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Endocrine Reviews, doi:10.1210/edrv-12-2-118
Endocrine Reviews 12 (2): 118-134
Copyright © 1991 by The Endocrine Society
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The Role of the Hippocampus in Feedback Regulation of the Hypothalamic-Pituitary-Adrenocortical Axis*

LAUREN JACOBSON and ROBERT SAPOLSKY

Department of Biological Sciences, Stanford University Stanford, California 94305-5020

Correspondence: Address correspondence and requests for reprints to: Dr. Lauren Jacobson, Department of Biological Sciences, Stanford University, Stanford, California 94305-5020.

Abstract

Introduction: THE hippocampus has received considerable attention as a potential regulator of the hypothalamic-pituitary-adrenocortical (HPA) axis. After the demonstration by Harris' laboratory (1) that the hypothalamus could affect adrenocortical function, investigation extended to identifying other brain areas that might influence hypothalamic activity. Early evidence for hippocampal projections to the hypothalamus and the role of the limbic system in emotions made the hippocampus a likely component of a stress-activated system such as the adrenocortical axis (2,3). This hypothesis has been borne out not only by physiological studies but also by pharmacological evidence that the hippocampus contains corticosteroid receptors. This review will focus solely on the physiological data for, and the possible mechanisms underlying, the hippocampal regulation of HPA sensitivity to corticosteroid feedback. This subject has been addressed by McEwen et al. (4) and more recently by Canny (5). However, the literature has expanded since the former review, and considerable controversy remains regarding the role of hippocampal corticosteroid receptors following the latter review; we believe these issues merit further attention. In focusing on the hippocampus, we do not intend to imply that it is the only brain corticosteroid feedback site, nor that it plays a more important role than the hypothalamus. However, the hippocampus is one of the regions most susceptible to damage by insults such as ischemia, hypoglycemia, and seizure (6). Consequently, the hippocampus is of particular interest among potential glucocorticoid feedback sites not only because of the considerable and varied evidence for its influence on HPA activity, but also because that influence may be so easily disrupted.

Footnotes

* Supported, in part, by NIH Grant AG-06633 (to R.M.S.) and by National Institutes of Mental Health individual postdoctoral fellowship MH-09796 (to L.J.).




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E. Arvat, B. Maccagno, J. Ramunni, L. DI Vito, R. Giordano, L. Gianotti, F. Broglio, F. Camanni, and E. Ghigo
The Inhibitory Effect of Alprazolam, a Benzodiazepine, Overrides the Stimulatory Effect of Metyrapone-Induced Lack of Negative Cortisol Feedback on Corticotroph Secretion in Humans
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P. Chen, M. Ganguli, B. H. Mulsant, and S. T. DeKosky
The Temporal Relationship Between Depressive Symptoms and Dementia: A Community-Based Prospective Study
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A. H. S. hassan, V. K. Patchev, P. V. Rosenstiel, F. Holsboer, and O. F. X. Almeida
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J. P. Herman and R. Spencer
Regulation of Hippocampal Glucocorticoid Receptor Gene Transcription and Protein Expression In Vivo
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G. Bowers, W. E. Cullinan, and J. P. Herman
Region-Specific Regulation of Glutamic Acid Decarboxylase (GAD) mRNA Expression in Central Stress Circuits
J. Neurosci., August 1, 1998; 18(15): 5938 - 5947.
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E. R. de Kloet, E. Vreugdenhil, M. S. Oitzl, and M. Joëls
Brain Corticosteroid Receptor Balance in Health and Disease
Endocr. Rev., June 1, 1998; 19(3): 269 - 301.
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M. Boscaro, A. Paoletta, E. Scarpa, L. Barzon, P. Fusaro, F. Fallo, and N. Sonino
Age-Related Changes in Glucocorticoid Fast Feedback Inhibition of Adrenocorticotropin in Man
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D. Y. Okuhara and S. G. Beck
Corticosteroids Alter 5-Hydroxytryptamine1A Receptor-effector Pathway in Hippocampal Subfield CA3 Pyramidal Cells
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B. S. McEwen
Protective and Damaging Effects of Stress Mediators
N. Engl. J. Med., January 15, 1998; 338(3): 171 - 179.
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R. M. Sapolsky, S. C. Alberts, and J. Altmann
Hypercortisolism Associated With Social Subordinance or Social Isolation Among Wild Baboons
Arch Gen Psychiatry, December 1, 1997; 54(12): 1137 - 1143.
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S. Kollack-Walker, S. J. Watson, and H. Akil
Social Stress in Hamsters: Defeat Activates Specific Neurocircuits within the Brain
J. Neurosci., November 15, 1997; 17(22): 8842 - 8855.
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S. Lee and C. Rivier
An Initial, Three-Day-Long Treatment with Alcohol Induces a Long-Lasting Phenomenon of Selective Tolerance in the Activity of the Rat Hypothalamic-Pituitary-Adrenal Axis
J. Neurosci., November 15, 1997; 17(22): 8856 - 8866.
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D. Liu, J. Diorio, B. Tannenbaum, C. Caldji, D. Francis, A. Freedman, S. Sharma, D. Pearson, P. M. Plotsky, and M. J. Meaney
Maternal Care, Hippocampal Glucocorticoid Receptors, and Hypothalamic-Pituitary-Adrenal Responses to Stress
Science, September 12, 1997; 277(5332): 1659 - 1662.
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T. E. Seeman, B. S. McEwen, B. H. Singer, M. S. Albert, and J. W. Rowe
Increase in Urinary Cortisol Excretion and Memory Declines: MacArthur Studies of Successful Aging
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D. S. Albeck, C. R. McKittrick, D. C. Blanchard, R. J. Blanchard, J. Nikulina, B. S. McEwen, and R. R. Sakai
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M. C. Holmes, K. L. French, and J. R. Seckl
Dysregulation of Diurnal Rhythms of Serotonin 5-HT2C and Corticosteroid Receptor Gene Expression in the Hippocampus with Food Restriction and Glucocorticoids
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M. B. Goldman, G. L. Robertson, D. J. Luchins, D. Hedeker, and G. N. Pandey
Psychotic Exacerbations and Enhanced Vasopressin Secretion in Schizophrenic Patients With Hyponatremia and Polydipsia
Arch Gen Psychiatry, May 1, 1997; 54(5): 443 - 449.
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R. S. Duman, V. A. Vaidya, M. Nibuya, S. Morinobu, and L. R. Fitzgerald
Review : Stress, Antidepressant Treatments, and Neurotrophic Factors: Molecular and Cellular Mechanisms
Neuroscientist, November 1, 1995; 1(6): 351 - 360.
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B. S. McEwen and E. Stellar
Stress and the Individual: Mechanisms Leading to Disease
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M. P. Lilly and D. S. Gann
The Hypothalamic-Pituitary-Adrenal--Immune Axis: A Critical Assessment
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