene-environment interactions and response to social intrusion in male and female rhesus macaques. Biol. Psychiatry 67, 323–330 (2010).

  137. 137.

    et al. Coaction of stress and serotonin transporter genotype in predicting aggression at the transition to adulthood. J. Clin. Child Adolesc. Psychol. 41, 53–63 (2012).

  138. 138.

    , , & Gender specific gene-environment interactions on laboratory-assessed aggression. Biol. Psychol. 71, 33–41 (2006).

  139. 139.

    , , , & The D-2 dopamine receptor (DRD2) gene is associated with comorbid depression, anxiety and social dysfunction in untreated veterans with post-traumatic stress disorder. Eur. Psychiatry 21, 180–185 (2006).

  140. 140.

    et al. Mothers' prenatal stress and their children's antisocial outcomes — a moderating role for the dopamine receptor D4 (DRD4) gene. J. Child Psychol. Psychiatry 55, 69–76 (2014).

  141. 141.

    et al. Interaction between prenatal stress and dopamine D4 receptor genotype in predicting aggression and cortisol levels in young adults. Psychopharmacology 231, 3089–3097 (2014).

  142. 142.

    & The role of corticotropin-releasing hormone in the pathophysiology of depression: therapeutic implications. Curr. Top. Med. Chem. 11, 609–617 (2011).

  143. 143.

    , , , & Neurobiological characteristics of rhesus macaque abusive mothers and their relation to social and maternal behavior. Neurosci. Biobehav Rev. 29, 51–57 (2005).

  144. 144.

    , & CRHR1 links peripuberty stress with deficits in social and stress-coping behaviors. J. Psychiatr. Res. 53, 1–7 (2014).

  145. 145.

    , , & Dysfunctional nurturing behavior in rat dams with limited access to nesting material: a clinically relevant model for early-life stress. Neuroscience 154, 1132–1142 (2008).

  146. 146.

    et al. Chronic stress-induced alterations in amygdala responsiveness and behavior—modulation by trait anxiety and corticotropin-releasing factor systems. Eur. J. Neurosci. 28, 1836–1848 (2008).

  147. 147.

    et al. Stress differentially modulates mRNA expression for corticotrophin-releasing hormone receptors in hypothalamus, hippocampus and pituitary of prairie voles. Neuropeptides 43, 113–123 (2009).

  148. 148.

    et al. Corticotropin-releasing factor antagonist blocks stress-induced fighting in rats. Regul. Pept. 18, 37–42 (1987).

  149. 149.

    & Corticotropin-releasing factor receptors in the dorsal raphe nucleus modulate social behavior in Syrian hamsters. Psychopharmacol. (Berl.) 194, 297–307 (2007).

  150. 150.

    , , , & The CRF system mediates increased passive stress-coping behavior following the loss of a bonded partner in a monogamous rodent. Neuropsychopharmacology 34, 1406–1415 (2009).

  151. 151.

    & The CRF system and social behavior: a review. Front. Neurosci. 7, 92 (2013).

  152. 152.

    & Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci. 35, 649–659 (2012).

  153. 153.

    , , & Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine. Nature Rev. Neurosci. 12, 524–538 (2011).

  154. 154.

    et al. Neonatal paternal deprivation impairs social recognition and alters levels of oxytocin and estrogen receptor alpha mRNA expression in the MeA and NAcc, and serum oxytocin in mandarin voles. Horm. Behav. 65, 57–65 (2014).

  155. 155.

    et al. The neuropeptide oxytocin facilitates pro-social behavior and prevents social avoidance in rats and mice. Neuropsychopharmacology 36, 2159–2168 (2011).

  156. 156.

    , , & Evidence for a role of oxytocin receptors in the long-term establishment of dominance hierarchies. Neuropsychopharmacology 36, 2349–2356 (2011).

  157. 157.

    & Stress amplifies memory for social hierarchy. Front. Neurosci. 1, 175–184 (2007).

  158. 158.

    , , & Oxytocin mediates rodent social memory within the lateral septum and the medial amygdala depending on the relevance of the social stimulus: male juvenile versus female adult conspecifics. Psychoneuroendocrinology 38, 916–926 (2013).

  159. 159.

    , , , & Prenatal stress generates deficits in rat social behavior: Reversal by oxytocin. Brain Res. 1156, 152–167 (2007).

  160. 160.

    Toward understanding how early-life social experiences alter oxytocin- and vasopressin-regulated social behaviors. Horm. Behav. 61, 304–312 (2012).

  161. 161.

    , , , & Early life stress impairs social recognition due to a blunted response of vasopressin release within the septum of adult male rats. Psychoneuroendocrinology 36, 843–853 (2011).

  162. 162.

    et al. Lower CSF oxytocin concentrations in women with a history of childhood abuse. Mol. Psychiatry 14, 954–958 (2009).

  163. 163.

    , , & Reduced plasma oxytocin levels in female patients with borderline personality disorder. Horm. Behav. 63, 424–429 (2013).

  164. 164.

    , , , & Social stress and the oxytocin receptor gene interact to predict antisocial behavior in an atrisk cohort. Dev. Psychopathol., 1–10 (2014).

  165. 165.

    , , & Interindividual variability in stress susceptibility: a role for epigenetic mechanisms in PTSD. Front. Psychiatry 4, 60 (2013).

  166. 166.

    et al. Epigenetic programming by maternal behavior. Nature Neurosci. 7, 847–854 (2004).

  167. 167.

    et al. Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression. Nature Med. 19, 337–344 (2013).

  168. 168.

    & Gene-environment interactions and intermediate phenotypes: early trauma and depression. Front. Endocrinol. (Lausanne) 5, 14 (2014).

  169. 169.

    Stress and cognition. WIREs Cogn. Sci. 4, 245–261 (2013).

  170. 170.

    The Better Angels of our Nature (Viking, 2011).

  171. 171.

    , , , & Why is working memory related to intelligence? Different contributions from storage and processing. Memory 22, 426–441 (2014).

  172. 172.

    & Inclusive altruism born of suffering: the relationship between adversity and prosocial attitudes and behavior toward disadvantaged outgroups. Am. J. Orthopsychiatry 81, 307–315 (2011).

  173. 173.

    , & Empathy in adults with clinical or subclinical depressive symptoms. J. Affect. Disord. 150, 1–16 (2013).

  174. 174.

    , , & Are empathic abilities impaired in posttraumatic stress disorder? Psychol. Rep. 106, 832–844 (2010).

  175. 175.

    et al. Social cognition disorders in military police officers affected by posttraumatic stress disorder after the attack of An-Nasiriyah in Iraq 2006. Psychiatry Res. 198, 248–252 (2012).

  176. 176.

    et al. Theory of mind performance in women with posttraumatic stress disorder related to childhood abuse. Acta Psychiatr. Scand. 129, 193–201 (2014).

  177. 177.

    The influence of social hierarchy on primate health. Science 308, 648–652 (2005). A pioneering work linking status in social hierarchy with different physiological outcomes.

  178. 178.

    , & Is the curve relating temperature to aggression linear or curvilinear? Assaults and temperature in Minneapolis reexamined. J. Pers. Soc.Psychol. 89, 62–66 (2005).

  179. 179.

    & Gun use, attitudes toward violence, and aggression among combat veterans with chronic posttraumatic stress disorder. J. Nerv. Mental Dis. 189, 317–320 (2001).

  180. 180.

    , & Relationship of anger and anger attacks with depression: a brief review. Eur. Arch. Psychiatry Clin. Neurosci. 255, 215–222 (2005).

  181. 181.

    , & Antecedents, concomitants and consequences of anger attacks in depression. Psychiatry Res. 153, 39–45 (2007).

  182. 182.

    , , , & Childhood maltreatment and social anxiety disorder: implications for symptom severity and response to pharmacotherapy. Depress. Anxiety 29, 131–138 (2012).

  183. 183.

    , & The relationship between memories for childhood teasing and anxiety and depression in adulthood. J. Anxiety Disord. 16, 149–164 (2002).

  184. 184.

    , , & Peer victimization and social anxiety in adolescence: A prospective study. Aggressive Behav. 31, 437–452 (2005).

  185. 185.

    , & Self-portrayal concerns mediate the relationship between recalled teasing and social anxiety symptoms in adults with anxiety disorders. J. Anxiety Disord. 27, 456–460 (2013).

  186. 186.

    et al. MAOA, maltreatment, and gene-environment interaction predicting children's mental health: new evidence and a meta-analysis. Mol. Psychiatry 11, 903–913 (2006).

  187. 187.

    & Emotional and behavioral sequelae of childhood maltreatment. Curr. Opin. Pediatr. 22, 610–615 (2010).

  188. 188.

    , & The mediating effect of parental neglect on adolescent and young adult anti-sociality: a longitudinal study of twins and their parents. Behav. Genet. 40, 425–437 (2010).

  189. 189.

    & The intergenerational transmission of externalizing behaviors in adult participants: the mediating role of childhood abuse. J. Consult Clin. Psychol. 73, 1135–1145 (2005).

  190. 190.

    , , & Childhood family violence and perpetration and victimization of intimate partner violence: findings from a national population-based study of couples. Ann. Epidemiol. 19, 25–32 (2009).

  191. 191.

    & Altruism born of suffering: the roots of caring and helping after victimization and other trauma. Am. J. Orthopsychiatry 78, 267–280 (2008).

  192. 192.

    , , , & The social dimension of stress reactivity acute stress increases prosocial behavior in humans. Psychol. Sci. 23, 651–660 (2012).

  193. 193.

    et al. Time-dependent changes in altruistic punishment following stress. Psychoneuroendocrinology 38, 1467–1475 (2013).

  194. 194.

    & Conflict, sticks and carrots: war increases prosocial punishments and rewards. Proc. Biol. Sci. 279, 219–223 (2012).

  195. 195.

    , , & War's enduring effects on the development of egalitarian motivations and ingroup biases. Psychol. Sci. 25, 47–57 (2014).

  196. 196.

    & Neurobiology of early life stress: rodent studies. Semin. Clin. Neuropsychiatry 7, 89–95 (2002).

  197. 197.

    & Epigenetic programming of the stress response in male and female rats by prenatal restraint stress. Brain Res. Rev. 57, 571–585 (2008).

  198. 198.

    et al. Early deprivation leads to altered behavioural, autonomic and endocrine responses to environmental challenge in adult Fischer rats. Eur. J. Neurosci. 24, 2879–2893 (2006).

  199. 199.

    Stress, cognitive impairment and cell adhesion molecules. Nature Rev. Neurosci. 5, 917–930 (2004).

  200. 200.

    & The role of NCAM in auditory fear conditioning and its modulation by stress: a focus on the amygdala. Genes. Brain Behav. 9, 353–364 (2010).

  201. 201.

    et al. The interplay of conditional NCAM-knockout and chronic unpredictable stress leads to increased aggression in mice. Stress 16, 647–654 (2013).

  202. 202.

    , , & Increased intermale aggression and neuroendocrine response in mice deficient for the neural cell adhesion molecule (NCAM). Eur. J. Neurosci. 9, 1117–1125 (1997).

  203. 203.

    , , , & Differential impact of polysialyltransferase ST8SiaII and ST8iaIV knockout on social interaction and aggression. Genes Brain Behav. 9, 958–967 (2010).

  204. 204.

    & Brain structures and neurotransmitters regulating aggression in cats: implications for human aggression. Prog. Neuropsychopharmacol. Biol. Psychiatry 25, 91–140 (2001).

  205. 205.

    Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455, 903–911 (2008).

  206. 206.

    et al. Common circuit defect of excitatory-inhibitory balance in mouse models of autism. J. Neurodev. Disord. 1, 172–181 (2009).

  207. 207.

    et al. Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature 477, 171–178 (2011).

  208. 208.

    & Effect of chronic stress on synaptic currents in rat hippocampal dentate gyrus neurons. J. Neurophysiol. 89, 625–633 (2003).

  209. 209.

    et al. Chronic restraint stress upregulates GLT1 mRNA and protein expression in the rat hippocampus: reversal by tianeptine. Proc. Natl Acad. Sci. USA 101, 2179–2184 (2004).

  210. 210.

    , , , & Stress impairs GABAergic network function in the hippocampus by activating nongenomic glucocorticoid receptors and affecting the integrity of the parvalbumin-expressing neuronal network. Neuropsychopharmacology 35, 1693–1707 (2010).

  211. 211.

    et al. Hippocampal neuroligin2 overexpression leads to reduced aggression and inhibited novelty reactivity in rats. PLoS ONE 8, e56871 (2013).

  212. 212.

    & Psychobiology of social support: the social dimension of stress buffering. Restor. Neurol. Neurosci. 32, 149–162 (2014).

  213. 213.

    , , & Central oxytocin administration reduces stress-induced corticosterone release and anxiety behavior in rats. Endocrinology 138, 2829–2834 (1997).

  214. 214.

    & Centrally released oxytocin mediates mating-induced anxiolysis in male rats. Proc. Natl Acad. Sci. USA 104, 16681–16684 (2007).

  215. 215.

    & Hypothalamic oxytocin mediates social buffering of the stress response. Biol. Psychiatry 76, 281–288 (2014).

  216. 216.

    et al. An updated animal model capturing both the cognitive and emotional features of post-traumatic stress disorder (PTSD). Front. Behav. Neurosci. 8, 142 (2014).

  217. 217.

    et al. Early experience of a novel-environment in isolation primes a fearful phenotype characterized by persistent amygdala activation. Psychoneuroendocrinology 39, 39–57 (2014). An interesting study showing that social buffering of stress is not only reflected in immediate effects but can also have long-term consequences when it occurs during early life.

  218. 218.

    , , , & Effects of an early experience involving training in a T-maze under either denial or receipt of expected reward through maternal contact. Front. Endocrinol. 4, 178 (2013).

  219. 219.

    & Early life trauma and attachment: immediate and enduring effects on neurobehavioral and stress axis development. Front. Endocrinol. 5, 33 (2014).

  220. 220.

    , & Maternal regulation of infant brain state. Curr. Biol. 24, 1664–1669 (2014).

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Acknowledgements

This study was supported by grants from the Swiss National Science Foundation (31003AB-135710 and 31003A_152614; the NCCR 'The synaptic basis of mental diseases'), the Oak Foundation, the European Union (MEMSTICK, FP7HEALTHF2M2007201600), the Hungarian Academy of Sciences Distinguished Visiting Scientist Program and intramural funding from the Swiss Federal Insitute of Technology Lausanne (EPFL) to C.S. and ERC2011ADG294313 (SERRACO) grant to J.H. The authors thank members of their respective laboratories for their original scientific contributions to the work reviewed here.

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Affiliations

  1. Brain Mind Institute, School of Life Sciences, École Polytechnique Federale de Lausanne (EPFL), Lausanne CH-1050, Switzerland.

    • Carmen Sandi
  2. Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest H-1450, Hungary.

    • József Haller

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Carmen Sandi.

Glossary

Stress response

The activation of coordinated neurophysiological responses in the brain and periphery — that is, the sympathetic nervous system and the hypothalamic–pituitary–adrenal (HPA) axis — to restore homeostasis disturbed by environmental demands or stressors.

Stressors

Noxious stimuli that elicit a stress response.

Conspecifics

Individuals of the same species.

Social defeat

After confrontation between conspecific individuals, social defeat may be experienced by the losing individual. Its symptoms are submissive postures shown to the winner and the avoidance of social and aggressive contacts.

Antisociality

Agonistic behaviours that break behavioural 'rules' that have evolved to limit dangerous forms of aggression. They include excessive levels and displaced targeting of attack and deficient social communication.

Behavioural agitation

Rapid switches from one behaviour to another, including running around the perimeter of the cage, jumping, repeated self-grooming and/or performing repeated, stereotypy-like behaviours.

Offensive ambiguity

Increased aggression against small opponents together with decreased aggression against large opponents. It is also characterized by increased defensiveness against a background of increased offensiveness.

Instrumental aggression

A premeditated aggressive action that has a specific goal, such as material gain. It is associated with low emotional and physiological arousal, and these features also characterize animal analogues of this behaviour.

Extrahypothalamic CRH system

Neurons containing corticotropin-releasing hormone (CRH) and/or CRH receptors that have their cell bodies localized in brain regions other than the hypothalamus.

Epigenetic mechanisms

Changes in gene expression that do not arise from changes to the DNA sequence and that include alterations in DNA methylation, histone modifications and non-coding RNAs (microRNAs and long non-coding RNAs).

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DOI

https://doi.org/10.1038/nrn3918

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