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Continuous expression of corticotropin-releasing factor in the central nucleus of the amygdala emulates the dysregulation of the stress and reproductive axes

Molecular Psychiatry volume 14, pages 37–50 (2009)Cite this article

Abstract

An increase in corticotropin-releasing factor (CRF) is a putative factor in the pathophysiology of stress-related disorders. As CRF expression in the central nucleus of the amygdala (CeA) is important in adaptation to chronic stress, we hypothesized that unrestrained synthesis of CRF in CeA would mimic the consequences of chronic stress exposure and cause dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, increase emotionality and disrupt reproduction. To test this hypothesis, we used a lentiviral vector to increase CRF-expression site specifically in CeA of female rats. Increased synthesis of CRF in CeA amplified CRF and arginine vasopressin peptide concentration in the paraventricular nucleus of the hypothalamus, and decreased glucocorticoid negative feedback, both markers associated with the pathophysiology of depression. In addition, continuous expression of CRF in CeA also increased the acoustic startle response and depressive-like behavior in the forced swim test. Protein levels of gonadotropin-releasing hormone in the medial preoptic area were significantly reduced by continuous expression of CRF in CeA and this was associated with a lengthening of estrous cycles. Finally, sexual motivation but not sexual receptivity was significantly attenuated by continuous CRF synthesis in ovariectomized estradiol-progesterone-primed females. These data indicate that unrestrained CRF synthesis in CeA produces a dysregulation of the HPA axis, as well as many of the behavioral, physiological and reproductive consequences associated with stress-related disorders.

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References

  1. Florio P, Zatelli MC, Reis FM, degli Uberti EC, Petraglia F . Corticotropin releasing hormone: a diagnostic marker for behavioral and reproductive disorders? Front Biosci 2007; 12: 551–560.

    Article  CAS  PubMed  Google Scholar 

  2. Centeno ML, Sanchez RL, Cameron JL, Bethea CL . Hypothalamic gonadotrophin-releasing hormone expression in female monkeys with different sensitivity to stress. J Neuroendocrinol 2007; 19: 594–604.

    Article  CAS  PubMed  Google Scholar 

  3. Bao AM, Meynen G, Swaab DF . The stress system in depression and neurodegeneration: focus on the human hypothalamus. Brain Res Rev 2007; 57: 531–553.

    Article  PubMed  CAS  Google Scholar 

  4. Schulkin J, Gold PW, McEwen BS . Induction of corticotropin-releasing hormone gene expression by glucocorticoids: implication for understanding the states of fear and anxiety and allostatic load. Psychoneuroendocrinology 1998; 23: 219–243.

    Article  CAS  PubMed  Google Scholar 

  5. Weissman MM, Olfson M . Depression in women: implications for health care research. Science 1995; 269: 799–801.

    Article  CAS  PubMed  Google Scholar 

  6. Berga SL, Loucks TL . The diagnosis and treatment of stress-induced anovulation. Minerva Ginecol 2005; 57: 45–54.

    CAS  PubMed  Google Scholar 

  7. Aihara M, Ida I, Yuuki N, Oshima A, Kumano H, Takahashi K et al. HPA axis dysfunction in unmedicated major depressive disorder and its normalization by pharmacotherapy correlates with alteration of neural activity in prefrontal cortex and limbic/paralimbic regions. Psychiatry Res 2007; 155: 245–256.

    Article  CAS  PubMed  Google Scholar 

  8. Kaplan JR, Manuck SB . Status, stress, and atherosclerosis: the role of environment and individual behavior. Ann NY Acad Sci 1999; 896: 145–161.

    Article  CAS  PubMed  Google Scholar 

  9. Sautter FJ, Bissette G, Wiley J, Manguno-Mire G, Schoenbachler B, Myers L et al. Corticotropin-releasing factor in posttraumatic stress disorder (PTSD) with secondary psychotic symptoms, nonpsychotic PTSD, and healthy control subjects. Biol Psychiatry 2003; 54: 1382–1388.

    Article  CAS  PubMed  Google Scholar 

  10. Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB . The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol 1999; 160: 1–12.

    Article  CAS  PubMed  Google Scholar 

  11. Nemeroff CB, Widerlov E, Bissette G, Walleus H, Karlsson I, Eklund K et al. Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 1984; 226: 1342–1344.

    Article  CAS  PubMed  Google Scholar 

  12. Polkowska J, Przekop F . The effect of corticotropin-releasing factor (CRF) on the gonadotropin hormone releasing hormone (GnRH) hypothalamic neuronal system during preovulatory period in the ewe. Acta Neurobiol Exp (Wars) 1997; 57: 91–99.

    CAS  Google Scholar 

  13. Rivier C, Rivest S . Effect of stress on the activity of the hypothalamic-pituitary-gonadal axis: peripheral and central mechanisms. Biol Reprod 1991; 45: 523–532.

    Article  CAS  PubMed  Google Scholar 

  14. Petraglia F, Sutton S, Vale W, Plotsky P . Corticotropin-releasing factor decreases plasma luteinizing hormone levels in female rats by inhibiting gonadotropin-releasing hormone release into hypophysial-portal circulation. Endocrinology 1987; 120: 1083–1088.

    Article  CAS  PubMed  Google Scholar 

  15. Sirinathsinghji DJ . Modulation of lordosis behaviour in the female rat by corticotropin releasing factor, beta-endorphin and gonadotropin releasing hormone in the mesencephalic central gray. Brain Res 1985; 336: 45–55.

    Article  CAS  PubMed  Google Scholar 

  16. Swanson LW, Sawchenko PE, Rivier J, Vale WW . Organization of ovine corticotropin-releasing factor immunoreactive cells and fibers in the rat brain: an immunohistochemical study. Neuroendocrinology 1983; 36: 165–186.

    Article  CAS  PubMed  Google Scholar 

  17. Beyer HS, Matta SG, Sharp BM . Regulation of the messenger ribonucleic acid for corticotropin-releasing factor in the paraventricular nucleus and other brain sites of the rat. Endocrinology 1988; 123: 2117–2123.

    Article  CAS  PubMed  Google Scholar 

  18. Sawchenko PE, Swanson LW . Localization, colocalization, and plasticity of corticotropin-releasing factor immunoreactivity in rat brain. Fed Proc 1985; 44 (1 Pt 2): 221–227.

    CAS  PubMed  Google Scholar 

  19. Albeck DS MC, Blanchard DC, Blanchard RJ, Nikulina J, McEwen BS, Sakai RR . Chronic social stress alters levels of corticotropin-releasing factor and arginine vasopressin mRNA in rat brain. J Neurosci 1997; 17: 4895–4903.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Shepard JD, Barron KW, Myers DA . Corticosterone delivery to the amygdala increases corticotropin-releasing factor mRNA in the central amygdaloid nucleus and anxiety-like behavior. Brain Res 2000; 861: 288–295.

    Article  CAS  PubMed  Google Scholar 

  21. Stout SC, Mortas P, Owens MJ, Nemeroff CB, Moreau J . Increased corticotropin-releasing factor concentrations in the bed nucleus of the stria terminalis of anhedonic rats. Eur J Pharmacol 2000; 401: 39–46.

    Article  CAS  PubMed  Google Scholar 

  22. Dallman MF, Pecoraro N, Akana SF, La Fleur SE, Gomez F, Houshyar H et al. Chronic stress and obesity: a new view of ‘comfort food’. Proc Natl Acad Sci USA 2003; 100: 11696–11701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ma XM, Levy A, Lightman SL . Emergence of an isolated arginine vasopressin (AVP) response to stress after repeated restraint: a study of both AVP and corticotropin-releasing hormone messenger ribonucleic acid (RNA) and heteronuclear RNA. Endocrinology 1997; 138: 4351–4357.

    Article  CAS  PubMed  Google Scholar 

  24. Aguilera G, Rabadan-Diehl C . Vasopressinergic regulation of the hypothalamic-pituitary-adrenal axis: implications for stress adaptation. Regul Pept 2000; 96: 23–29.

    Article  CAS  PubMed  Google Scholar 

  25. Makino S, Smith MA, Gold PW . Increased expression of corticotropin-releasing hormone and vasopressin messenger ribonucleic acid (mRNA) in the hypothalamic paraventricular nucleus during repeated stress: association with reduction in glucocorticoid receptor mRNA levels. Endocrinology 1995; 136: 3299–3309.

    Article  CAS  PubMed  Google Scholar 

  26. Raadsheer FC, Hoogendijk WJ, Stam FC, Tilders FJ, Swaab DF . Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 1994; 60: 436–444.

    Article  CAS  PubMed  Google Scholar 

  27. Bhatnagar S, Dallman M . Neuroanatomical basis for facilitation of hypothalamic-pituitary-adrenal responses to a novel stressor after chronic stress. Neuroscience 1998; 84: 1025–1039.

    Article  CAS  PubMed  Google Scholar 

  28. Makino S, Hashimoto K, Gold PW . Multiple feedback mechanisms activating corticotropin-releasing hormone system in the brain during stress. Pharmacol Biochem Behav 2002; 73: 147–158.

    Article  CAS  PubMed  Google Scholar 

  29. Herman JP, Figueiredo H, Mueller NK, Ulrich-Lai Y, Ostrander MM, Choi DC et al. Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo-pituitary-adrenocortical responsiveness. Front Neuroendocrinol 2003; 24: 151–180.

    Article  CAS  PubMed  Google Scholar 

  30. Lai Z, Brady RO . Gene transfer into the central nervous system in vivo using a recombinanat lentivirus vector. J Neurosci Res 2002; 67: 363–371.

    Article  CAS  PubMed  Google Scholar 

  31. Naldini L, Blomer U, Gage FH, Trono D, Verma IM . Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector. Proc Natl Acad Sci USA 1996; 93: 11382–11388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Miyoshi H, Blomer U, Takahashi M, Gage FH, Verma IM . Development of a self-inactivating lentivirus vector. J Virol 1998; 72: 8150–8157.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Abordo-Adesida E, Follenzi A, Barcia C, Sciascia S, Castro MG, Naldini L et al. Stability of lentiviral vector-mediated transgene expression in the brain in the presence of systemic antivector immune responses. Hum Gene Ther 2005; 16: 741–751.

    Article  CAS  PubMed  Google Scholar 

  34. Jakobsson J, Lundberg C . Lentiviral vectors for use in the central nervous system. Mol Ther 2006; 13: 484–493.

    Article  CAS  PubMed  Google Scholar 

  35. Zufferey R, Dull T, Mandel RJ, Bukovsky A, Quiroz D, Naldini L et al. Self-inactivating lentivirus vector for safe and efficient in vivo gene delivery. J Virol 1998; 72: 9873–9880.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Zufferey R, Donello JE, Trono D, Hope TJ . Woodchuck Hepatitis Virus Posttranscriptional Regulatory Element Enhances Expression of Transgenes Delivered by Retroviral Vectors. J Virol 1999; 73: 2886–2892.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Naldini L, Blomer U, Gage FH, Trono D, Verma IM . Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector. PNAS 1996; 93: 11382–11388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Heldt SA, Stanek L, Chhatwal JP, Ressler KJ . Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories. Mol Psychiatry 2007; 12: 656–670.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Rattiner LM, Davis M, French CT, Ressler KJ . Brain-derived neurotrophic factor and tyrosine kinase receptor B involvement in amygdala-dependent fear conditioning. J Neurosci 2004; 24: 4796–4806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Long JA, Evans HM . The Oestrous Cycle in the Rat and its Associated Phenomena. University of California Press: Berkeley, 1922, pp 1–48.

    Google Scholar 

  41. Everett JW . Neurobiology of Reproduction in the Female Rat, vol. 32. Springer-Verlag: Berlin, Germany, 1989, pp 1–133.

    Book  Google Scholar 

  42. Mizoguchi K, Yuzurihara M, Ishige A, Sasaki H, Chui DH, Tabira T . Chronic stress differentially regulates glucocorticoid negative feedback response in rats. Psychoneuroendocrinology 2001; 26: 443–459.

    Article  CAS  PubMed  Google Scholar 

  43. Porsolt RD, Anton G, Blavet N, Jalfre M . Behavioural despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol 1978; 47: 379–391.

    Article  CAS  PubMed  Google Scholar 

  44. Toufexis DJ, Davis C, Hammond A, Davis M . Progesterone attenuates corticotropin-releasing factor-enhanced but not fear-potentiated startle via the activity of its neuroactive metabolite, allopregnanolone. J Neurosci 2004; 24: 10280–10287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Uphouse L, Selvamani A, Lincoln C, Morales L, Comeaux D . Mild restraint reduces the time hormonally primed rats spend with sexually active males. Behav Brain Res 2005; 157: 343–350.

    Article  CAS  PubMed  Google Scholar 

  46. Patisaul HB, Luskin JR, Wilson ME . A soy supplement and tamoxifen inhibit sexual behavior in female rats. Horm Behav 2004; 45: 270–277.

    Article  CAS  PubMed  Google Scholar 

  47. Gibbs RA, Rogers J, Katze MG, Bumgarner R, Weinstock GM, Mardis ER et al. Evolutionary and biomedical insights from the rhesus macaque genome. Science 2007; 316: 222–234.

    Article  CAS  PubMed  Google Scholar 

  48. Simmons DM, Arriza JL, Swanson LW . A complete protocol for in situ hybridization of messenger RNAs in brain and other tissues with radiolabeled single-stranded RNA probes. J Histotechnol 1989; 12: 169–181.

    Article  CAS  Google Scholar 

  49. Paxinos G, Watson C . The Rat Brain in Stereotaxic Coordinates. Academic Press: San Diego, CA, 1986.

    Google Scholar 

  50. Pike AC, Brzozowski AM, Walton J, Hubbard RE, Bonn T, Gustafsson JA et al. Structural aspects of agonism and antagonism in the oestrogen receptor. Biochem Soc Trans 2000; 28: 396–400.

    Article  CAS  PubMed  Google Scholar 

  51. Merali Z, Kent P, Du L, Hrdina P, Palkovits M, Faludi G et al. Corticotropin-releasing hormone, arginine vasopressin, gastrin-releasing peptide, and neuromedin B alterations in stress-relevant brain regions of suicides and control subjects. Biol Psychiatry 2006; 59: 594–602.

    Article  CAS  PubMed  Google Scholar 

  52. Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB . The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol 1999; 160: 1–12.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  54. de Kloet ER . Hormones, brain and stress. Endocr Regul 2003; 37: 51–68.

    CAS  PubMed  Google Scholar 

  55. Ma XM, Lightman SL, Aguilera G . Vasopressin and corticotropin-releasing hormone gene responses to novel stress in rats adapted to repeated restraint. Endocrinology 1999; 140: 3623–3632.

    Article  CAS  PubMed  Google Scholar 

  56. Bonaz B, Rivest S . Effect of a chronic stress on CRF neuronal activity and expression of its type 1 receptor in the rat brain. Am J Physiol 1998; 275 (5 Part 2): R1438–R1449.

    CAS  PubMed  Google Scholar 

  57. Aguilera G, Kiss A, Liu Y, Kamitakahara A . Negative regulation of corticotropin releasing factor expression and limitation of stress response. Stress 2007; 10: 153–161.

    Article  CAS  PubMed  Google Scholar 

  58. Mansi JA, Rivest S, Drolet G . Regulation of corticotropin-releasing factor type 1 (CRF1) receptor messenger ribonucleic acid in the paraventricular nucleus of rat hypothalamus by exogenous CRF. Endocrinology 1996; 137: 4619–4629.

    Article  CAS  PubMed  Google Scholar 

  59. Viau V, Meaney MJ . Variations in the hypothalamic-pituitary-adrenal response to stress during the estrous cycle in the rat. Endocrinology 1991; 129: 2503–2511.

    Article  CAS  PubMed  Google Scholar 

  60. Handa RJ, Burgess LH, Kerr JE, O'Keefe JA . Gonadal steroid hormone receptors and sex differences in the hypothalamo-pituitary-adrenal axis. Horm Behav 1994; 28: 464–476.

    Article  CAS  PubMed  Google Scholar 

  61. Kerdelhue B, Jones GS, Gordon K, Seltman H, Lenoir V, Melik Parsadaniantz S et al. Activation of the hypothalamo-anterior pituitary corticotropin-releasing hormone, adrenocorticotropin hormone and beta-endorphin systems during the estradiol 17 beta-induced plasma LH surge in the ovariectomized monkey. J Neurosci Res 1995; 42: 228–235.

    Article  CAS  PubMed  Google Scholar 

  62. Roy BN, Reid RL, Van Vugt DA . The effects of estrogen and progesterone on corticotropin-releasing hormone and arginine vasopressin messenger ribonucleic acid levels in the paraventricular nucleus and supraoptic nucleus of the rhesus monkey. Endocrinology 1999; 140: 2191–2198.

    Article  CAS  PubMed  Google Scholar 

  63. Li XF, Mitchell JC, Wood S, Coen CW, Lightman SL, O'Byrne KT . The effect of oestradiol and progesterone on hypoglycaemic stress-induced suppression of pulsatile luteinizing hormone release and on corticotropin-releasing hormone mRNA expression in the rat. J Neuroendocrinol 2003; 15: 468–476.

    Article  CAS  PubMed  Google Scholar 

  64. Paulmyer-Lacroix O, Hery M, Pugeat M, Grino M . The modulatory role of estrogens on corticotropin-releasing factor gene expression in the hypothalamic paraventricular nucleus of ovariectomized rats: role of the adrenal gland. J Neuroendocrinol 1996; 8: 515–519.

    Article  CAS  PubMed  Google Scholar 

  65. Pelletier G, Li S, Luu-The V, Labrie F . Oestrogenic regulation of pro-opiomelanocortin, neuropeptide Y and corticotrophin-releasing hormone mRNAs in mouse hypothalamus. J Neuroendocrinol 2007; 19: 426–431.

    Article  CAS  PubMed  Google Scholar 

  66. Greer ER, Caldwell JD, Johnson MF, Prange Jr AJ, Pedersen CA . Variations in concentration of oxytocin and vasopressin in the paraventricular nucleus of the hypothalamus during the estrous cycle in rats. Life Sci 1986; 38: 2311–2318.

    Article  CAS  PubMed  Google Scholar 

  67. Heuser I . Anna-Monika-Prize paper. The hypothalamic-pituitary-adrenal system in depression. Pharmacopsychiatry 1998; 31: 10–13.

    Article  CAS  PubMed  Google Scholar 

  68. Calfa G, Kademian S, Ceschin D, Vega G, Rabinovich GA, Volosin M . Characterization and functional significance of glucocorticoid receptors in patients with major depression: modulation by antidepressant treatment. Psychoneuroendocrinology 2003; 28: 687–701.

    Article  CAS  PubMed  Google Scholar 

  69. Wang X, Wu H, Miller AH . Interleukin 1alpha (IL-1alpha) induced activation of p38 mitogen-activated protein kinase inhibits glucocorticoid receptor function. Mol Psychiatry 2004; 9: 65–75.

    Article  CAS  PubMed  Google Scholar 

  70. Risbrough VB, Stein MB . Role of corticotropin releasing factor in anxiety disorders: a translational research perspective. Horm Behav 2006; 50: 550–561.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Fossey MD, Lydiard RB, Ballenger JC, Laraia MT, Bissette G, Nemeroff CB . Cerebrospinal fluid corticotropin-releasing factor concentrations in patients with anxiety disorders and normal comparison subjects. Biol Psychiatry 1996; 39: 703–707.

    Article  CAS  PubMed  Google Scholar 

  72. de Kloet CS, Vermetten E, Geuze E, Kavelaars A, Heijnen CJ, Westenberg HG . Assessment of HPA-axis function in posttraumatic stress disorder: pharmacological and non-pharmacological challenge tests, a review. J Psychiatr Res 2006; 40: 550–567.

    Article  CAS  PubMed  Google Scholar 

  73. Groenink L, Dirks A, Verdouw PM, Schipholt M, Veening JG, van der Gugten J et al. HPA axis dysregulation in mice overexpressing corticotropin releasing hormone. Biol Psychiatry 2002; 51: 875–881.

    Article  CAS  PubMed  Google Scholar 

  74. Peeters PJ, Fierens FL, van den Wyngaert I, Goehlmann HW, Swagemakers SM, Kass SU et al. Gene expression profiles highlight adaptive brain mechanisms in corticotropin releasing factor overexpressing mice. Brain Res Mol Brain Res 2004; 129: 135–150.

    Article  CAS  PubMed  Google Scholar 

  75. Roland BL, Sawchenko PE . Local origins of some GABAergic projections to the paraventricular and supraoptic nuclei of the hypothalamus in the rat. J Comp Neurol 1993; 332: 123–143.

    Article  CAS  PubMed  Google Scholar 

  76. Cullinan WE, Herman JP, Watson SJ . Ventral subicular interaction with the hypothalamic paraventricular nucleus: evidence for a relay in the bed nucleus of the stria terminalis. J Comp Neurol 1993; 332: 1–20.

    Article  CAS  PubMed  Google Scholar 

  77. Cullinan WE, Helmreich DL, Watson SJ . Fos expression in forebrain afferents to the hypothalamic paraventricular nucleus following swim stress. J Comp Neurol 1996; 368: 88–99.

    Article  CAS  PubMed  Google Scholar 

  78. Herman JP, Cullinan WE, Young EA, Akil H, Watson SJ . Selective forebrain fiber tract lesions implicate ventral hippocampal structures in tonic regulation of paraventricular nucleus corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) mRNA expression. Brain Res 1992; 592: 228–238.

    Article  CAS  PubMed  Google Scholar 

  79. Jacobson L, Akana SF, Cascio CS, Shinsako J, Dallman MF . Circadian variations in plasma corticosterone permit normal termination of adrenocorticotropin responses to stress. Endocrinology 1988; 122: 1343–1348.

    Article  CAS  PubMed  Google Scholar 

  80. Prewitt CM, Herman JP . Anatomical interactions between the central amygdaloid nucleus and the hypothalamic paraventricular nucleus of the rat: a dual tract-tracing analysis. J Chem Neuroanat 1998; 15: 173–185.

    Article  CAS  PubMed  Google Scholar 

  81. Spencer SJ, Buller KM, Day TA . Medial prefrontal cortex control of the paraventricular hypothalamic nucleus response to psychological stress: possible role of the bed nucleus of the stria terminalis. J Comp Neurol 2005; 481: 363–376.

    Article  PubMed  Google Scholar 

  82. Crane JW, Buller KM, Day TA . Evidence that the bed nucleus of the stria terminalis contributes to the modulation of hypophysiotropic corticotropin-releasing factor cell responses to systemic interleukin-1beta. J Comp Neurol 2003; 467: 232–242.

    Article  CAS  PubMed  Google Scholar 

  83. Canteras NS, Simerly RB, Swanson LW . Organization of projections from the medial nucleus of the amygdala: a PHAL study in the rat. J Comp Neurol 1995; 360: 213–245.

    Article  CAS  PubMed  Google Scholar 

  84. Dunn JD . Differential plasma corticosterone responses to electrical stimulation of the medial and lateral septal nuclei. Neuroendocrinology 1987; 46: 406–411.

    Article  CAS  PubMed  Google Scholar 

  85. Herman JP, Cullinan WE, Watson SJ . Involvement of the bed nucleus of the stria terminalis in tonic regulation of paraventricular hypothalamic CRH and AVP mRNA expression. J Neuroendocrinol 1994; 6: 433–442.

    Article  CAS  PubMed  Google Scholar 

  86. Gray TS, Piechowski RA, Yracheta JM, Rittenhouse PA, Bethea CL, Van de Kar LD . Ibotenic acid lesions in the bed nucleus of the stria terminalis attenuate conditioned stress-induced increases in prolactin, ACTH and corticosterone. Neuroendocrinology 1993; 57: 517–524.

    Article  CAS  PubMed  Google Scholar 

  87. Dong HW, Petrovich GD, Watts AG, Swanson LW . Basic organization of projections from the oval and fusiform nuclei of the bed nuclei of the stria terminalis in adult rat brain. J Comp Neurol 2001; 436: 430–455.

    Article  CAS  PubMed  Google Scholar 

  88. Dong HW, Petrovich GD, Swanson LW . Topography of projections from amygdala to bed nuclei of the stria terminalis. Brain Res Brain Res Rev 2001; 38: 192–246.

    Article  CAS  PubMed  Google Scholar 

  89. Barbas H . Flow of information for emotions through temporal and orbitofrontal pathways. J Anat 2007; 211: 237–249.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Jacobson L, Sapolsky R . The role of the hippocampus in feedback regulation of the hypothalamic-pituitary-adrenocortical axis. Endocr Rev 1991; 12: 118–134.

    Article  CAS  PubMed  Google Scholar 

  91. Orr SP, Metzger LJ, Pitman RK . Psychophysiology of post-traumatic stress disorder. Psychiatr Clin North Am 2002; 25: 271–293.

    Article  PubMed  Google Scholar 

  92. Swerdlow NR, Britton KT, Koob GF . Potentiation of acoustic startle by corticotropin-releasing factor (CRF) and by fear are both reversed by alpha-helical CRF (9-41). Neuropsychopharmacology 1989; 2: 285–292.

    Article  CAS  PubMed  Google Scholar 

  93. Liang KC, Melia KR, Miserendino MJ, Falls WA, Campeau S, Davis M . Corticotropin-releasing factor: long-lasting facilitation of the acoustic startle reflex. J Neurosci 1992; 12: 2303–2312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Davis M . Neural systems involved in fear and anxiety measured with fear-potentiated startle. Am Psychol 2006; 61: 741–756.

    Article  PubMed  Google Scholar 

  95. Sakanaka M, Shibasaki T, Lederis K . Distribution and efferent projections of corticotropin-releasing factor-like immunoreactivity in the rat amygdaloid complex. Brain Res 1986; 382: 213–238.

    Article  CAS  PubMed  Google Scholar 

  96. Swerdlow NR, Geyer MA, Vale WW, Koob GF . Corticotropin-releasing factor potentiates acoustic startle in rats: blockade by chlordiazepoxide. Psychopharmacology (Berl) 1986; 88: 147–152.

    Article  CAS  Google Scholar 

  97. Kitada Y, Miyauchi T, Satoh A, Satoh S . Effects of antidepressants in the rat forced swimming test. Eur J Pharmacol 1981; 72: 145–152.

    Article  CAS  PubMed  Google Scholar 

  98. Wilson ME, Gordon TP, Bernstein IS . Timing of births and reproductive success in rhesus monkey social groups. J Med Primatol 1978; 7: 202–212.

    Article  CAS  PubMed  Google Scholar 

  99. Adams MR, Kaplan JR, Koritnik DR . Psychosocial influences on ovarian endocrine and ovulatory function in Macaca fascicularis. Physiol Behav 1985; 35: 935–940.

    Article  CAS  PubMed  Google Scholar 

  100. Baker SL, Kentner AC, Konkle AT, Santa-Maria Barbagallo L, Bielajew C . Behavioral and physiological effects of chronic mild stress in female rats. Physiol Behav 2006; 87: 314–322.

    Article  CAS  PubMed  Google Scholar 

  101. Tsigos C, Chrousos GP . Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res 2002; 53: 865–871.

    Article  PubMed  Google Scholar 

  102. Rivest S, Plotsky PM, Rivier C . CRF alters the infundibular LHRH secretory system from the medial preoptic area of female rats: possible involvement of opioid receptors. Neuroendocrinology 1993; 57: 236–246.

    Article  CAS  PubMed  Google Scholar 

  103. Ortega E, Ruiz E, Rodriguez E, Frias J . Effect of corticotropin releasing factor (CRF) in the median eminence on gonadotropins in ovariectomized rats with or without steroid priming: dose-response study. Neurochem Res 1994; 19: 1225–1230.

    Article  CAS  PubMed  Google Scholar 

  104. Kalantaridou SN, Makrigiannakis A, Zoumakis E, Chrousos GP . Stress and the female reproductive system. J Reprod Immunol 2004; 62: 61–68.

    Article  CAS  PubMed  Google Scholar 

  105. Frohlich J, Ogawa S, Morgan M, Burton L, Pfaff D . Hormones, genes and the structure of sexual arousal. Behav Brain Res 1999; 105: 5–27.

    Article  CAS  PubMed  Google Scholar 

  106. Wallen K . Desire and ability: hormones and the regulation of female sexual behavior. Neurosci Biobehav Rev 1990; 14: 233–241.

    Article  CAS  PubMed  Google Scholar 

  107. Xiao L, Becker JB . Hormonal activation of the striatum and the nucleus accumbens modulates paced mating behavior in the female rat. Horm Behav 1997; 32: 114–124.

    Article  CAS  PubMed  Google Scholar 

  108. Kato A, Sakuma Y . Neuronal activity in female rat preoptic area associated with sexually motivated behavior. Brain Res 2000; 862: 90–102.

    Article  CAS  PubMed  Google Scholar 

  109. Green B . Post-traumatic stress disorder: symptom profiles in men and women. Curr Med Res Opin 2003; 19: 200–204.

    Article  PubMed  Google Scholar 

  110. Davidson RJ . Anxiety and affective style: role of prefrontal cortex and amygdala. Biol Psychiatry 2002; 51: 68–80.

    Article  PubMed  Google Scholar 

  111. Whalen PJ, Shin LM, Somerville LH, McLean AA, Kim H . Functional neuroimaging studies of the amygdala in depression. Semin Clin Neuropsychiatry 2002; 7: 234–242.

    Article  PubMed  Google Scholar 

  112. Drevets WC, Price JL, Bardgett ME, Reich T, Todd RD, Raichle ME . Glucose metabolism in the amygdala in depression: relationship to diagnostic subtype and plasma cortisol levels. Pharmacol Biochem Behav 2002; 71: 431–447.

    Article  CAS  PubMed  Google Scholar 

  113. Davis M, Whalen PJ . The amygdala: vigilance and emotion. Mol Psychiatry 2001; 6: 13–34.

    Article  CAS  PubMed  Google Scholar 

  114. Merali Z, McIntosh J, Kent P, Michaud D, Anisman H . Aversive and appetitive events evoke the release of corticotropin-releasing hormone and bombesin-like peptides at the central nucleus of the amygdala. J Neurosci 1998; 18: 4758–4766.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Plotsky PM, Thrivikraman KV, Nemeroff CB, Caldji C, Sharma S, Meaney MJ . Long-term consequences of neonatal rearing on central corticotropin-releasing factor systems in adult male rat offspring. Neuropsychopharmacology 2005; 30: 2192–2204.

    Article  CAS  PubMed  Google Scholar 

  116. Takahashi LK, Kalin NH, Vanden Burgt JA, Sherman JE . Corticotropin-releasing factor modulates defensive-withdrawal and exploratory behavior in rats. Behav Neurosci 1989; 103: 648–654.

    Article  CAS  PubMed  Google Scholar 

  117. Kalin NH, Takahashi LK . Fear-motivated behavior induced by prior shock experience is mediated by corticotropin-releasing hormone systems. Brain Res 1990; 509: 80–84.

    Article  CAS  PubMed  Google Scholar 

  118. Koob GF, Heinrichs SC, Pich EM, Menzaghi F, Baldwin H, Miczek K et al. The role of corticotropin-releasing factor in behavioural responses to stress. Ciba Found Symp 1993; 172: 277–289; discussion 290–275.

    CAS  PubMed  Google Scholar 

  119. Baram TZ, Chalmers DT, Chen C, Koutsoukos Y, De Souza EB . The CRF1 receptor mediates the excitatory actions of corticotropin releasing factor (CRF) in the developing rat brain: in vivo evidence using a novel, selective, non-peptide CRF receptor antagonist. Brain Res 1997; 770: 89–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Gallager DW, Kehne JH, Wakeman EA, Davis M . Development changes in pharmacological responsivity of the acoustic startle reflex: effects of picrotoxin. Psychopharmacology (Berl) 1983; 79: 87–93.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Ruth Connelly, Laura Canepa, Valencia Coston and Teal Pelish for their expert technical assistance. We also thank Dr. Gloria Hoffman and Dr Andrea Gore for their immunohistochemistry expertise. This project was supported by a pilot grant from the Center for Behavioral Neuroscience as a part of the STC Program of the National Science Foundation under Agreement No. IBN-9876754 and by NIH grants HD46501, MH-42088, MH-52899, RR00165, and 5K12-GM00680.

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Authors and Affiliations

  1. Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA

    E Keen-Rhinehart, V Michopoulos, D J Toufexis, H Nair, K J Ressler, M Davis & M E Wilson

  2. Center for Behavioral Neuroscience, Emory University, Atlanta, GA, USA

    E Keen-Rhinehart, V Michopoulos, D J Toufexis, H Nair, K J Ressler, M Davis & M E Wilson

  3. Department of Psychiatry and Behavioral Sciences, School of Medicine, Emory University, Atlanta, GA, USA

    D J Toufexis, E I Martin, K J Ressler, M Davis, M J Owens & C B Nemeroff

Authors
  1. E Keen-Rhinehart
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  2. V Michopoulos
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  3. D J Toufexis
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  4. E I Martin
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  5. H Nair
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  6. K J Ressler
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  7. M Davis
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  8. M J Owens
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  9. C B Nemeroff
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  10. M E Wilson
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Corresponding author

Correspondence to M E Wilson.

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Author contributions

E Keen-Rhinehart oversaw the conduct of the studies, performed the ICC and participated as first author. V Michopoulos assisted Dr Keen-Rhinehart with the conduct of the study and participated as first author. D Toufexis conducted the startle tests and participated as first author. EI Martin worked on the development and characterization of the Lenti-CMV-CRF vector and contributed to the preparation of the article. H Nair contributed to the development of the Lenti-CMV-CRF vector and the preparation of the article. KJ Ressler supervised the development and characterization of the Lenti-CMV-CRF vector and contributed to the preparation of the article. The startle studies were conducted in M Davis' laboratory and he contributed to the preparation of the article. The Lenti-CMV-CRF vector was developed in MJ Owens' and CB Nemeroff's laboratories and both contributed to the preparation of the article. With the exception of the startle tests, the in vivo studies were conducted in ME Wilson's laboratory and he contributed to the analysis of the data and the preparation of the article.

Disclosure statement

Currently, Dr Nemeroff has served on the Scientific Advisory Board for Astra-Zeneca, Johnson & Johnson, Pharma Neuroboost, Forest laboratories, Quintiles and NARSAD. He is a grant recipient from NIH, NovaDel Pharmaceuticals, Mt. Cook Pharma, Inc. and the George West Mental Health Foundation. He owns equity in CeNeRx and Reevax. He owns stock or stock options in Corcept and NovaDel. In the past 3 years, Dr Owens has had research grants from Pfizer, GlaxoSmithKline, Merck, Lundbeck, Cyberonics and Johnson & Johnson. He has consulted to Pfizer, Lundbeck, Sepracor, Johnson & Johnson, Sanofi-Aventis and Forest Labs, and received speaker's honaria from GlaxoSmithKline. Dr Owens has a patent entitled ‘A method to estimate transporter occupancy’.

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Keen-Rhinehart, E., Michopoulos, V., Toufexis, D. et al. Continuous expression of corticotropin-releasing factor in the central nucleus of the amygdala emulates the dysregulation of the stress and reproductive axes. Mol Psychiatry 14, 37–50 (2009). https://doi.org/10.1038/mp.2008.91

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