Skip to main content
Log in

Chronic Stress- and Sex-Specific Neuromorphological and Functional Changes in Limbic Structures

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Chronic stress produces sex-specific neuromorphological changes in a variety of brain regions, which likely contribute to the gender differences observed in stress-related illnesses and cognitive ability. Here, we review the literature investigating the relationship between chronic stress and sex differences on brain plasticity and function, with an emphasis on morphological changes in dendritic arborization and spines in the hippocampus, prefrontal cortex, and amygdala. These brain structures are highly interconnected and sensitive to stress and gonadal hormones, and influence a variety of cognitive abilities. Although much less work has been published using female subjects than with male subjects, the findings suggest that the relationship between brain morphology and function is very different between the sexes. After reviewing the literature, we present a model showing how chronic stress influences the morphology of these brain regions and changes the dynamic of how these limbic structures interact with each other to produce altered behavioral outcomes in spatial ability, behavioral flexibility/executive function, and emotional arousal.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

AMY:

Amygdala

CA:

Cornu ammonis

GC:

Glucocorticoid

HPA:

Hypothalamic–pituitary–adrenal

MDD:

Major depressive disorder

OVX:

Ovariectomized

PFC:

Prefrontal cortex

PTSD:

Post-traumatic stress disorder

References

  1. Hamann S, Canli T (2004) Individual differences in emotion processing. Curr Opin Neurobiol 14(2):233–238

    PubMed  CAS  Google Scholar 

  2. Eichenbaum H, Yonelinas AP, Ranganath C (2007) The medial temporal lobe and recognition memory. Annu Rev Neurosci 30:123–152

    PubMed  CAS  Google Scholar 

  3. Lipton PA, Eichenbaum H (2008) Complementary roles of hippocampus and medial entorhinal cortex in episodic memory. Neural Plast 2008:1–8

    Google Scholar 

  4. Bird CM, Burgess N (2008) The hippocampus and memory: insights from spatial processing. Nat Rev Neurosci 9(3):182–194

    PubMed  CAS  Google Scholar 

  5. Burgess N (2008) Spatial cognition and the brain. Ann N Y Acad Sci 1124:77–97

    PubMed  Google Scholar 

  6. O’Keefe J, Nadel L (1978) The hippocampus as a cognitive map. Clarendon, Oxford

    Google Scholar 

  7. Kesner RP, Hopkins RO (2006) Mnemonic functions of the hippocampus: a comparison between animals and humans. Biol Psychol 73(1):3–18

    PubMed  Google Scholar 

  8. Aggleton JP, Hunt PR, Rawlins JN (1986) The effects of hippocampal lesions upon spatial and non-spatial tests of working memory. Behav Brain Res 19:133–146

    PubMed  CAS  Google Scholar 

  9. Kessels RP, de Haan EH, Kappelle LJ, Postma A (2001) Varieties of human spatial memory: a meta-analysis on the effects of hippocampal lesions. Brain Res Brain Res Rev 35(3):295–303

    PubMed  CAS  Google Scholar 

  10. Morris RGM, Garrud P, Rawlins JNP, O’Keefe J (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297:681–683

    PubMed  CAS  Google Scholar 

  11. McEwen BS, Milner TA (2007) Hippocampal formation: shedding light on the influence of sex and stress on the brain. Brain Res Rev 55(2):343–355

    PubMed  Google Scholar 

  12. Luine V (2002) Sex differences in chronic stress effects on memory in rats. Stress 5(3):205–216

    PubMed  CAS  Google Scholar 

  13. Luine VN, Beck KD, Bowman RE, Frankfurt M, Maclusky NJ (2007) Chronic stress and neural function: accounting for sex and age. J Neuroendocrinol 19(10):743–751

    PubMed  CAS  Google Scholar 

  14. Ragozzino ME (2007) The contribution of the medial prefrontal cortex, orbitofrontal cortex, and dorsomedial striatum to behavioral flexibility. Ann N Y Acad Sci 1121:355–375

    PubMed  Google Scholar 

  15. Dalley JW, Cardinal RN, Robbins TW (2004) Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates. Neurosci Biobehav Rev 28(7):771–784

    PubMed  CAS  Google Scholar 

  16. Cahill L, McGaugh JL (1998) Mechanisms of emotional arousal and lasting declarative memory. Trends Neurosci 21:294–299

    PubMed  CAS  Google Scholar 

  17. LeDoux J (2000) The amygdala and emotion: a view through fear. In: Aggleton JP (ed) The amygdala: a functional analysis. Oxford University Press, New York, pp 289–310

    Google Scholar 

  18. LeDoux JE (2000) Emotion circuits in the brain. Annu Rev Neurosci 23:155–184

    PubMed  CAS  Google Scholar 

  19. Diamond DM, Campbell AM, Park CR, Halonen J, Zoladz PR (2007) The temporal dynamics model of emotional memory processing: a synthesis on the neurobiological basis of stress-induced amnesia, flashbulb and traumatic memories, and the Yerkes–Dodson law. Neural Past 2007:1–33

    Google Scholar 

  20. Quirk GJ, Russo GK, Barron JL, Lebron K (2000) The role of ventromedial prefrontal cortex in the recovery of extinguished fear. J Neurosci 20(16):6225–6231

    PubMed  CAS  Google Scholar 

  21. Gao YJ, Ren WH, Zhang YQ, Zhao ZQ (2004) Contributions of the anterior cingulate cortex and amygdala to pain- and fear-conditioned place avoidance in rats. Pain 110(1–2):343–353

    PubMed  Google Scholar 

  22. Phillips RG, LeDoux JE (1992) Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci 106(2):274–285

    PubMed  CAS  Google Scholar 

  23. Conrad CD, Magariños AM, LeDoux JE, McEwen BS (1999) Repeated restraint stress facilitates fear conditioning independently of causing hippocampal CA3 dendritic atrophy. Behav Neurosci 113(5):902–913

    PubMed  CAS  Google Scholar 

  24. Conrad CD, MacMillan DD II, Tsekhanov S, Wright RL, Baran SE, Fuchs RE (2004) Influence of chronic corticosterone and glucocorticoid receptor antagonism in the amygdala on fear conditioning. Neurobiol Learn Mem 81(3):185–199

    PubMed  CAS  Google Scholar 

  25. Miracle AD, Brace MF, Huyck KD, Singler SA, Wellman CL (2006) Chronic stress impairs recall of extinction of conditioned fear. Neurobiol Learn Mem 85(3):213–218

    PubMed  Google Scholar 

  26. Garcia R, Spennato G, Nilsson-Todd L, Moreau JL, Deschaux O (2008) Hippocampal low-frequency stimulation and chronic mild stress similarly disrupt fear extinction memory in rats. Neurobiol Learn Mem 89(4):560–566

    PubMed  Google Scholar 

  27. Baran SE, Armstrong CE, Niren DC, Hanna JJ, Conrad CD (2009) Chronic stress and sex differences on the recall of fear conditioning and extinction. Neurobiol Learn Mem 91:323–332

    PubMed  Google Scholar 

  28. Cahill L (2005) His brain, her brain. Sci Am 292(5):40–47

    PubMed  Google Scholar 

  29. Cahill L (2006) Why sex matters for neuroscience. Nat Rev Neurosci 7(6):477–484

    PubMed  CAS  Google Scholar 

  30. Amaral DG, Lavenex P (2007) Hippocampal neuroanatomy. In: Andersen P, Morris RG, Amaral DG, Bliss T, O’Keefe J (eds) The hippocampus book. Oxford University Press, New York, pp 37–114

    Google Scholar 

  31. Smith TC, Wingard DL, Ryan MA, Kritz-Silverstein D, Slymen DJ, Sallis JF (2008) Prior assault and posttraumatic stress disorder after combat deployment. Epidemiology 19(3):505–512

    PubMed  Google Scholar 

  32. Weber K, Rockstroh B, Borgelt J, Awiszus B, Popov T, Hoffmann K, Schonauer K, Watzl H, Propster K (2008) Stress load during childhood affects psychopathology in psychiatric patients. BMC Psychiatry 8:63

    PubMed  Google Scholar 

  33. Kendler KS, Prescott CA (1999) A population-based twin study of lifetime major depression in men and women. Arch Gen Psychiatry 56(1):39–44

    PubMed  CAS  Google Scholar 

  34. Patten SB, Stuart HL, Russell ML, Maxwell CJ, Arboleda-Florez J (2003) Epidemiology of major depression in a predominantly rural health region. Soc Psychiatry Psychiatr Epidemiol 38(7):360–365

    PubMed  Google Scholar 

  35. Paykel ES (2003) Life events and affective disorders. Acta Psychiatr Scand Suppl 108(418):61–66

    Google Scholar 

  36. Bale TL (2006) Stress sensitivity and the development of affective disorders. Horm Behav 50(4):529–533

    PubMed  CAS  Google Scholar 

  37. Hammen C, Kim EY, Eberhart NK, Brennan PA (2009) Chronic and acute stress and the prediction of major depression in women. Depress Anxiety (in press). doi:10.1002/da.20571

  38. Gold PW, Chrousos GP (2002) Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol Psychiatry 7(3):254–275

    PubMed  CAS  Google Scholar 

  39. Breslau N, Davis GC, Andreski P, Peterson EL, Schultz LR (1997) Sex differences in posttraumatic stress disorder. Arch Gen Psychiatry 54(11):1044–1048

    PubMed  CAS  Google Scholar 

  40. Chida Y, Hamer M (2008) Chronic psychosocial factors and acute physiological responses to laboratory-induced stress in healthy populations: a quantitative review of 30 years of investigations. Psychol Bull 134(6):829–885

    PubMed  Google Scholar 

  41. Weber K, Rockstroh B, Borgelt J, Awiszus B, Popov T, Hoffmann K, Schonauer K, Watzl H, Propster K (2008) Stress load during childhood affects psychopathology in psychiatric patients. BMC Psychiatry 8:63–72

    PubMed  Google Scholar 

  42. Agid O, Kohn Y, Lerer B (2000) Environmental stress and psychiatric illness. Biomed Pharmacother 54(3):135–141

    PubMed  CAS  Google Scholar 

  43. De Bellis MD, Baum AS, Birmaher B, Keshavan MS, Eccard CH, Boring AM, Jenkins FJ, Ryan ND (1999) A.E. Bennett Research Award. Developmental traumatology. Part I: biological stress systems. Biol Psychiatry 45(10):1259–1270

    PubMed  Google Scholar 

  44. De Bellis MD, Thomas LA (2003) Biologic findings of post-traumatic stress disorder and child maltreatment. Curr Psychiatry Rep 5(2):108–117

    PubMed  Google Scholar 

  45. Reus VI, Wolkowitz OM (2001) Antiglucocorticoid drugs in the treatment of depression. Expert Opin Investig Drugs 10:1789–1796

    PubMed  CAS  Google Scholar 

  46. Brown ES, Varghese FP, McEwen BS (2004) Association of depression with medical illness: does cortisol play a role? Biol Psychiatry 55(1):1–9

    PubMed  CAS  Google Scholar 

  47. Swaab DF, Bao AM, Lucassen PJ (2005) The stress system in the human brain in depression and neurodegeneration. Ageing Res Rev 4(2):141–194

    PubMed  CAS  Google Scholar 

  48. Gomez RG, Fleming SH, Keller J, Flores B, Kenna H, Debattista C, Solvason B, Schatzberg AF (2006) The neuropsychological profile of psychotic major depression and its relation to cortisol. Biol Psychiatry 60:472–478

    PubMed  Google Scholar 

  49. Reppermund S, Zihl J, Lucae S, Horstmann S, Kloiber S, Holsboer F, Ising M (2007) Persistent cognitive impairment in depression: the role of psychopathology and altered hypothalamic–pituitary–adrenocortical (HPA) system regulation. Biol Psychiatry 62(5):400–406

    PubMed  CAS  Google Scholar 

  50. Beck AT (2008) The evolution of the cognitive model of depression and its neurobiological correlates. Am J Psychiatry 165(8):969–977

    PubMed  Google Scholar 

  51. Pardon MC, Rattray I (2008) What do we know about the long-term consequences of stress on ageing and the progression of age-related neurodegenerative disorders? Neurosci Biobehav Rev 32(6):1103–1120

    PubMed  Google Scholar 

  52. Sotiropoulos I, Cerqueira JJ, Catania C, Takashima A, Sousa N, Almeida OF (2008) Stress and glucocorticoid footprints in the brain—the path from depression to Alzheimer’s disease. Neurosci Biobehav Rev 32(6):1161–1173

    PubMed  CAS  Google Scholar 

  53. Willner P (1997) Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation. Psychopharmacology 134:319–329

    PubMed  CAS  Google Scholar 

  54. McEwen BS, Weiss JM, Schwartz LS (1968) Selective retention of corticosterone by limbic structures in rat brain. Nature 220:911–912

    PubMed  CAS  Google Scholar 

  55. McEwen BS, Weiss JM, Schwartz LS (1969) Uptake of corticosterone by rat brain and its concentration by certain limbic structures. Brain Res 16:227–241

    PubMed  CAS  Google Scholar 

  56. Sapolsky RM (2000) Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry 57:925–935

    PubMed  CAS  Google Scholar 

  57. Bremner JD, Elzinga B, Schmahl C, Vermetten E (2008) Structural and functional plasticity of the human brain in posttraumatic stress disorder. Prog Brain Res 167:171–186

    PubMed  Google Scholar 

  58. Bremner JD (2006) The relationship between cognitive and brain changes in posttraumatic stress disorder. Ann N Y Acad Sci 1071:80–86

    PubMed  Google Scholar 

  59. Karl A, Schaefer M, Malta LS, Dörfel D, Rohleder N, Werner A (2006) A meta-analysis of structural brain abnormalities in PTSD. Neurosci Biobehav Rev 30:1004–1031

    PubMed  Google Scholar 

  60. Gilbertson MW, Shenton ME, Ciazewski A, Kasai K, Lasko NB, Orr SP, Pitman RK (2002) Smaller hippocampal volume predicts pathological vulnerability to psychological trauma. Nat Neurosci 5:1242–1247

    PubMed  CAS  Google Scholar 

  61. Lindauer RJ, Vlieger EJ, Jalink M, Olff M, Carlier IV, Majoie CB, den Heeten GJ, Gersons BP (2004) Smaller hippocampal volume in Dutch police officers with posttraumatic stress disorder. Biol Psychiatry 56(5):356–363

    PubMed  Google Scholar 

  62. Wignall EL, Dickson JM, Vaughan P, Farrow TF, Wilkinson ID, Hunter MD, Woodruff PW (2004) Smaller hippocampal volume in patients with recent-onset posttraumatic stress disorder. Biol Psychiatry 56(11):832–836

    PubMed  Google Scholar 

  63. Brown ES, Rush AJ, McEwen BS (1999) Hippocampal remodeling and damage by corticosteroids: implications for mood disorders. Neuropsychopharmacology 21:474–484

    PubMed  CAS  Google Scholar 

  64. Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS (2000) Hippocampal volume reduction in major depression. Am J Psychiatry 157(1):115–117

    PubMed  CAS  Google Scholar 

  65. Sheline YI, Gado MH, Kraemer HC (2003) Untreated depression and hippocampal volume loss. Am J Psychiatr 160(8):1516–1518

    PubMed  Google Scholar 

  66. Campbell S, Marriott M, Nahmias C, MacQueen GM (2004) Lower hippocampal volume in patients suffering from depression: a meta-analysis. Am J Psychiatry 161(4):598–607

    PubMed  Google Scholar 

  67. Lange C, Irle E (2004) Enlarged amygdala volume and reduced hippocampal volume in young women with major depression. Psychol Med 34(6):1059–1064

    PubMed  CAS  Google Scholar 

  68. Vasic N, Walter H, Hose A, Wolf RC (2008) Gray matter reduction associated with psychopathology and cognitive dysfunction in unipolar depression: a voxel-based morphometry study. J Affect Disord 109(1–2):107–116

    PubMed  Google Scholar 

  69. Sheline YI, Wang PW, Gado MH, Csernansky JC, Vannier MW (1996) Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A 93:3908–3913

    PubMed  CAS  Google Scholar 

  70. Vakili K, Pillay SS, Lafer B, Fava M, Renshaw PF, Bonello-Cintron CM, Yurgelun-Todd DA (2000) Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study. Biol Psychiatry 47(12):1087–1090

    PubMed  CAS  Google Scholar 

  71. von Gunten A, Fox NC, Cipolotti L, Ron MA (2000) A volumetric study of hippocampus and amygdala in depressed patients with subjective memory problems. J Neuropsychiatry Clin Neurosci 12(4):493–498

    Google Scholar 

  72. Frodl T, Meisenzahl EM, Zetzsche T, Born C, Groll C, Jager M, Leinsinger G, Bottlender R, Hahn K, Moller HJ (2002) Hippocampal changes in patients with a first episode of major depression. Am J Psychiatry 159(7):1112–1118

    PubMed  Google Scholar 

  73. Keller J, Shen L, Gomez RG, Garrett A, Solvason HB, Reiss A, Schatzberg AF (2008) Hippocampal and amygdalar volumes in psychotic and nonpsychotic unipolar depression. Am J Psychiatr 165(7):872–880

    PubMed  Google Scholar 

  74. Sheline YI, Mittler BL, Mintun MA (2002) The hippocampus and depression. Eur Psychiatry 17(Suppl 3):300–305

    PubMed  Google Scholar 

  75. Frodl TS, Koutsouleris N, Bottlender R, Born C, Jager M, Scupin I, Reiser M, Moller HJ, Meisenzahl EM (2008) Depression-related variation in brain morphology over 3 years: effects of stress? Arch Gen Psychiatry 65(10):1156–1165

    PubMed  Google Scholar 

  76. Ahima RS, Harlan RE (1990) Charting of type II glucocorticoid receptor-like immunoreactivity in the rat central nervous system. Neuroscience 39(3):579–604

    PubMed  CAS  Google Scholar 

  77. Ahima RS, Harlan RE (1991) Differential corticosteroid regulation of type II glucocorticoid receptor-like immunoreactivity in the rat central nervous system: topography and implications. Endocrinology 129(1):226–236

    PubMed  CAS  Google Scholar 

  78. Ahima R, Krozowski Z, Harlan R (1991) Type I corticosteroid receptor-like immunoreactivity in the rat CNS: distribution and regulation by corticosteroids. J Comp Neurol 313(3):522–538

    PubMed  CAS  Google Scholar 

  79. Herman JP, Figueiredo H, Mueller NK, Ulrich-Lai Y, Ostrander MM, Choi DC, Cullinan WE (2003) Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo-pituitary-adrenocortical responsiveness. Front Neuroendocrinol 24(3):151–180

    PubMed  CAS  Google Scholar 

  80. Bremner JD, Vythilingam M, Vermetten E, Nazeer A, Adil J, Khan S, Staib LH, Charney DS (2002) Reduced volume of orbitofrontal cortex in major depression. Biol Psychiatry 51(4):273–279

    PubMed  Google Scholar 

  81. Coryell W, Nopoulos P, Drevets W, Wilson T, Andreasen NC (2005) Subgenual prefrontal cortex volumes in major depressive disorder and schizophrenia: diagnostic specificity and prognostic implications. Am J Psychiatry 162(9):1706–1712

    PubMed  Google Scholar 

  82. Konarski JZ, McIntyre RS, Kennedy SH, Rafi-Tari S, Soczynska JK, Ketter TA (2008) Volumetric neuroimaging investigations in mood disorders: bipolar disorder versus major depressive disorder. Bipolar Disord 10(1):1–37

    PubMed  Google Scholar 

  83. Brown ES, Woolston DJ, Frol AB (2008) Amygdala volume in patients receiving chronic corticosteroid therapy. Biol Psychiatry 63(7):705–709

    PubMed  CAS  Google Scholar 

  84. Sheline YI, Gado MH, Price JL (1998) Amygdala core nuclei volumes are decreased in recurrent major depression. NeuroReport 9(9):2023–2028

    PubMed  CAS  Google Scholar 

  85. Yoshikawa E, Matsuoka Y, Yamasue H, Inagaki M, Nakano T, Akechi T, Kobayakawa M, Fujimori M, Nakaya N, Akizuki N, Imoto S, Murakami K, Kasai K, Uchitomi Y (2006) Prefrontal cortex and amygdala volume in first minor or major depressive episode after cancer diagnosis. Biol Psychiatry 59(8):707–712

    PubMed  Google Scholar 

  86. Frodl T, Meisenzahl E, Zetzsche T, Bottlender R, Born C, Groll C, Jager M, Leinsinger G, Hahn K, Moller HJ (2002) Enlargement of the amygdala in patients with a first episode of major depression. Biol Psychiatry 51(9):708–714

    PubMed  Google Scholar 

  87. Ramel W, Goldin PR, Eyler LT, Brown GG, Gotlib IH, McQuaid JR (2007) Amygdala reactivity and mood-congruent memory in individuals at risk for depressive relapse. Biol Psychiatry 61(2):231–239

    PubMed  Google Scholar 

  88. Kemp AH, Felmingham K, Das P, Hughes G, Peduto AS, Bryant RA, Williams LM (2007) Influence of comorbid depression on fear in posttraumatic stress disorder: an fMRI study. Psychiatry Res 155(3):265–259

    PubMed  Google Scholar 

  89. Shin LM, Rauch SL, Pitman RK (2006) Amygdala, medial prefrontal cortex, and hippocampal function in PTSD. Ann N Y Acad Sci 1071:67–79

    PubMed  Google Scholar 

  90. Shin LM, Wright CI, Cannistraro PA, Wedig MM, McMullin K, Martis B, Macklin ML, Lasko NB, Cavanagh SR, Krangel TS, Orr SP, Pitman RK, Whalen PJ, Rauch SL (2005) 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(3):273–281

    PubMed  Google Scholar 

  91. Woon FL, Hedges DW (2008) Hippocampal and amygdala volumes in children and adults with childhood maltreatment-related posttraumatic stress disorder: a meta-analysis. Hippocampus 18(8):729–736

    PubMed  Google Scholar 

  92. Becker JB, Arnold AP, Berkley KJ, Blaustein JD, Eckel LA, Hampson E, Herman JP, Marts S, Sadee W, Steiner M, Taylor J, Young E (2005) Strategies and methods for research on sex differences in brain and behavior. Endocrinology 146:1650–1673

    PubMed  CAS  Google Scholar 

  93. Olff M, Langeland W, Draijer N, Gersons BP (2007) Gender differences in posttraumatic stress disorder. Psychol Bull 133(2):183–204

    PubMed  Google Scholar 

  94. Richter R, Flowers T (2008) Gendered dimensions of disaster care: critical distinctions in female psychosocial needs, triage, pain assessment, and care. Am J Disaster Med 3(1):31–37

    PubMed  Google Scholar 

  95. Heller W (1993) Gender differences in depression: perspectives from neuropsychology. J Affect Disord 29(2–3):129–143

    PubMed  CAS  Google Scholar 

  96. Kessler RC, McGonagle KA, Swartz M, Blazer DG, Nelson CB (1993) Sex and depression in the National Comorbidity Survey. I: Lifetime prevalence, chronicity and recurrence. J Affect Disord 29(2-3):85–96

    PubMed  CAS  Google Scholar 

  97. Weissman MM, Bland R, Joyce PR, Newman S, Wells JE, Wittchen HU (1993) Sex differences in rates of depression: cross-national perspectives. J Affect Disord 29(2–3):77–84

    PubMed  CAS  Google Scholar 

  98. Gao S, Hendrie HC, Hall KS, Hui S (1998) The relationships between age, sex, and the incidence of dementia and Alzheimer disease: a meta-analysis. Arch Gen Psychiatry 55(9):809–815

    PubMed  CAS  Google Scholar 

  99. Azad NA, Al Bugami M, Loy-English I (2007) Gender differences in dementia risk factors. Gend Med 4(2):120–129

    PubMed  Google Scholar 

  100. Altemus KL, Almi CR (1997) Neonatal hippocampal damage in rats: long-term spatial memory deficits and associations with magnitude of hippocampal damage. Hippocampus 7:403–414

    PubMed  CAS  Google Scholar 

  101. Parry BL, Javeed S, Laughlin GA, Hauger R, Clopton P (2000) Cortisol circadian rhythms during the menstrual cycle and with sleep deprivation in premenstrual dysphoric disorder and normal control subjects. Biol Psychiatry 48(9):920–931

    PubMed  CAS  Google Scholar 

  102. Kajantie E, Phillips DI (2006) The effects of sex and hormonal status on the physiological response to acute psychosocial stress. Psychoneuroendocrinology 31(2):151–178

    PubMed  CAS  Google Scholar 

  103. Young EA, Altemus M (2004) Puberty, ovarian steroids, and stress. Ann N Y Acad Sci 1021:124–133

    PubMed  CAS  Google Scholar 

  104. Endicott J (1993) The menstrual cycle and mood disorders. J Affect Disord 29(2–3):193–200

    PubMed  CAS  Google Scholar 

  105. Goldstein JM, Jerram M, Poldrack R, Ahern T, Kennedy DN, Seidman LJ, Makris N (2005) Hormonal cycle modulates arousal circuitry in women using functional magnetic resonance imaging. J Neurosci 25(40):9309–9316

    PubMed  CAS  Google Scholar 

  106. Protopopescu X, Pan H, Altemus M, Tuescher O, Polanecsky M, McEwen B, Silbersweig D, Stern E (2005) Orbitofrontal cortex activity related to emotional processing changes across the menstrual cycle. Proc Natl Acad Sci U S A 102(44):16060–16065

    PubMed  CAS  Google Scholar 

  107. Genazzani AR, Pluchino N, Luisi S, Luisi M (2007) Estrogen, cognition and female ageing. Hum Reprod Update 13(2):175–187

    PubMed  CAS  Google Scholar 

  108. Garcia-Bueno B, Caso JR, Leza JC (2008) Stress as a neuroinflammatory condition in brain: damaging and protective mechanisms. Neurosci Biobehav Rev 32(6):1136–1151

    PubMed  CAS  Google Scholar 

  109. Buynitsky T, Mostofsky DI (2009) Restraint stress in biobehavioral research: recent developments. Neurosci Biobehav Rev 33:1089–1098

    PubMed  Google Scholar 

  110. Conrad CD, Galea LAM, Kuroda Y, McEwen BS (1996) Chronic stress impairs rat spatial memory on the Y-maze, and this effect is blocked by tianeptine pretreatment. Behav Neurosci 110(6):1321–1334

    PubMed  CAS  Google Scholar 

  111. Wright RL, Conrad CD (2005) Chronic stress leaves novelty-seeking intact while impairing spatial recognition memory in the Y-maze. Stress 8(2):151–154

    PubMed  Google Scholar 

  112. Wright RL, Lightner EN, Harman JS, Meijer OC, Conrad CD (2006) Attenuating corticosterone levels on the day of memory assessment prevents chronic stress-induced impairments in spatial memory. Eur J NeuroSci 24:595–605

    PubMed  Google Scholar 

  113. Kleen JK, Sitomer MT, Killeen PR, Conrad CD (2006) Chronic stress impairs spatial memory and motivation for reward without disrupting motor ability and motivation to explore. Behav Neurosci 120(4):842–851

    PubMed  Google Scholar 

  114. Bellani R, Luecken L, Conrad CD (2006) Peripubertal anxiety profile can predict spatial memory impairments following chronic stress. Behav Brain Res 166(2):263–270

    PubMed  Google Scholar 

  115. Duman RS (2004) Depression: a case of neuronal life and death? Biol Psychiatry 56(3):140–145

    PubMed  Google Scholar 

  116. Dranovsky A, Hen R (2006) Hippocampal neurogenesis: regulation by stress and antidepressants. Biol Psychiatry 59(12):1136–1143

    PubMed  CAS  Google Scholar 

  117. Vyas A, Mitra R, Shankaranarayana Rao BS, Chattarji S (2002) Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J Neurosci 22:6810–6818

    PubMed  CAS  Google Scholar 

  118. McLaughlin KJ, Gomez JL, Baran SE, Conrad CD (2007) The effects of chronic stress on hippocampal morphology and function: an evaluation of chronic restraint paradigms. Brain Res 1161:56–64

    PubMed  CAS  Google Scholar 

  119. Magariños AM, McEwen BS, Flügge G, Fuchs E (1996) Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews. J Neurosci 16:3534–3540

    PubMed  Google Scholar 

  120. Cook SC, Wellman CL (2004) Chronic stress alters dendritic morphology in rat medial prefrontal cortex. J Neurobiol 60(2):236–248

    PubMed  Google Scholar 

  121. Brown SM, Henning S, Wellman CL (2005) Mild, short-term stress alters dendritic morphology in rat medial prefrontal cortex. Cereb Cortex 15(11):1714–1722

    PubMed  Google Scholar 

  122. Radley JJ, Sisti HM, Hao J, Rocher AB, McCall T, Hof PR, McEwen BS, Morrison JH (2004) Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex. Neuroscience 125:1–6

    PubMed  CAS  Google Scholar 

  123. Vyas A, Jadhav S, Chattarji S (2006) Prolonged behavioral stress enhances synaptic connectivity in the basolateral amygdala. Neuroscience 143(2):387–393

    PubMed  CAS  Google Scholar 

  124. Cui H, Sakamoto H, Higashi S, Kawata M (2008) Effects of single-prolonged stress on neurons and their afferent inputs in the amygdala. Neuroscience 152(3):703–712

    PubMed  CAS  Google Scholar 

  125. Colla M, Kronenberg G, Deuschle M, Meichel K, Hagen T, Bohrer M, Heuser I (2007) Hippocampal volume reduction and HPA-system activity in major depression. J Psychiatry Res 41(7):553–560

    Google Scholar 

  126. Watanabe Y, Gould E, Daniels DC, Cameron H, McEwen BS (1992) Tianeptine attenuates stress-induced morphological changes in the hippocampus. Eur J Pharmacol 222:157–162

    PubMed  CAS  Google Scholar 

  127. Luo L, Tan RX (2001) Fluoxetine inhibits dendrite atrophy of hippocampal neurons by decreasing nitric oxide synthase expression in rat depression model. Acta Pharmacol Sin 22(10):865–870

    PubMed  CAS  Google Scholar 

  128. Bao AM, Meynen G, Swaab DF (2008) The stress system in depression and neurodegeneration: focus on the human hypothalamus. Brain Res Rev 57:531–553

    PubMed  CAS  Google Scholar 

  129. Purves D, Lichtman JW (1985) Geometrical differences among homologous neurons in mammals. Science 228(4697):298–302

    PubMed  CAS  Google Scholar 

  130. Schaefer AT, Larkum ME, Sakmann B, Roth A (2003) Coincidence detection in pyramidal neurons is tuned by their dendritic branching pattern. J Neurophysiol 89(6):3143–3154

    PubMed  Google Scholar 

  131. Spruston N (2008) Pyramidal neurons: dendritic structure and synaptic integration. Nat Rev Neurosci 9(3):206–221

    PubMed  CAS  Google Scholar 

  132. Cove J, Blinder P, Baranes D (2009) Contacts among non-sister dendritic branches at bifurcations shape neighboring dendrites and pattern their synaptic inputs. Brain Res 1251:30–41

    PubMed  CAS  Google Scholar 

  133. Martinez JL Jr, Barea-Rodriguez EJ (1997) How the brain stores information: Hebbian mechanisms. In: Lueer G, Lass U (eds) Erinnern und Behalten Wege zur Erforschung des menschlichen gedaechtnisses. Vandenhoeck & Ruprecht, Goettingen, pp 39–59

    Google Scholar 

  134. Conrad CD (2006) What is the functional significance of chronic stress-induced CA3 dendritic retraction within the hippocampus? Behav Cogn Neurosci Rev 5(1):41–60

    PubMed  Google Scholar 

  135. Pittenger C, Duman RS (2008) Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 33(1):88–109

    PubMed  CAS  Google Scholar 

  136. Calabrese F, Molteni R, Racagni G, Riva MA (2009) Neuronal plasticity: a link between stress and mood disorders. Psychoneuroendocrinology (in press). doi:10.1016/j.psyneuen.2009.05.014

  137. Grossman AW, Churchill JD, McKinney BC, Kodish IM, Otte SL, Greenough WT (2003) Experience effects on brain development: possible contributions to psychopathology. J Child Psychol Psychiatry 44(1):33–63

    PubMed  Google Scholar 

  138. Fiala JC, Spacek J, Harris KM (2002) Dendritic spine pathology: cause or consequence of neurological disorders? Brain Res Rev 39(1):29–54

    PubMed  Google Scholar 

  139. Sjostrom PJ, Rancz EA, Roth A, Hausser M (2008) Dendritic excitability and synaptic plasticity. Physiol Rev 88(2):769–840

    PubMed  CAS  Google Scholar 

  140. Viau V (2002) Functional cross-talk between the hypothalamic–pituitary–gonadal and –adrenal axes. J Neuroendocrinol 14(6):506–513

    PubMed  CAS  Google Scholar 

  141. Aloisi AM, Bonifazi M (2006) Sex hormones, central nervous system and pain. Horm Behav 50(1):1–7

    PubMed  CAS  Google Scholar 

  142. Altemus M, Redwine L, Leong Y, Yoshikawa T, Yehuda R, Detera-Wadleigh S, Murphy DL (1997) Reduced sensitivity to glucocorticoid feedback and reduced glucocorticoid receptor mRNA expression in the luteal phase of the menstrual cycle. Neuropsychopharmacology 17:100–109

    PubMed  CAS  Google Scholar 

  143. Viau V, Meaney MJ (1991) Variations in the hypothalamic–pituitary–adrenal response to stress during the estrous cycle in the rat. Endocrinology 129(5):2503–2511

    PubMed  CAS  Google Scholar 

  144. Atkinson HC, Waddell BJ (1997) Circadian variation in basal plasma corticosterone and adrenocorticotropin in the rat: sexual dimorphism and changes across the estrous cycle. Endocrinology 138(9):3842–3848

    PubMed  CAS  Google Scholar 

  145. Haim S, Shakhar G, Rossene E, Taylor AN, Ben-Eliyahu S (2003) Serum levels of sex hormones and corticosterone throughout 4- and 5-day estrous cycles in Fischer 344 rats and their simulation in ovariectomized females. J Endocrinol Invest 26(10):1013–1022

    PubMed  CAS  Google Scholar 

  146. Conrad CD, Jackson JL, Wieczorek L, Baran SE, Harman JS, Wright RL, Korol DL (2004) Acute restraint stress impairs spatial memory in male but not female rats: influence of estrous cycle. Pharmacol Biochem Behav 78(3):569–579

    PubMed  CAS  Google Scholar 

  147. Dalla C, Antoniou K, Drossopoulou G, Xagoraris M, Kokras N, Sfikakis A, Papadopoulou-Daifoti Z (2005) Chronic mild stress impact: are females more vulnerable? Neuroscience 135(3):703–714

    PubMed  CAS  Google Scholar 

  148. McEwen BS, Conrad CD, Kuroda Y, Frankfurt M, Magariños AM, McKittrick C (1997) Prevention of stress-induced morphological and cognitive consequences. Eur Neuropsychopharm 7:S323–S328

    Google Scholar 

  149. McEwen BS, Magariños AM (1997) Stress effects on morphology and function of the hippocampus. Ann N Y Acad Sci 821:271–284

    PubMed  CAS  Google Scholar 

  150. McEwen BS (2005) Glucocorticoids, depression, and mood disorders: structural remodeling in the brain. Metabolism 54(5 Suppl 1):20–23

    PubMed  CAS  Google Scholar 

  151. Lambert KG, Buckelew SK, Staffiso-Sandoz G, Gaffga S, Carpenter W, Fisher J, Kinsely CH (1998) Activity-stress induces atrophy of apical dendrites of hippocampal pyramidal neurons in male rats. Physiol Behav 65:43–49

    PubMed  CAS  Google Scholar 

  152. Sousa N, Lukoyanov NV, Madeira MD, Almeida OFX, Paula-Barbosa MM (2000) Reorganization of the morphology of hippocampal neurites and synapses after stress-induced damage correlates with behavioral improvement. Neuroscience 97:253–266

    PubMed  CAS  Google Scholar 

  153. Woolley CS, Gould E, McEwen BS (1990) Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res 531:225–231

    PubMed  CAS  Google Scholar 

  154. Magariños AM, McEwen BS (1995) Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: comparison of stressors. Neuroscience 69(1):83–88

    PubMed  Google Scholar 

  155. Sandi C, Davies HA, Cordero MI, Rodriquez JJ, Popov VI, Stewart MG (2003) Rapid reversal of stress induced loss of synapses in CA3 of rat hippocampus following water maze training. Eur J NeuroSci 17:2447–2456

    PubMed  Google Scholar 

  156. Fuchs E, Uno H, Flügge G (1995) Chronic psychosocial stress induces morphological alterations in hippocampal pyramidal neurons of the tree shrew. Brain Res 673(2):275–282

    PubMed  CAS  Google Scholar 

  157. Conrad CD, McLaughlin KJ, Harman JS, Foltz C, Wieczorek L, Lightner E, Wright RL (2007) Chronic glucocorticoids increase hippocampal vulnerability to neurotoxicity under conditions that produce CA3 dendritic retraction but fail to impair spatial recognition memory. J Neurosci 27(31):8278–8285

    PubMed  CAS  Google Scholar 

  158. Luine VN, Spencer RL, McEwen BS (1993) Effects of chronic corticosterone ingestion on spatial memory performance and hippocampal serotonergic function. Brain Res 616:65–70

    PubMed  CAS  Google Scholar 

  159. Luine V, Villegas M, Martinez C, McEwen BS (1994) Repeated stress causes reversible impairments of spatial memory performance. Brain Res 639:167–170

    PubMed  CAS  Google Scholar 

  160. Park CR, Campbell AM, Diamond DM (2001) Chronic psychosocial stress impairs learning and memory and increases sensitivity to yohimbine in rats. Biol Psychiatry 50:994–1004

    PubMed  CAS  Google Scholar 

  161. Gerges NZ, Alzoubi KH, Park CR, Diamond DM, Alkadhi KA (2004) Adverse effect of the combination of hypothyroidism and chronic psychosocial stress on hippocampus-dependent memory in rats. Behav Brain Res 155(1):77–84

    PubMed  Google Scholar 

  162. Srivareerat M, Tran TT, Alzoubi KH, Alkadhi KA (2009) Chronic psychosocial stress exacerbates impairment of cognition and long-term potentiation in beta-amyloid rat model of Alzheimer’s disease. Biol Psychiatry 65(11):918–926

    PubMed  CAS  Google Scholar 

  163. Sunanda, Shankaranarayana Rao BS, Raju TR (2000) Chronic restraint stress impairs acquisition and retention of spatial memory task in rats. Curr Sci 79:14581–1584

    Google Scholar 

  164. Ohl F, Fuchs E (1999) Differential effects of chronic stress on memory processes in the tree shrew. Cogn Brain Res 7:379–387

    CAS  Google Scholar 

  165. Venero C, Tilling T, Hermans-Borgmeyer I, Schmidt R, Schachner M, Sandi C (2002) Chronic stress induces opposite changes in the mRNA expression of the cell adhesion molecules NCAM and L1. Neuroscience 115(4):1211–1219

    PubMed  CAS  Google Scholar 

  166. Wright RL, Conrad CD (2008) Enriched environment prevents chronic stress-induced spatial learning and memory deficits. Behav Brain Res 187(1):41–47

    PubMed  Google Scholar 

  167. Ma WP, Cao J, Tian M, Cui MH, Han HL, Yang YX, Xu L (2007) Exposure to chronic constant light impairs spatial memory and influences long-term depression in rats. Neurosci Res 59(2):224–230

    PubMed  Google Scholar 

  168. Song L, Che W, Min-Wei W, Murakami Y, Matsumoto K (2006) Impairment of the spatial learning and memory induced by learned helplessness and chronic mild stress. Pharmacol Biochem Behav 83(2):186–193

    PubMed  CAS  Google Scholar 

  169. Walesiuk A, Trofimiuk E, Braszko JJ (2005) Gingko biloba extract diminishes stress-induced memory deficits in rats. Pharmacol Rep 57(2):176–187

    PubMed  Google Scholar 

  170. Watanabe Y, Gould E, Cameron HA, Daniels DC, McEwen BS (1992) Phenytoin prevents stress- and corticosterone-induced atrophy of CA3 pyramidal neurons. Hippocampus 2(4):431–436

    PubMed  CAS  Google Scholar 

  171. Lathe R (2001) Hormones and hippocampus. J Endocrinol 169:205–231

    PubMed  CAS  Google Scholar 

  172. Galea LAM, McEwen BS, Tanapat P, Deak T, Spencer RL, Dhabhar FS (1997) Sex differences in dendritic atrophy of CA3 pyramidal neurons in response to chronic restraint stress. Neuroscience 81(3):689–697

    PubMed  CAS  Google Scholar 

  173. McLaughlin KJ, Wilson JO, Harman J, Wright RL, Wieczorek L, Gomez J, Korol DL, Conrad CD (2009) Chronic 17β-estradiol or cholesterol prevents stress-induced hippocampal CA3 dendritic retraction in ovariectomized females: possible correspondence between CA1 spine properties and spatial acquisition. Hippocampus (in press)

  174. McLaughlin KJ, Baran SE, Wright RL, Conrad CD (2005) Chronic stress enhances spatial memory in ovariectomized female rats despite CA3 dendritic retraction: possible involvement of CA1 neurons. Neuroscience 135(4):1045–1054

    PubMed  CAS  Google Scholar 

  175. Bowman RE, Zrull MC, Luine VN (2001) Chronic restraint stress enhances radial arm maze performance in female rats. Brain Res 904:279–289

    PubMed  CAS  Google Scholar 

  176. Kitraki E, Kremmyda O, Youlatos D, Alexis MN, Kittas C (2004) Gender-dependent alterations in corticosteroid receptor status and spatial performance following 21 days of restraint stress. Neuroscience 125:47–55

    PubMed  CAS  Google Scholar 

  177. Kitraki E, Kremmyda O, Youlatos D, Alexis M, Kittas C (2004) Spatial performance and corticosteroid receptor status in the 21-day restraint stress paradigm. Ann N Y Acad Sci 1018:323–327

    PubMed  CAS  Google Scholar 

  178. Conrad CD, Grote KA, Hobbs RJ, Ferayorni A (2003) Sex differences in spatial and non-spatial Y-maze performance after chronic stress. Neurobiol Learn Mem 79:32–40

    PubMed  Google Scholar 

  179. Bowman RE, Ferguson D, Luine VN (2002) Effects of chronic restraint stress and estradiol on open field activity, spatial memory, and monoaminergic neurotransmitters in ovariectomized rats. Neuroscience 113:401–410

    PubMed  CAS  Google Scholar 

  180. McEwen BS, Alves SE (1999) Estrogen actions in the central nervous system. Endocr Rev 20(3):279–307

    PubMed  CAS  Google Scholar 

  181. Lee SJ, McEwen BS (2001) Neurotrophic and neuroprotective actions of estrogens and their therapeutic implications. Annu Rev Pharmacol Toxicol 41:569–591

    PubMed  CAS  Google Scholar 

  182. Loy R, Gerlach JL, McEwen BS (1988) Autoradiographic localization of estradiol-binding neurons in the rat hippocampal formation and entorhinal cortex. Brain Res 467(2):245–251

    PubMed  CAS  Google Scholar 

  183. Blurton-Jones M, Tuszynski MH (2002) Estrogen receptor-beta colocalizes extensively with parvalbumin-labeled inhibitory neurons in the cortex, amygdala, basal forebrain, and hippocampal formation of intact and ovariectomized adult rats. J Comp Neurol 452(3):276–287

    PubMed  Google Scholar 

  184. Kretz O, Fester L, Wehrenberg U, Zhou L, Brauckmann S, Zhao S, Prange-Kiel J, Naumann T, Jarry H, Frotscher M, Rune GM (2004) Hippocampal synapses depend on hippocampal estrogen synthesis. J Neurosci 24(26):5913–5921

    PubMed  CAS  Google Scholar 

  185. Cornil CA, Ball GF, Balthazart J (2006) Functional significance of the rapid regulation of brain estrogen action: where do the estrogens come from? Brain Res 1126(1):2–26

    PubMed  CAS  Google Scholar 

  186. Conrad CD, Jackson JL, Wise L (2004) Chronic stress enhances ibotenic acid-induced damage selectively within the hippocampal CA3 region of male, but not female rats. Neuroscience 125(3):759–767

    PubMed  CAS  Google Scholar 

  187. Takuma K, Matsuo A, Himeno Y, Hoshina Y, Ohno Y, Funatsu Y, Arai S, Kamei H, Mizoguchi H, Nagai T, Koike K, Inoue M, Yamada K (2007) 17β-Estradiol attenuates hippocampal neuronal loss and cognitive dysfunction induced by chronic restraint stress in ovariectomized rats. Neuroscience 146(1):60–68

    PubMed  CAS  Google Scholar 

  188. Bowman RE, Beck KD, Luine VN (2003) Chronic stress effects on memory: sex differences in performance and monoaminergic activity. Horm Behav 43:48–59

    PubMed  CAS  Google Scholar 

  189. Brun VH, Otnass MK, Molden S, Steffenach HA, Witter MP, Moser MB, Moser EI (2002) Place cells and place recognition maintained by direct entorhinal–hippocampal circuitry. Science 296(5576):2243–2246

    PubMed  CAS  Google Scholar 

  190. Vago DR, Bevan A, Kesner RP (2007) The role of the direct perforant path input to the CA1 subregion of the dorsal hippocampus in memory retention and retrieval. Hippocampus 17(10):977–987

    PubMed  Google Scholar 

  191. Brun VH, Leutgeb S, Wu HQ, Schwarcz R, Witter MP, Moser EI, Moser MB (2008) Impaired spatial representation in CA1 after lesion of direct input from entorhinal cortex. Neuron 57(2):290–302

    PubMed  CAS  Google Scholar 

  192. Kajiwara R, Wouterlood FG, Sah A, Boekel AJ, Baks-te Bulte LT, Witter MP (2008) Convergence of entorhinal and CA3 inputs onto pyramidal neurons and interneurons in hippocampal area CA1—an anatomical study in the rat. Hippocampus 18(3):266–280

    PubMed  Google Scholar 

  193. Poirier GL, Amin E, Aggleton JP (2008) Qualitatively different hippocampal subfield engagement emerges with mastery of a spatial memory task by rats. J Neurosci 28:1034–1045

    PubMed  CAS  Google Scholar 

  194. Vago DR, Kesner RP (2008) Disruption of the direct perforant path input to the CA1 subregion of the dorsal hippocampus interferes with spatial working memory and novelty detection. Behav Brain Res 189(2):273–283

    PubMed  Google Scholar 

  195. Goodrich-Hunsaker NJ, Hunsaker MR, Kesner RP (2008) The interactions and dissociations of the dorsal hippocampus subregions: how the dentate gyrus, CA3, and CA1 process spatial information. Behav Neurosci 122(1):16–26

    PubMed  Google Scholar 

  196. Hoang LT, Kesner RP (2008) Dorsal hippocampus, CA3, and CA1 lesions disrupt temporal sequence completion. Behav Neurosci 122(1):9–15

    PubMed  Google Scholar 

  197. Hunsaker MR, Lee B, Kesner RP (2008) Evaluating the temporal context of episodic memory: the role of CA3 and CA1. Behav Brain Res 188(2):310–315

    PubMed  CAS  Google Scholar 

  198. Okada K, Okaichi H (2009) Functional differentiation and cooperation among the hippocampal subregions in rats to effect spatial memory processes. Behav Brain Res 200(1):181–191

    PubMed  Google Scholar 

  199. Nakazawa K, Sun LD, Quirk MC, Rondi-Reig L, Wilson MA, Tonegawa S (2003) Hippocampal CA3 NMDA receptors are crucial for memory acquisition of one-time experience. Neuron 38(2):305–315

    PubMed  CAS  Google Scholar 

  200. Gold AE, Kesner RP (2005) The role of the CA3 subregion of the dorsal hippocampus in spatial pattern completion in the rat. Hippocampus 15(6):808–814

    PubMed  Google Scholar 

  201. Lee I, Jerman TS, Kesner RP (2005) Disruption of delayed memory for a sequence of spatial locations following CA1- or CA3-lesions of the dorsal hippocampus. Neurobiol Learn Mem 84(2):138–147

    PubMed  Google Scholar 

  202. Maclusky NJ, Hajszan T, Prange-Kiel J, Leranth C (2006) Androgen modulation of hippocampal synaptic plasticity. Neuroscience 138:957–965

    PubMed  CAS  Google Scholar 

  203. Cunningham RL, Claiborne BJ, McGinnis MY (2007) Pubertal exposure to anabolic androgenic steroids increases spine densities on neurons in the limbic system of male rats. Neuroscience 150(3):609–615

    PubMed  CAS  Google Scholar 

  204. Hajszan T, MacLusky NJ, Leranth C (2008) Role of androgens and the androgen receptor in remodeling of spine synapses in limbic brain areas. Horm Behav 53(5):638–646

    PubMed  CAS  Google Scholar 

  205. Prange-Kiel J, Rune GM (2006) Direct and indirect effects of estrogen on the rat hippocampus. Neuroscience 138:765–772

    PubMed  CAS  Google Scholar 

  206. Woolley CS (2007) Acute effects of estrogen on neuronal physiology. Annu Rev Pharmacol Toxicol 47:657–680

    PubMed  CAS  Google Scholar 

  207. McLaughlin KJ, Bimonte-Nelson HA, Neisewander JL, Conrad CD (2008) Assessment of estradiol influence on spatial tasks and hippocampal CA1 spines: evidence that the duration of hormone deprivation after ovariectomy compromises 17β-estradiol effectiveness in altering CA1 spines. Horm Behav 54(3):386–395

    PubMed  CAS  Google Scholar 

  208. Woolley CS, Gould E, Frankfurt M, McEwen BS (1990) Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons. J Neurosci 10:4035–4039

    PubMed  CAS  Google Scholar 

  209. Woolley CS, McEwen BS (1992) Estradiol mediates fluctuation in hippocampal synapse density during the estrous cycle in the adult rat. J Neurosci 12(7):2549–2554

    PubMed  CAS  Google Scholar 

  210. Woolley CS (1998) Estrogen-mediated structural and functional synaptic plasticity in the female rat hippocampus. Horm Behav 34:140–148

    PubMed  CAS  Google Scholar 

  211. Garza-Meilandt A, Cantu RE, Claiborne BJ (2006) Estradiol’s effects on learning and neuronal morphology vary with route of administration. Behav Neurosci 120(4):905–916

    PubMed  Google Scholar 

  212. Wallace M, Luine V, Arellanos A, Frankfurt M (2006) Ovariectomized rats show decreased recognition memory and spine density in the hippocampus and prefrontal cortex. Brain Res 1126(1):176–182

    PubMed  CAS  Google Scholar 

  213. Sandstrom NJ, Williams CL (2001) Memory retention is modulated by acute estradiol and progesterone replacement. Behav Neurosci 115:384–393

    PubMed  CAS  Google Scholar 

  214. Sandstrom NJ, Williams CL (2004) Spatial memory retention is enhanced by acute and continuous estradiol replacement. Horm Behav 45(2):128–135

    PubMed  CAS  Google Scholar 

  215. Donohue HS, Gabbott PLA, Davies HA, Rodriguez JJ, Cordero MI, Sandi C, Medvedev NI, Popov VI, Colyer FM, Peddie CJ, Stewart MG (2006) Chronic restraint stress induces changes in synapse morphology in stratum lacunosum-moleculare CA1 rat hippocampus: a stereological and three-dimensional ultrastructural study. Neuroscience 140(2):597–606

    PubMed  CAS  Google Scholar 

  216. Shors TJ (2006) Significant life events and the shape of memories to come: a hypothesis. Neurobiol Learn Mem 85:103–115

    PubMed  Google Scholar 

  217. Dalla C, Whetstone AS, Hodes GE, Shors TJ (2009) Stressful experience has opposite effects on dendritic spines in the hippocampus of cycling versus masculinized females. Neurosci Lett 449(1):52–56

    PubMed  CAS  Google Scholar 

  218. Diamond DM, Campbell AM, Park CR, Woodson JC, Conrad CD, Bachstetter AD, Mervis R (2006) Influence of predator stress on the consolidation versus retrieval of long-term spatial memory and hippocampal spinogenesis. Hippocampus 16:571–576

    PubMed  Google Scholar 

  219. Cerqueira JJ, Almeida OF, Sousa N (2008) The stressed prefrontal cortex. Left? Right!. Brain Behav Immun 22(5):630–638

    PubMed  CAS  Google Scholar 

  220. Holmes A, Wellman CL (2009) Stress-induced prefrontal reorganization and executive dysfunction in rodents. Neurosci Biobehav Rev 33(6):773–783

    PubMed  Google Scholar 

  221. Singewald N (2007) Altered brain activity processing in high-anxiety rodents revealed by challenge paradigms and functional mapping. Neurosci Biobehav Rev 31(1):18–40

    PubMed  Google Scholar 

  222. Del Arco A, Segovia G, Garrido P, de Blas M, Mora F (2007) Stress, prefrontal cortex and environmental enrichment: studies on dopamine and acetylcholine release and working memory performance in rats. Behav Brain Res 176(2):267–273

    PubMed  Google Scholar 

  223. Mizoguchi K, Yuzurihara M, Ishige A, Sasaki H, Chui DH, Tabira T (2000) Chronic stress induces impairment of spatial working memory because of prefrontal dopaminergic dysfunction. J Neurosci 20(4):1568–1574

    PubMed  CAS  Google Scholar 

  224. Moghaddam B (1993) Stress preferentially increases extraneuronal levels of excitatory amino acids in the prefrontal cortex: comparison to hippocampus and basal ganglia. J Neurochem 60:1650–1557

    PubMed  CAS  Google Scholar 

  225. Miner LH, Jedema HP, Moore FW, Blakely RD, Grace AA, Sesack SR (2006) Chronic stress increases the plasmalemmal distribution of the norepinephrine transporter and the coexpression of tyrosine hydroxylase in norepinephrine axons in the prefrontal cortex. J Neurosci 26(5):1571–1578

    PubMed  CAS  Google Scholar 

  226. Herman JP, Ostrander MM, Mueller NK, Figueiredo H (2005) Limbic system mechanisms of stress regulation: hypothalamo-pituitary-adrenocortical axis. Prog Neuropsychopharmacol Biol Psychiatry 29(8):1201–1213

    PubMed  CAS  Google Scholar 

  227. Liston C, Miller MM, Goldwater DS, Radley JJ, Rocher AB, Hof PR, Morrison JH, McEwen BS (2006) Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J Neurosci 26(30):7870–7874

    PubMed  CAS  Google Scholar 

  228. Garrett JE, Wellman CL (2009) Chronic stress effects on dendritic morphology in medial prefrontal cortex: sex differences and estrogen dependence. Neuroscience 162(1):195–207

    PubMed  CAS  Google Scholar 

  229. Izquierdo A, Wellman CL, Holmes A (2006) Brief uncontrollable stress causes dendritic retraction in infralimbic cortex and resistance to fear extinction in mice. J Neurosci 26(21):5733–5738

    PubMed  CAS  Google Scholar 

  230. Seib LM, Wellman CL (2003) Daily injections alter spine density in rat medial prefrontal cortex. Neurosci Lett 337(1):29–32

    PubMed  CAS  Google Scholar 

  231. Czéh B, Perez-Cruz C, Fuchs E, Flügge G (2008) Chronic stress-induced cellular changes in the medial prefrontal cortex and their potential clinical implications: does hemisphere location matter? Behav Brain Res 190(1):1–13

    PubMed  Google Scholar 

  232. Cerqueira JJ, Pego JM, Taipa R, Bessa JM, Almeida OF, Sousa N (2005) Morphological correlates of corticosteroid-induced changes in prefrontal cortex-dependent behaviors. J Neurosci 25(34):7792–7800

    PubMed  CAS  Google Scholar 

  233. Cerqueira JJ, Mailliet F, Almeida OF, Jay TM, Sousa N (2007) The prefrontal cortex as a key target of the maladaptive response to stress. J Neurosci 27(11):2781–2787

    PubMed  CAS  Google Scholar 

  234. Grootendorst J, de Kloet ER, Vossen C, Dalm S, Oitzl MS (2001) Repeated exposure to rats has persistent genotype-dependent effects on learning and locomotor activity of apolipoprotein E knockout and C57Bl/6 mice. Behav Brain Res 125(1–2):249–259

    PubMed  CAS  Google Scholar 

  235. Grootendorst J, de Kloet ER, Dalm S, Oitzl MS (2001) Reversal of cognitive deficit of apolipoprotein E knockout mice after repeated exposure to a common environmental experience. Neuroscience 108(2):237–247

    PubMed  CAS  Google Scholar 

  236. Schwabe L, Dalm S, Schachinger H, Oitzl MS (2008) Chronic stress modulates the use of spatial and stimulus-response learning strategies in mice and man. Neurobiol Learn Mem 90(3):495–503

    PubMed  Google Scholar 

  237. Wellman CL (2001) Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration. Brain Res 828:127–134

    Google Scholar 

  238. Cerqueira JJ, Taipa R, Uylings HB, Almeida OF, Sousa N (2007) Specific configuration of dendritic degeneration in pyramidal neurons of the medial prefrontal cortex induced by differing corticosteroid regimens. Cereb Cortex 17(9):1998–2006

    PubMed  Google Scholar 

  239. Wang VC, Sable HJ, Ju YH, Allred CD, Helferich WG, Korol DL, Schantz SL (2008) Effects of chronic estradiol treatment on delayed spatial alternation and differential reinforcement of low rates of responding. Behav Neurosci 122(4):794–804

    PubMed  CAS  Google Scholar 

  240. Cahill L, Babinsky R, Markowitsch HJ, McGaugh JL (1995) The amygdala and emotional memory. Nature 377:295–296

    PubMed  CAS  Google Scholar 

  241. Sarter M, Markowitsch HJ (1985) Involvement of the amygdala in learning and memory: a critical review, with emphasis on anatomical relations. Behav Neurosci 99(2):342–380

    PubMed  CAS  Google Scholar 

  242. McGaugh JL, Roozendaal B (2002) Role of adrenal stress hormones in forming lasting memories in the brain. Curr Opin Neurobiol 12:205–210

    PubMed  CAS  Google Scholar 

  243. Roozendaal B (2002) Stress and memory: opposing effects of glucocorticoids on memory consolidation and memory retrieval. Neurobiol Learn Mem 78:578–595

    PubMed  CAS  Google Scholar 

  244. Roozendaal B, Portillo-Marquez G, McGaugh JL (1996) Basolateral amygdala lesions block glucocorticoid-induced modulation of memory for spatial learning. Behav Neurosci 110(5):1074–1083

    PubMed  CAS  Google Scholar 

  245. Roozendaal B, McGaugh JL (1997) Basolateral amygdala lesions block the memory-enhancing effect of glucocorticoid administration in the dorsal hippocampus of rats. Eur J NeuroSci 9:76–83

    PubMed  CAS  Google Scholar 

  246. Rodriguez Manzanares PA, Isoardi NA, Carrer HF, Molina VA (2005) Previous stress facilitates fear memory, attenuates GABAergic inhibition, and increases synaptic plasticity in the rat basolateral amygdala. J Neurosci 25(38):8725–8734

    PubMed  Google Scholar 

  247. Roozendaal B, McReynolds JR, McGaugh JL (2004) The basolateral amygdala interacts with the medial prefrontal cortex in regulating glucocorticoid effects on working memory impairment. J Neurosci 24(6):1385–1392

    PubMed  CAS  Google Scholar 

  248. Anglada-Figueroa D, Quirk GJ (2005) Lesions of the basal amygdala block expression of conditioned fear but not extinction. J Neurosci 25(42):9680–9685

    PubMed  CAS  Google Scholar 

  249. Conrad CD, Mauldin-Jourdain ML, Hobbs RJ (2001) Metyrapone reveals that previous chronic stress differentially impairs hippocampal-dependent memory. Stress 4(4):305–318

    Article  PubMed  CAS  Google Scholar 

  250. Vyas A, Pillai AG, Chattarji S (2004) Recovery after chronic stress fails to reverse amygdaloid neuronal hypertrophy and enhanced anxiety-like behavior. Neuroscience 128(4):667–673

    PubMed  CAS  Google Scholar 

  251. Jackson ED, Payne JD, Nadel L, Jacobs WJ (2006) Stress differentially modulates fear conditioning in healthy men and women. Biol Psychiatry 59(6):516–522

    PubMed  Google Scholar 

  252. Zorawski M, Blanding NQ, Kuhn CM, LaBar KS (2006) Effects of stress and sex on acquisition and consolidation of human fear conditioning. Learn Mem 13(4):441–450

    PubMed  CAS  Google Scholar 

  253. Shors TJ, Weiss C, Thompson RF (1992) Stress-induced facilitation of classical conditioning. Science 257:537–539

    PubMed  CAS  Google Scholar 

  254. Bangasser DA, Shors TJ (2004) Acute stress impairs trace eyeblink conditioning in females without altering the unconditional response. Neurobiol Learn Mem 82:57–60

    PubMed  Google Scholar 

  255. Wood GE, Shors TJ (1998) Stress facilitates classical conditioning in males, but impairs classical conditioning in females through activational effects of ovarian hormones. Proc Natl Acad Sci U S A 95(7):4066–4071

    PubMed  CAS  Google Scholar 

  256. Shors TJ (2001) Acute stress rapidly and persistently enhances memory formation in the male rat. Neurobiol Learn Mem 75:10–29

    PubMed  CAS  Google Scholar 

  257. Waddell J, Bangasser DA, Shors TJ (2008) The basolateral nucleus of the amygdala is necessary to induce the opposing effects of stressful experience on learning in males and females. J Neurosci 28(20):5290–5294

    PubMed  CAS  Google Scholar 

  258. Turner BB (1997) Influence of gonadal steroids on brain corticosteroid receptors: a minireview. Neurochem Res 22(11):1375–1385

    PubMed  CAS  Google Scholar 

  259. Karandrea D, Kittas C, Kitraki E (2000) Contribution of sex and cellular context in the regulation of brain corticosteroid receptors following restraint stress. Neuroendocrinology 71:343–353

    PubMed  CAS  Google Scholar 

  260. Alves SE, Hoskin E, Lee SJ, Brake WG, Ferguson D, Luine V, Allen PB, Greengard P, McEwen BS (2002) Serotonin mediates CA1 spine density but is not crucial for ovarian steroid regulation of synaptic plasticity in the adult rat dorsal hippocampus. Synapse 45(2):143–151

    PubMed  CAS  Google Scholar 

  261. Beck KD, Luine VN (2002) Sex differences in behavioral and neurochemical profiles after chronic stress: role of housing conditions. Physiol Behav 75:661–673

    PubMed  CAS  Google Scholar 

  262. Inoue T, Li XB, Abekawa T, Kitaichi Y, Izumi T, Nakagawa S, Koyama T (2004) Selective serotonin reuptake inhibitor reduces conditioned fear through its effect in the amygdala. Eur J Pharmacol 497(3):311–316

    PubMed  CAS  Google Scholar 

  263. Mitsushima D, Yamada K, Takase K, Funabashi T, Kimura F (2006) Sex differences in the basolateral amygdala: the extracellular levels of serotonin and dopamine, and their responses to restraint stress in rats. Eur J NeuroSci 24(11):3245–3254

    PubMed  Google Scholar 

  264. Conrad CD (2008) Chronic stress-induced hippocampal vulnerability: the glucocorticoid vulnerability hypothesis. Rev Neurosci 19(6):395–412

    PubMed  Google Scholar 

  265. Conrad CD, Wright RL, McLaughlin KJ (2009) Stress and vulnerability to brain damage. In: Squire LR (ed) Encyclopedia of neuroscience. Academic, Oxford, pp 481–488

    Google Scholar 

  266. Foy MR, Baudry M, Briton RD, Thompson RF (2008) Estrogen and hippocampal plasticity in rodent models. J Alzheim Dis 15:589–603

    CAS  Google Scholar 

  267. Foy MR, Baudry M, Foy JG, Thompson RF (2008) 17b-estradiol modifies stress-induced and age-related changes in hippocampal synaptic plasticity. Behav Neurosci 122(2):301–309

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by MH64727, a grant from the Institute for Mental Health Research, and the Arizona Biomedical Research Commission.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Cheryl D. Conrad.

Rights and permissions

Reprints and permissions

About this article

Cite this article

McLaughlin, K.J., Baran, S.E. & Conrad, C.D. Chronic Stress- and Sex-Specific Neuromorphological and Functional Changes in Limbic Structures. Mol Neurobiol 40, 166–182 (2009). https://doi.org/10.1007/s12035-009-8079-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-009-8079-7

Keyword

Navigation