Elsevier

Biological Psychiatry

Volume 86, Issue 6, 15 September 2019, Pages 410-420
Biological Psychiatry

Review
Neurobiology of Resilience: Interface Between Mind and Body

https://doi.org/10.1016/j.biopsych.2019.04.011Get rights and content

Abstract

Stress-related neuropsychiatric disorders, such as major depressive disorder and posttraumatic stress disorder, exact enormous socioeconomic and individual consequences. Resilience, the process of adaptation in the face of adversity, is an important concept that is enabling the field to understand individual differences in stress responses, with the hope of harnessing this information for the development of novel therapeutics that mimic the body’s natural resilience mechanisms. This review provides an update on the current state of research of the neurobiological mechanisms of stress resilience. We focus on physiological and transcriptional adaptations of specific brain circuits, the role of cellular and humoral factors of the immune system, the gut microbiota, and changes at the interface between the brain and the periphery, the blood-brain barrier. We propose viewing resilience as a process that requires the integration of multiple central and peripheral systems and that elucidating the underlying neurobiological mechanisms will ultimately lead to novel therapeutic options.

Section snippets

Stress, Resilience, and the Hypothalamic-Pituitary-Adrenal Axis

An adequate reaction of the body to acute threats is a crucial mechanism to adapt to environmental changes that occur in different developmental stages throughout life. The autonomic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis play a key role in orchestrating the body’s reaction to threats (2). Upon danger, the hypothalamus secretes corticotropin-releasing hormone, which via the pituitary hormone adrenocorticotropin induces the production of cortisol from the adrenal

Rodent Models of Susceptibility and Resilience

The neurobiological mechanisms underlying resilience have long been difficult to uncover, primarily because creating significant adversity in humans in controlled experimental settings is impossible and because the exploration of molecular and circuit brain mechanisms in humans remains limited. Over the past decade, advances in preclinical animal stress models that uncover individual differences in stress reactivity have allowed detailed neurobiological characterization of the precise

Hippocampal Neurogenesis

The hippocampus is important in mediating responses to stress. Both mineralocorticoid and glucocorticoid receptors are vastly expressed in the hippocampus, making it a region that is highly responsive to activation of the HPA axis 40, 41. The dentate gyrus of the hippocampus is capable of generating functional neurons from adult neural precursors, a process called adult neurogenesis (42). Stress and glucocorticoid release decrease adult hippocampal neurogenesis, a process that is reversed by

The Innate Immune System

Both preclinical animal models and human studies show that repeated psychosocial stress leads to profound peripheral immunological changes 98, 99. Evidence from human studies linking stress vulnerability and resilience to immune alterations exists at multiple levels: a subset of patients with MDD show elevated levels of several proinflammatory cytokines 100, 101, MDD has high comorbidity with chronic inflammatory illnesses such as autoimmune disorders, cardiovascular disorders, or cancer 102,

Conclusions

The societal and individual burden entailed by stress-related neuropsychiatric disorders is immense. Efforts in developing treatments for such disorders have focused on preventing or reversing the damaging effects of stress. Understanding the neurobiological mechanisms that promote resilience to stress in some individuals, but lacking in those who are inherently more susceptible, constitutes a novel, additional important approach in stress biology. Indeed, early clinical studies suggest that

Acknowledgments and Disclosures

This work was supported by National Institute of Mental Health Grant Nos. R01 MH090264, P50 MH096890, and R01 MH104559 (to SJR), R56 MH115409 (to M-HH), and P50 MH096890 (to EJN), National Center for Complementary and Integrative Health Grant No. P50 AT008661-01 (to SJR), and an Early Postdoc Mobility Fellowship of the Swiss National Science Foundation and a Walter and Gertrud Siegenthaler Postdoctoral Fellowship (to FC).

SJR has provided consultation services to Danone and Sunovion

References (150)

  • B.R. Levone et al.

    Role of adult hippocampal neurogenesis in stress resilience

    Neurobiol Stress

    (2015)
  • G.L. Ming et al.

    Adult neurogenesis in the mammalian brain: Significant answers and significant questions

    Neuron

    (2011)
  • E.J. Nestler et al.

    The mesolimbic dopamine reward circuit in depression

    Biol Psychiatry

    (2006)
  • S. Lammel et al.

    Reward and aversion in a heterogeneous midbrain dopamine system

    Neuropharmacology

    (2014)
  • M.H. Han et al.

    Neural substrates of depression and resilience

    Neurotherapeutics

    (2017)
  • S.M. Ku et al.

    HCN channel targets for novel antidepressant treatment

    Neurotherapeutics

    (2017)
  • J.P. Britt et al.

    Synaptic and behavioral profile of multiple glutamatergic inputs to the nucleus accumbens

    Neuron

    (2012)
  • T.C. Francis et al.

    Nucleus accumbens medium spiny neuron subtypes mediate depression-related outcomes to social defeat stress

    Biol Psychiatry

    (2015)
  • L.A. Khibnik et al.

    Stress and cocaine trigger divergent and cell type-specific regulation of synaptic transmission at single spines in nucleus accumbens

    Biol Psychiatry

    (2016)
  • N.R. Wall et al.

    Differential innervation of direct- and indirect-pathway striatal projection neurons

    Neuron

    (2013)
  • J.H. Krystal et al.

    Noradrenergic and serotonergic mechanisms in the neurobiology of posttraumatic stress disorder and resilience

    Brain Res

    (2009)
  • H. Zhang et al.

    α1- and β3-adrenergic receptor-mediated mesolimbic homeostatic plasticity confers resilience to social stress in susceptible mice

    Biol Psychiatry

    (2019)
  • E.J. Nestler

    Role of the brain’s reward circuitry in depression: Transcriptional mechanisms

    Int Rev Neurobiol

    (2015)
  • R.C. Bagot et al.

    Circuit-wide transcriptional profiling reveals brain region-specific gene networks regulating depression susceptibility

    Neuron

    (2016)
  • R.C. Bagot et al.

    Ketamine and imipramine reverse transcriptional signatures of susceptibility and induce resilience-specific gene expression profiles

    Biol Psychiatry

    (2017)
  • E.J. Nestler

    FosB: A transcriptional regulator of stress and antidepressant responses

    Eur J Pharmacol

    (2015)
  • R.J. Donahue et al.

    Effects of striatal DeltaFosB overexpression and ketamine on social defeat stress-induced anhedonia in mice

    Biol Psychiatry

    (2014)
  • W. Renthal et al.

    Histone deacetylase 5 epigenetically controls behavioral adaptations to chronic emotional stimuli

    Neuron

    (2007)
  • S. Uchida et al.

    Epigenetic status of Gdnf in the ventral striatum determines susceptibility and adaptation to daily stressful events

    Neuron

    (2011)
  • F. Fuks

    DNA methylation and histone modifications: Teaming up to silence genes

    Curr Opin Genet Dev

    (2005)
  • A. Torres-Berrio et al.

    DCC Confers susceptibility to depression-like behaviors in humans and mice and is regulated by miR-218

    Biol Psychiatry

    (2017)
  • A. Steptoe et al.

    The effects of acute psychological stress on circulating inflammatory factors in humans: A review and meta-analysis

    Brain Behav Immun

    (2007)
  • Y. Dowlati et al.

    A meta-analysis of cytokines in major depression

    Biol Psychiatry

    (2010)
  • The road to resilience

  • J.P. Herman et al.

    Regulation of the hypothalamic-pituitary-adrenocortical stress response

    Compr Physiol

    (2016)
  • S.M. Smith et al.

    The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress

    Dialogues Clin Neurosci

    (2006)
  • Y.M. Ulrich-Lai et al.

    Neural regulation of endocrine and autonomic stress responses

    Nat Rev Neurosci

    (2009)
  • C. Hammen

    Stress and depression

    Ann Rev Clin Psychol

    (2005)
  • B.S. McEwen

    Stress, adaptation, and disease. Allostasis and allostatic load

    Ann N Y Acad Sci

    (1998)
  • D.S. Charney

    Psychobiological mechanisms of resilience and vulnerability: Implications for successful adaptation to extreme stress

    Am J Psychiatry

    (2004)
  • N. Garmezy

    Vulnerability research and the issue of primary prevention

    Am J Orthopsychiatry

    (1971)
  • A.S. Masten

    Ordinary magic. Resilience processes in development

    Am Psychol

    (2001)
  • F. Ozbay et al.

    Social support and resilience to stress across the life span: A neurobiologic framework

    Curr Psychiatry Rep

    (2008)
  • A. Feder et al.

    Psychobiology and molecular genetics of resilience

    Nat Rev Neurosci

    (2009)
  • S.J. Russo et al.

    Neurobiology of resilience

    Nat Neurosci

    (2012)
  • S.K. Wood et al.

    Resilience to the effects of social stress: Evidence from clinical and preclinical studies on the role of coping strategies

    Neurobiol Stress

    (2014)
  • S.M. Southwick et al.

    The psychobiology of depression and resilience to stress: Implications for prevention and treatment

    Ann Rev Clin Psychol

    (2005)
  • M.E. Seligman et al.

    Learned helplessness in the rat

    J Comp Physiol Psychol

    (1975)
  • J.F. Cryan et al.

    In search of a depressed mouse: Utility of models for studying depression-related behavior in genetically modified mice

    Mol Psychiatry

    (2004)
  • C. Nasca et al.

    Mind the gap: Glucocorticoids modulate hippocampal glutamate tone underlying individual differences in stress susceptibility

    Mol Psychiatry

    (2015)
  • Cited by (162)

    • 5-HT1A receptors within the intermediate lateral septum modulate stress vulnerability in male mice

      2024, Progress in Neuro-Psychopharmacology and Biological Psychiatry
    View all citing articles on Scopus
    View full text