Focus on stress

Neighborhood matters: divergent patterns of stress-induced plasticity across the brain

Journal name:
Nature Neuroscience
Year published:
Published online


The fact that exposure to severe stress leads to the development of psychiatric disorders serves as the basic rationale for animal models of stress disorders. Clinical and neuroimaging studies have shown that three brain areas involved in learning and memory—the hippocampus, amygdala and prefrontal cortex—undergo distinct structural and functional changes in individuals with stress disorders. These findings from patient studies pose several challenges for animal models of stress disorders. For instance, why does stress impair cognitive function, yet enhance fear and anxiety? Can the same stressful experience elicit contrasting patterns of plasticity in the hippocampus, amygdala and prefrontal cortex? How does even a brief exposure to traumatic stress lead to long-lasting behavioral abnormalities? Thus, animal models of stress disorders must not only capture the unique spatio-temporal features of structural and functional alterations in these brain areas, but must also provide insights into the underlying neuronal plasticity mechanisms. This Review will address some of these key questions by describing findings from animal models on how stress-induced plasticity varies across different brain regions and thereby gives rise to the debilitating emotional and cognitive symptoms of stress-related psychiatric disorders.

At a glance


  1. Brain areas implicated in stress-related psychiatric disorders.
    Figure 1: Brain areas implicated in stress-related psychiatric disorders.

    The amygdala, PFC and hippocampus undergo contrasting structural and functional changes in stress disorders and in turn differentially regulate the stress response through HPA activity (both positively and negatively).

  2. Commonly used rodent models of stress.
    Figure 2: Commonly used rodent models of stress.

    Several stress procedures (acute stressors, blue; chronic stressors, red) have been used to study the effects of stress on neural plasticity in rodents. Widely used physical stressors include repeated exposure to immobilization and restraint stress29, 72, 147. In contrast, a range of naturalistic or ethologically relevant stressors have also been used to trigger innate fear. These commonly used models of psychosocial stress include predator odor and exposure to bright elevated platform42, 80, 148, as well as maternal separation and social defeat136, 149, 150.

  3. Behavioral stress triggers distinct spatiotemporal patterns of plasticity at multiple levels of neural organization.
    Figure 3: Behavioral stress triggers distinct spatiotemporal patterns of plasticity at multiple levels of neural organization.

    (a) Contrasting patterns of plasticity across brain areas induced by chronic stress. At the behavioral level, chronic stress enhances fear and anxiety while impairing spatial and working memory and fear extinction. At the network level, stress causes an increase in neural activity in the amygdala, whereas it has the opposite effect in the hippocampus. At the levels of neurons and synapses, repeated stress leads to growth of dendrites and spines in the amygdala, but loss of dendritic arbors and spines in the hippocampus and mPFC. These morphological changes are accompanied by enhanced LTP in the amygdala, as well as by impaired and/or reduced LTP in the hippocampus and mPFC. At the molecular level, BDNF protein is increased in the amygdala, but decreased in the hippocampus. In the mPFC, certain forms of stress increase BDNF mRNA expression, whereas others do not. The effect of chronic stress on BDNF protein levels in the mPFC is not known (Fig. 5). (b) Short-term (immediate to 24 h after) and delayed (10 d later) effects of a single episode of acute stress. Both the short and delayed effects of stress are different between the hippocampus and amygdala. In terms of the short-term effects, although some measures of plasticity are impaired in the hippocampus, others are enhanced in the amygdala. In both areas some parameters remain unaffected. All of the parameters exhibit a delayed increase in the amygdala.

  4. Stress enhances fear by forming new synapses with greater capacity for LTP in the lateral amygdala.
    Figure 4: Stress enhances fear by forming new synapses with greater capacity for LTP in the lateral amygdala.

    Chronic stress strengthens the structural basis of synaptic connectivity causing dendritic growth and spinogenesis. These newly formed dendritic spines have larger NMDAR-mediated synaptic currents as a result of the formation of NMDAR-only or silent synapses. Stress also lowers synaptic inhibition. This creates conditions that facilitate the induction of greater LTP in the amygdala. This, in turn, gives rise to stronger auditory-evoked potentials (AEPs) in awake, behaving animals. Together, these cellular and network level changes give rise to stronger fear memories.

  5. Temporal features of stress-induced plasticity in the amygdala and hippocampus.
    Figure 5: Temporal features of stress-induced plasticity in the amygdala and hippocampus.

    Effect of 10-d chronic immobilization stress on in vivo neuronal activity in the hippocampus and the amygdala in awake, behaving rodents. (a) Chronic stress impairs spatial discrimination at the network level in the hippocampus. On day 11, 24 h after the end of 10-d chronic stress, mice were challenged to discriminate between two linear tracks (track 1 and track 2) that were similar in shape and dimensions with only some differences in color and texture. Examples show firing rate maps of different place cells on these tracks for control (left) and stressed (right) mice. Analysis of the ensemble representation, but not at the single neuron level, suggested that stress limits the ability of the CA1 pyramidal population to properly distinguish the two similar tracks, although context discrimination was not affected in control mice (adapted from ref. 119). (bd) During chronic stress, AEPs were simultaneously monitored in areas CA1 (b), CA3 (c) and LA (d). On day 1, 1 h (indicated by black inverted triangle) after a single exposure to acute stress, AEP amplitudes were enhanced in all three areas. This increase was evident even 1 d later in the LA, but not in the CA1 and CA3 areas. 1 d after the tenth day of chronic stress, AEP amplitudes were back to baseline in the CA1 and CA3 areas, whereas a significant increase was still visible in the LA. This enhancement returns to baseline after a 10-d stress free recovery. (e) Chronic stress causes a gradual impairment of directional coupling from hippocampal areas CA1 to CA3 and a gradual enhancement from the LA to CA1. 1 h after the first episode of acute stress (day 1), functional coupling was strengthened between CA3–CA1, CA1–LA and LA–CA1. 24 h after the tenth day of stress, only LA–CA1 connectivity continued to be strong. This persisted even after a 10-d stress-free recovery. The strength of Granger spectral causality values are coded by the thickness of lines between the three recording sites. The arrowheads indicate the direction of Granger causal influence. Solid and dotted lines indicate presence and absence of dominant directional influence, respectively (adapted from ref. 137).

  6. Interactions and interdependence of stress-induced plasticity between brain areas.
    Figure 6: Interactions and interdependence of stress-induced plasticity between brain areas.

    (a) Stress impairs in vivo LTP in the BLA–mPFC and hippocampus–mPFC pathways. Stress also suppresses the modulation of hippocampal LTP by the BLA. Origin of the arrow indicates the location of stimulation and arrowhead indicates site of recording of changes in plasticity. Lesion or inactivation (×) of the BLA rescues behavioral deficits in spatial (hippocampus) and working memory (mPFC) caused by stress. These BLA manipulations also reverse stress-induced LTP deficits in the hippocampus. (b) Granger causality graphs depicting the modulation of directional influence. Chronic stress causes a persistent impairment of directional coupling from hippocampal area CA3 to CA1. In contrast, directional coupling from the LA to area CA1 is enhanced after chronic stress. The strength of Granger spectral causality values are coded by the thickness of lines between the three recording sites. The arrowheads indicate the direction of Granger causal influence. Solid and dotted lines indicate presence and absence of dominant directional influence, respectively (adapted from ref. 137).


  1. Bremner, J.D. et al. Magnetic resonance imaging-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse—a preliminary report. Biol. Psychiatry 41, 2332 (1997).
  2. Liberzon, I. et al. Brain activation in PTSD in response to trauma-related stimuli. Biol. Psychiatry 45, 817826 (1999).
  3. Rauch, S.L. et al. Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: a functional MRI study. Biol. Psychiatry 47, 769776 (2000).
  4. Shin, L.M. et al. A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder. Arch. Gen. Psychiatry 62, 273281 (2005).
  5. Hamilton, J.P., Siemer, M. & Gotlib, I.H. Amygdala volume in major depressive disorder: a meta-analysis of magnetic resonance imaging studies. Mol. Psychiatry 13, 9931000 (2008).
  6. Lorenzetti, V., Allen, N.B., Fornito, A. & Yücel, M. Structural brain abnormalities in major depressive disorder: a selective review of recent MRI studies. J. Affect. Disord. 117, 117 (2009).
  7. Ulrich-Lai, Y.M. & Herman, J.P. Neural regulation of endocrine and autonomic stress responses. Nat. Rev. Neurosci. 10, 397409 (2009).
  8. Popoli, M., Yan, Z., McEwen, B.S. & Sanacora, G. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat. Rev. Neurosci. 13, 2237 (2012).
  9. Roozendaal, B., McEwen, B.S. & Chattarji, S. Stress, memory and the amygdala. Nat. Rev. Neurosci. 10, 423433 (2009).
  10. McEwen, B.S. & Morrison, J.H. The brain on stress: vulnerability and plasticity of the prefrontal cortex over the life course. Neuron 79, 1629 (2013).
  11. Bremner, J.D. et al. MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am. J. Psychiatry 152, 973981 (1995).
  12. Gilbertson, M.W. et al. Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma. Nat. Neurosci. 5, 12421247 (2002).
  13. Armony, J.L., Corbo, V., Clément, M.-H. & Brunet, A. Amygdala response in patients with acute PTSD to masked and unmasked emotional facial expressions. Am. J. Psychiatry 162, 19611963 (2005).
  14. Shin, L.M., Rauch, S.L. & Pitman, R.K. Amygdala, medial prefrontal cortex, and hippocampal function in PTSD. Ann. NY Acad. Sci. 1071, 6779 (2006).
  15. Woodward, S.H. et al. Decreased anterior cingulate volume in combat-related PTSD. Biol. Psychiatry 59, 582587 (2006).
  16. Britton, J.C., Phan, K.L., Taylor, S.F., Fig, L.M. & Liberzon, I. Corticolimbic blood flow in posttraumatic stress disorder during script-driven imagery. Biol. Psychiatry 57, 832840 (2005).
  17. Jose, M. et al. Hippocampal and anterior cingulate activation deficits in patients with geriatric depression. Am. J. Psychiatry 158, 13211323 (2001).
  18. Roberson-Nay, R. et al. Increased amygdala activity during successful memory encoding in adolescent major depressive disorder: An FMRI study. Biol. Psychiatry 60, 966973 (2006).
  19. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5 (American Psychiatric Publishing, 2013).
  20. O'Keefe, J. & Nadel, L. Precis of O'Keefe & Nadel's The hippocampus as a cognitive map. Behav. Brain Sci. 2, 487494 (1979).
  21. Squire, L.R. & Zola-Morgan, S. The medial temporal lobe memory system. Science 253, 13801386 (1991).
  22. McEwen, B.S. Stress and hippocampal plasticity. Annu. Rev. Neurosci. 22, 105122 (1999).
  23. Martin, S.J., Grimwood, P. & Morris, R. Synaptic plasticity and memory: an evaluation of the hypothesis. Annu. Rev. Neurosci. 23, 649711 (2000).
  24. Jacobson, L. & Sapolsky, R. The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis. Endocr. Rev. 12, 118134 (1991).
  25. Herman, J.P. & Cullinan, W.E. Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis. Trends Neurosci. 20, 7884 (1997).
  26. Watanabe, Y., Gould, E. & McEwen, B.S. Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res. 588, 341345 (1992).
    An influential study that analyzed how repeated restraint stress leads to dendritic atrophy in Golgi-stained hippocampal CA3 pyramidal neurons.
  27. Magariños, A.M. & McEwen, B.S. Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: Comparison of stressors. Neuroscience 69, 8388 (1995).
  28. Sousa, N., Lukoyanov, N., Madeira, M., Almeida, O. & Paula-Barbosa, M. Reorganization of the morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral improvement. Neuroscience 97, 253266 (2000).
  29. Conrad, C.D., LeDoux, J.E., Magariños, A.M. & McEwen, B.S. Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy. Behav. Neurosci. 113, 902913 (1999).
  30. Magariños, A.M. & McEwen, B.S. Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: Involvement of glucocorticoid secretion and excitatory amino acid receptors. Neuroscience 69, 8998 (1995).
  31. McEwen, B.S. et al. Mechanisms of stress in the brain. Nat. Neurosci. 18, 13531363 (2015).
  32. Pawlak, R. et al. Tissue plasminogen activator and plasminogen mediate stress-induced decline of neuronal and cognitive functions in the mouse hippocampus. Proc. Natl. Acad. Sci. USA 102, 1820118206 (2005).
  33. Chen, Y., Dubé, C.M., Rice, C.J. & Baram, T.Z. Rapid loss of dendritic spines after stress involves derangement of spine dynamics by corticotropin-releasing hormone. J. Neurosci. 28, 29032911 (2008).
  34. Chen, Y. et al. Correlated memory defects and hippocampal dendritic spine loss after acute stress involve corticotropin-releasing hormone signaling. Proc. Natl. Acad. Sci. USA 107, 1312313128 (2010).
  35. Starkman, M.N., Gebarski, S.S., Berent, S. & Schteingart, D.E. Hippocampal formation volume, memory dysfunction and cortisol levels in patients with Cushing's syndrome. Biol. Psychiatry 32, 756765 (1992).
  36. Sheline, Y.I., Wang, P.W., Gado, M.H., Csernansky, J.G. & Vannier, M.W. Hippocampal atrophy in recurrent major depression. Proc. Natl. Acad. Sci. USA 93, 39083913 (1996).
  37. Starkman, M.N. et al. Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing's disease. Biol. Psychiatry 46, 15951602 (1999).
  38. Kim, J.J. & Diamond, D.M. The stressed hippocampus, synaptic plasticity and lost memories. Nat. Rev. Neurosci. 3, 453462 (2002).
  39. Diamond, D.M. & Rose, G.M. Stress impairs LTP and hippocampal-dependent memory. Ann. NY Acad. Sci. 746, 411414 (1994).
  40. Diamond, D.M., Bennett, M.C., Fleshner, M. & Rose, G.M. Inverted-U relationship between the level of peripheral corticosterone and the magnitude of hippocampal primed burst potentiation. Hippocampus 2, 421430 (1992).
  41. Kole, M.H., Costoli, T., Koolhaas, J. & Fuchs, E. Bidirectional shift in the cornu ammonis 3 pyramidal dendritic organization following brief stress. Neuroscience 125, 337347 (2004).
  42. Xu, L., Anwyl, R. & Rowan, M.J. Behavioural stress facilitates the induction of long-term depression in the hippocampus. Nature 387, 497500 (1997).
    The first in vivo recording study in awake rats to show that the induction of LTD in the CA1 area is facilitated, rather than inhibited, by exposure to mild naturalistic stress.
  43. Xu, L., Holscher, C., Anwyl, R. & Rowan, M.J. Glucocorticoid receptor and protein/RNA synthesis-dependent mechanisms underlie the control of synaptic plasticity by stress. Proc. Natl. Acad. Sci. USA 95, 32043208 (1998).
  44. Cerqueira, J.J., Mailliet, F., Almeida, O.F., Jay, T.M. & Sousa, N. The prefrontal cortex as a key target of the maladaptive response to stress. J. Neurosci. 27, 27812787 (2007).
  45. Cook, S.C. & Wellman, C.L. Chronic stress alters dendritic morphology in rat medial prefrontal cortex. J. Neurobiol. 60, 236248 (2004).
    Another important study that reported stress-induced dendritic atrophy in the mPFC of rodents.
  46. Radley, J.J. et al. Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex. Neuroscience 125, 16 (2004).
    The first study showing that repeated restraint stress elicits significant reduction in the total length and branch numbers of apical dendrites of pyramidal neurons in layer II/III of the anterior cingulate and prelimbic cortices. This study demonstrated similarities between stress-induced structural plasticity in the hippocampus and PFC.
  47. Radley, J.J. et al. Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex. Cereb. Cortex 16, 313320 (2006).
  48. Liston, C. et al. Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J. Neurosci. 26, 78707874 (2006).
  49. Wellman, C.L. Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration. J. Neurobiol. 49, 245253 (2001).
  50. Arnsten, A.F.T. Stress weakens prefrontal cortex network connections: molecular events affecting cognitive disorders. Nat. Neurosci. 18, 13761385 (2015).
  51. Goldwater, D.S. et al. Structural and functional alterations to rat medial prefrontal cortex following chronic restraint stress and recovery. Neuroscience 164, 798808 (2009).
  52. Zhong, P., Liu, W., Gu, Z. & Yan, Z. Serotonin facilitates long-term depression induction in prefrontal cortex via p38 MAPK/Rab5-mediated enhancement of AMPA receptor internalization. J. Physiol. (Lond.) 586, 44654479 (2008).
  53. Holderbach, R., Clark, K., Moreau, J.-L., Bischofberger, J. & Normann, C. Enhanced long-term synaptic depression in an animal model of depression. Biol. Psychiatry 62, 92100 (2007).
  54. Davis, M. The role of the amygdala in fear and anxiety. Annu. Rev. Neurosci. 15, 353375 (1992).
  55. LeDoux, J.E. Emotion, memory and the brain. Sci. Am. 270, 5057 (1994).
  56. Pitkänen, A. & Amaral, D. The distribution of GABAergic cells, fibers, and terminals in the monkey amygdaloid complex: an immunohistochemical and in situ hybridization study. J. Neurosci. 14, 22002224 (1994).
  57. Herman, J.P., Tasker, J.G., Ziegler, D.R. & Cullinan, W.E. Local circuit regulation of paraventricular nucleus stress integration: glutamate–GABA connections. Pharmacol. Biochem. Behav. 71, 457468 (2002).
  58. Mandell, A.J., Chapman, L.F., Rand, R.W. & Walter, R.D. Plasma corticosteroids: changes in concentration after stimulation of hippocampus and amygdala. Science 139, 1212 (1963).
  59. Rubin, R.T., Mandell, A.J. & Crandall, P.H. Corticosteroid responses to limbic stimulation in man: localization of stimulus sites. Science 153, 767768 (1966).
  60. Conrad, C.D., LeDoux, J.E., Magariños, A.M. & McEwen, B.S. Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy. Behav. Neurosci. 113, 902913 (1999).
  61. Vyas, A., Pillai, A.G. & Chattarji, S. Recovery after chronic stress fails to reverse amygdaloid neuronal hypertrophy and enhanced anxiety-like behavior. Neuroscience 128, 667673 (2004).
  62. Vyas, A. & Chattarji, S. Modulation of different states of anxiety-like behavior by chronic stress. Behav. Neurosci. 118, 14501454 (2004).
  63. McGaugh, J.L. & Roozendaal, B. Role of adrenal stress hormones in forming lasting memories in the brain. Curr. Opin. Neurobiol. 12, 205210 (2002).
  64. Luine, V., Villegas, M., Martinez, C. & McEwen, B.S. Repeated stress causes reversible impairments of spatial memory performance. Brain Res. 639, 167170 (1994).
  65. Conrad, C.D., Galea, L.A., Kuroda, Y. & McEwen, B.S. Chronic stress impairs rat spatial memory on the Y maze, and this effect is blocked by tianeptine pretreatment. Behav. Neurosci. 110, 13211334 (1996).
  66. Liang, K.C., Hon, W. & Davis, M. Pre-and posttraining infusion of N-methyl-D-aspartate receptor antagonists into the amygdala impair memory in an inhibitory avoidance task. Behav. Neurosci. 108, 241 (1994).
  67. Shors, T.J. & Mathew, P.R. NMDA receptor antagonism in the lateral/basolateral but not central nucleus of the amygdala prevents the induction of facilitated learning in response to stress. Learn. Mem. 5, 220230 (1998).
  68. Vyas, A., Mitra, R., Shankaranarayana Rao, B.S. & Chattarji, S. Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J. Neurosci. 22, 68106818 (2002).
    This was the first report to reveal that, unlike in the hippocampus, chronic immobilization stress leads to dendritic growth in principal neurons of the BLA. Furthermore, this study showed that only those chronic stress paradigms that lead to enhanced anxiety-like behavior cause this dendritic hypertrophy.
  69. McDonald, A.J. Neurons of the lateral and basolateral amygdaloid nuclei: a Golgi study in the rat. J. Comp. Neurol. 212, 293312 (1982).
  70. McDonald, A.J. Projection neurons of the basolateral amygdala: a correlative Golgi and retrograde tract tracing study. Brain Res. Bull. 28, 179185 (1992).
  71. McDonald, A. Cell types and intrinsic connections of the amygdala. in The Amygdala: Neurobiological Aspects of Emotion, Memory and Mental Dysfunction (ed. Aggleton, J.P.) 6796 (1992).
  72. Mitra, R., Jadhav, S., McEwen, B.S., Vyas, A. & Chattarji, S. Stress duration modulates the spatiotemporal patterns of spine formation in the basolateral amygdala. Proc. Natl. Acad. Sci. USA 102, 93719376 (2005).
    This paper demonstrated for the first time how a single and repeated exposure to the same stressor differentially modifies the structural basis of synaptic connectivity in the BLA. Specifically, it showed that even an acute episode of stress can elicit a delayed increase in anxiety that is paralleled by a gradual increase in spine density in the BLA.
  73. Mitra, R. & Sapolsky, R.M. Acute corticosterone treatment is sufficient to induce anxiety and amygdaloid dendritic hypertrophy. Proc. Natl. Acad. Sci. USA 105, 55735578 (2008).
  74. Yehuda, R., McFarlane, A. & Shalev, A. Predicting the development of posttraumatic stress disorder from the acute response to a traumatic event. Biol. Psychiatry 44, 13051313 (1998).
  75. Schelling, G. et al. Stress doses of hydrocortisone, traumatic memories, and symptoms of posttraumatic stress disorder in patients after cardiac surgery: a randomized study. Biol. Psychiatry 55, 627633 (2004).
  76. Schelling, G. et al. Efficacy of hydrocortisone in preventing posttraumatic stress disorder following critical illness and major surgery. Ann. NY Acad. Sci. 1071, 4653 (2006).
  77. Resnick, H.S., Yehuda, R., Pitman, R.K. & Foy, D.W. Effect of previous trauma on acute plasma cortisol level following rape. Am. J. Psychiatry 152, 1675 (1995).
  78. Zohar, J. et al. High dose hydrocortisone immediately after trauma may alter the trajectory of PTSD: Interplay between clinical and animal studies. Eur. Neuropsychopharmacol. 21, 796809 (2011).
  79. Rao, R.P., Anilkumar, S., McEwen, B.S. & Chattarji, S. Glucocorticoids protect against the delayed behavioral and cellular effects of acute stress on the amygdala. Biol. Psychiatry 72, 466475 (2012).
    This study reports that the presence of elevated levels of corticosterone at the time of acute stress confers protection against the delayed enhancing effect of stress on BLA synaptic connectivity and anxiety-like behavior. These observations are consistent with clinical reports on the protective effects of glucocorticoids against the development of posttraumatic symptoms triggered by traumatic stress.
  80. Cohen, H., Matar, M.A., Buskila, D., Kaplan, Z. & Zohar, J. Early post-stressor intervention with high-dose corticosterone attenuates posttraumatic stress response in an animal model of posttraumatic stress disorder. Biol. Psychiatry 64, 708717 (2008).
    An important study reporting an animal model wherein the development of PTSD-like symptoms was blocked by the administration of glucocorticoids shortly after exposure to psychogenic stress.
  81. Karst, H., Berger, S., Erdmann, G., Schütz, G. & Joëls, M. Metaplasticity of amygdalar responses to the stress hormone corticosterone. Proc. Natl. Acad. Sci. USA 107, 1444914454 (2010).
  82. Nibuya, M., Morinobu, S. & Duman, R.S. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J. Neurosci. 15, 75397547 (1995).
  83. Smith, M.A., Makino, S., Kvetnansky, R. & Post, R.M. Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J. Neurosci. 15, 17681777 (1995).
  84. Chen, B., Dowlatshahi, D., MacQueen, G.M., Wang, J.-F. & Young, L.T. Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol. Psychiatry 50, 260265 (2001).
  85. Duman, R.S. & Monteggia, L.M. A neurotrophic model for stress-related mood disorders. Biol. Psychiatry 59, 11161127 (2006).
  86. Nestler, E.J. et al. Neurobiology of depression. Neuron 34, 1325 (2002).
  87. Shirayama, Y., Chen, A.C.-H., Nakagawa, S., Russell, D.S. & Duman, R.S. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J. Neurosci. 22, 32513261 (2002).
  88. Siuciak, J.A., Lewis, D.R., Wiegand, S.J. & Lindsay, R.M. Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol. Biochem. Behav. 56, 131137 (1997).
  89. Govindarajan, A. et al. Transgenic brain-derived neurotrophic factor expression causes both anxiogenic and antidepressant effects. Proc. Natl. Acad. Sci. USA 103, 1320813213 (2006).
    This study reported that morphological changes in the amygdala and hippocampus, caused by genetic overexpression in mice of the same molecule BDNF, give rise to contrasting effects on anxiety and depressive symptoms, both of which are major behavioral correlates of stress disorders.
  90. Lakshminarasimhan, H. & Chattarji, S. Stress leads to contrasting effects on the levels of brain derived neurotrophic factor in the hippocampus and amygdala. PLoS ONE 7, e30481 (2012).
  91. McAllister, A.K., Lo, D.C. & Katz, L.C. Neurotrophins regulate dendritic growth in developing visual cortex. Neuron 15, 791803 (1995).
  92. Davis, M. & Shi, C. The extended amygdala: are the central nucleus of the amygdala and the bed nucleus of the stria terminalis differentially involved in fear versus anxiety? Ann. NY Acad. Sci. 877, 281291 (1999).
  93. Vyas, A., Bernal, S. & Chattarji, S. Effects of chronic stress on dendritic arborization in the central and extended amygdala. Brain Res. 965, 290294 (2003).
  94. Hong, W., Kim, D.-W. & Anderson, D.J. Antagonistic control of social versus repetitive self-grooming behaviors by separable amygdala neuronal subsets. Cell 158, 13481361 (2014).
  95. Pawlak, R., Magarinos, A.M., Melchor, J., McEwen, B. & Strickland, S. Tissue plasminogen activator in the amygdala is critical for stress-induced anxiety-like behavior. Nat. Neurosci. 6, 168174 (2003).
  96. Bennur, S. et al. Stress-induced spine loss in the medial amygdala is mediated by tissue-plasminogen activator. Neuroscience 144, 816 (2007).
  97. Suvrathan, A. et al. Stress enhances fear by forming new synapses with greater capacity for long-term potentiation in the amygdala. Philos. Trans. R. Soc. B Biol. Sci. 369, 151159 (2014).
    Using whole-cell recordings in amygdala slices, this study identified specific changes in excitatory and inhibitory synaptic transmission that underlie stress-induced enhancement in LTP in the LA and fear learning.
  98. Sandi, C. & Pinelo-Nava, M.T. Stress and memory: behavioral effects and neurobiological mechanisms. Neural Plast. 2007, 78970 (2007).
  99. Conrad, C.D., Galea, L.A., Kuroda, Y. & McEwen, B.S. Chronic stress impairs rat spatial memory on the Y maze, and this effect is blocked by tianeptine pretreatment. Behav. Neurosci. 110, 13211334 (1996).
  100. Bauer, E.P., Schafe, G.E. & LeDoux, J.E. NMDA receptors and L-type voltage-gated calcium channels contribute to long-term potentiation and different components of fear memory formation in the lateral amygdala. J. Neurosci. 22, 52395249 (2002).
  101. Cordero, M.I., Venero, C., Kruyt, N.D. & Sandi, C. Prior exposure to a single stress session facilitates subsequent contextual fear conditioning in rats. Horm. Behav. 44, 338345 (2003).
  102. Rau, V., DeCola, J.P. & Fanselow, M.S. Stress-induced enhancement of fear learning: an animal model of posttraumatic stress disorder. Neurosci. Biobehav. Rev. 29, 12071223 (2005).
  103. Rodrigues, S.M., LeDoux, J.E. & Sapolsky, R.M. The influence of stress hormones on fear circuitry. Annu. Rev. Neurosci. 32, 289313 (2009).
  104. Shors, T.J., Weiss, C. & Thompson, R.F. Stress-induced facilitation of classical conditioning. Science 257, 537539 (1992).
  105. Stewart, M.G. et al. Stress suppresses and learning induces plasticity in CA3 of rat hippocampus: a three-dimensional ultrastructural study of thorny excrescences and their postsynaptic densities. Neuroscience 131, 4354 (2005).
  106. Padival, M., Quinette, D. & Rosenkranz, J.A. Effects of repeated stress on excitatory drive of Basal amygdala neurons in vivo. Neuropsychopharmacoly 38, 17481762 (2013).
  107. Rodríguez Manzanares, P.A., Isoardi, N.A., Carrer, H.F. & Molina, V.A. Previous stress facilitates fear memory, attenuates GABAergic inhibition, and increases synaptic plasticity in the rat basolateral amygdala. J. Neurosci. 25, 87258734 (2005).
  108. Vouimba, R.-M., Yaniv, D., Diamond, D. & Richter-Levin, G. Effects of inescapable stress on LTP in the amygdala versus the dentate gyrus of freely behaving rats. Eur. J. Neurosci. 19, 18871894 (2004).
  109. Vouimba, R.-M., Muñoz, C. & Diamond, D.M. Differential effects of predator stress and the antidepressant tianeptine on physiological plasticity in the hippocampus and basolateral amygdala. Stress 9, 2940 (2006).
  110. File, S.E. in The Amygdala: a Functional Analysis (ed. Aggleton, J.P.) 195212 (Oxford University Press, Oxford, 2000).
  111. Adamec, R.E., Burton, P., Shallow, T. & Budgell, J. NMDA receptors mediate lasting increases in anxiety-like behavior produced by the stress of predator exposure–implications for anxiety associated with posttraumatic stress disorder. Physiol. Behav. 65, 723737 (1999).
  112. De Kloet, C.S. et al. Assessment of HPA-axis function in posttraumatic stress disorder: pharmacological and non-pharmacological challenge tests, a review. J. Psychiatr. Res. 40, 550567 (2006).
  113. Bardeleben, U. & Holsboer, F. Cortisol response to a combined dexamethasone-human corticotrophin-releasing hormone challenge in patients with depression. J. Neuroendocrinol. 1, 485488 (1989).
  114. Pitkänen, A., Savander, V. & LeDoux, J.E. Organization of intra-amygdaloid circuitries in the rat: an emerging framework for understanding functions of the amygdala. Trends Neurosci. 20, 517523 (1997).
  115. Pikkarainen, M., Rönkkö, S., Savander, V., Insausti, R. & Pitkänen, A. Projections from the lateral, basal and accessory basal nuclei of the amygdala to the hippocampal formation in rat. J. Comp. Neurol. 403, 229260 (1999).
  116. Petrovich, G.D., Canteras, N.S. & Swanson, L.W. Combinatorial amygdalar inputs to hippocampal domains and hypothalamic behavior systems. Brain Res. Brain Res. Rev. 38, 247289 (2001).
  117. Kim, J.J. et al. Stress-induced alterations in hippocampal plasticity, place cells and spatial memory. Proc. Natl. Acad. Sci. USA 104, 1829718302 (2007).
  118. McHugh, T.J., Blum, K.I., Tsien, J.Z., Tonegawa, S. & Wilson, M.A. Impaired hippocampal representation of space in CA1-specific NMDAR1 knockout mice. Cell 87, 13391349 (1996).
  119. Tomar, A., Polygalov, D., Chattarji, S. & McHugh, T.J. The dynamic impact of repeated stress on the hippocampal spatial map. Hippocampus 25, 3850 (2015).
    This study provided new insights into the gradual progression of the complex effects of chronic stress on hippocampal place cell activity and suggests that a loss of hippocampal network flexibility may contribute to some of the behavioral deficits caused by chronic stress.
  120. Sapolsky, R.M., Krey, L.C. & McEwen, B.S. The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. Endocr. Rev. 7, 284301 (1986).
  121. McEwen, B.S. Stress and hippocampal plasticity. Annu. Rev. Neurosci. 22, 105122 (1999).
  122. Wilson, I.A., Ikonen, S., Gallagher, M., Eichenbaum, H. & Tanila, H. Age-associated alterations of hippocampal place cells are subregion specific. J. Neurosci. 25, 68776886 (2005).
  123. Kim, E.J. et al. Alterations of hippocampal place cells in foraging rats facing a 'predatory' threat. Curr. Biol. 25, 13621367 (2015).
  124. Maroun, M. & Richter-Levin, G. Exposure to acute stress blocks the induction of long-term potentiation of the amygdala–prefrontal cortex pathway in vivo. J. Neurosci. 23, 44064409 (2003).
    The first study, using in vivo extracellular field recordings, that demonstrated how the same stress that blocks LTP in the hippocampus also occludes LTP in the BLA-mPFC pathway.
  125. Richter-Levin, G. & Maroun, M. Stress and amygdala suppression of metaplasticity in the medial prefrontal cortex. Cereb. Cortex 20, 24332441 (2010).
  126. Akirav, I. & Richter-Levin, G. Biphasic modulation of hippocampal plasticity by behavioral stress and basolateral amygdala stimulation in the rat. J. Neurosci. 19, 1053010535 (1999).
  127. Akirav, I. & Richter-Levin, G. Mechanisms of amygdala modulation of hippocampal plasticity. J. Neurosci. 22, 99129921 (2002).
    An influential study that reported how priming of the BLA leads to enhanced LTP at perforant path inputs to the DG. This priming-induced enhancement was blocked by as systemic treatment with corticosterone.
  128. Packard, M.G., Cahill, L. & McGaugh, J.L. Amygdala modulation of hippocampal-dependent and caudate nucleus-dependent memory processes. Proc. Natl. Acad. Sci. USA 91, 84778481 (1994).
  129. McGaugh, J.L. Memory—a century of consolidation. Science 287, 248251 (2000).
  130. Roozendaal, B., Griffith, Q.K., Buranday, J., Dominique, J.-F. & McGaugh, J.L. The hippocampus mediates glucocorticoid-induced impairment of spatial memory retrieval: dependence on the basolateral amygdala. Proc. Natl. Acad. Sci. USA 100, 13281333 (2003).
  131. Abe, K. Modulation of hippocampal long-term potentiation by the amygdala: a synaptic mechanism linking emotion and memory. Jpn. J. Pharmacol. 86, 1822 (2001).
  132. Roozendaal, B. & McGaugh, J.L. Amygdaloid nuclei lesions differentially affect glucocorticoid-induced memory enhancement in an inhibitory avoidance task. Neurobiol. Learn. Mem. 65, 18 (1996).
  133. Kim, J.J., Lee, H.J., Han, J.S. & Packard, M.G. Amygdala is critical for stress-induced modulation of hippocampal long-term potentiation and learning. J. Neurosci. 21, 52225228 (2001).
    This study provided early evidence that the amygdala plays a role in stress-induced modulation of hippocampal function in rodents. Lesions of the amygdala were shown to block stress-induced impairment of hippocampal LTP and retention of water-maze spatial training.
  134. Kim, J.J., Koo, J.W., Lee, H.J. & Han, J.-S. Amygdalar inactivation blocks stress-induced impairments in hippocampal long-term potentiation and spatial memory. J. Neurosci. 25, 15321539 (2005).
  135. Roozendaal, B., McReynolds, J.R. & McGaugh, J.L. The basolateral amygdala interacts with the medial prefrontal cortex in regulating glucocorticoid effects on working memory impairment. J. Neurosci. 24, 13851392 (2004).
    This study showed that amygdala activation reverses stress-induced impairment in working memory, thereby providing evidence for interactions between the BLA and mPFC.
  136. Kumar, S. et al. Prefrontal cortex reactivity underlies trait vulnerability to chronic social defeat stress. Nat. Commun. 5, 4537 (2014).
  137. Ghosh, S., Laxmi, T.R. & Chattarji, S. Functional connectivity from the amygdala to the hippocampus grows stronger after stress. J. Neurosci. 33, 72347244 (2013).
    This study provided new insights into the functional consequences of the contrasting patterns of stress-induced plasticity in the intact hippocampus and amygdala in awake, behaving rats. Granger causality analysis identified a strong directional influence from the LA to area CA1 that persisted throughout and even after chronic stress, whereas directional coupling from area CA3 to CA1 became weaker.
  138. Liang, Z., King, J. & Zhang, N. Neuroplasticity to a single-episode traumatic stress revealed by resting-state fMRI in awake rats. Neuroimage 103, 485491 (2014).
  139. Likhtik, E., Stujenske, J.M., Topiwala, M.A., Harris, A.Z. & Gordon, J.A. Prefrontal entrainment of amygdala activity signals safety in learned fear and innate anxiety. Nat. Neurosci. 17, 106113 (2014).
    This study analyzed dynamic interactions in the mPFC-BLA network in learned fear and innate anxiety. States of high fear and anxiety were accompanied by enhanced theta-frequency power and synchrony in the mPFC-BLA circuit, thereby providing a powerful framework for investigating the neural basis of stress-induced modulation of fear and anxiety-related behaviors.
  140. Allsop, S.A., Vander Weele, C.M., Wichmann, R. & Tye, K.M. Optogenetic insights on the relationship between anxiety-related behaviors and social deficits. Front. Behav. Neurosci. 8, 241 (2014).
  141. Root, C.M., Denny, C.A., Hen, R. & Axel, R. The participation of cortical amygdala in innate, odor-driven behaviour. Nature 515, 269273 (2014).
  142. Namburi, P. et al. A circuit mechanism for differentiating positive and negative associations. Nature 520, 675678 (2015).
  143. Koob, G.F. A role for brain stress systems in addiction. Neuron 59, 1134 (2008).
  144. Koob, G.F. Brain stress systems in the amygdala and addiction. Brain Res. 1293, 6175 (2009).
  145. Krishnan, V. & Nestler, E.J. The molecular neurobiology of depression. Nature 455, 894902 (2008).
  146. Anisman, H. & Matheson, K. Stress, depression, and anhedonia: caveats concerning animal models. Neurosci. Biobehav. Rev. 29, 525546 (2005).
  147. Wang, M. et al. Acute restraint stress enhances hippocampal endocannabinoid function via glucocorticoid receptor activation. J. Psychopharmacol. 26, 5670 (2012).
  148. Yuen, E.Y. et al. Acute stress enhances glutamatergic transmission in prefrontal cortex and facilitates working memory. Proc. Natl. Acad. Sci. USA 106, 1407514079 (2009).
  149. Francis, D.D., Diorio, J., Plotsky, P.M. & Meaney, M.J. Environmental enrichment reverses the effects of maternal separation on stress reactivity. J. Neurosci. 22, 78407843 (2002).
  150. Krugers, H.J., Koolhaas, J., Bohus, B. & Korf, J. A single social stress-experience alters glutamate receptor-binding in rat hippocampal CA3 area. Neurosci. Lett. 154, 7377 (1993).

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  1. Centre for Brain Development and Repair, Institute of Stem Cell Biology and Regenerative Medicine, National Centre for Biological Sciences, Bangalore, India.

    • Sumantra Chattarji &
    • Mohammed Mostafizur Rahman
  2. Laboratory for Circuit and Behavioral Physiology, RIKEN Brain Science Institute, Wakoshi, Saitama, Japan.

    • Anupratap Tomar
  3. Department of Neurobiology, Stanford University, Stanford, California, USA.

    • Aparna Suvrathan
  4. Department of Neurobiology, University of Chicago, Chicago, Illinois, USA.

    • Supriya Ghosh

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