Welcome to the Section on Functional Neuroanatomy
Laboratory of Cellular and Molecular Regulation, IRP
National Institute of Mental Health
National Institutes of Health, DHHS
Miles Herkenham, Ph.D., Chief
Molecular, Anatomical, Neuroendocrinological, and Neuroimmune Studies of Psychosocial Stress and Environmental Enrichment
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Our group previously studied the mechanisms of action of antidepressant drugs in animal models of depression. We documented changes in the hypothalamic-pituitary-adrenal (HPA) axis in response to acute or repeated immobilization in rats and mice. We showed that the corticotropin releasing hormone (CRH) and vasopressin systems of the hypothalamic paraventricular nucleus (PVN, seen in picture) and the locus coeruleus-norepinephrine system were involved in mediating both the effects of immobilization stress and compensatory actions of chronically administered antidepressant drugs. We showed similar kinds of changes in the HPA axis and in the hippocampus and bed nucleus of the stria terminalis, key way stations to the PVN, in animals given St. John's wort (Hypericum) chronically. |
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A more naturalistic model of chronic stress that mimics depressive conditions in humans is psychosocial stress, achieved in mice by creating a housing condition in which two mice are separated by a perforated barrier that is lifted every day to permit agonistic encounters. The persistent conflict between the mice creates a dominant-subordinate social hierarchy. The socially defeated subordinate mice show behavioral signs of increased anxiety, helplessness, anhedonia, and inappropriate social interaction, assessed in multiple behavioral tests. We next showed that environmental enrichment, consisting of housing in large cages with tubes, toys, and a running wheel, following social defeat, restores the normal behavior of the subordinate mice. We also found that adult neurogenesis is required for the restorative effects. We are now exploring the protective effect of environmental enrichment when it is given prior to the psychosocial stress, and we are studying the mechanisms that confer stress resilience. Current work explores the anatomical and endocrine components that form the basis for stress coping and resiliency. We are also examining immune system interactions with the CNS processes involved in stress and resiliency. |
References
Brady, L. S., Whitfield, H. J. Jr., Fox, R. J., Gold, P. W., and Herkenham, M. Long-term imipramine administration increases mineralocorticoid receptor mRNA in the hippocampus and decreases corticotropin-releasing hormone mRNA in the hypothalamus of rats. J. Clin. Invest., 87: 831-837, 1991.
Butterweck, V. Winterhoff, H. and Herkenham, M. St. John's wort, hypericin, and imipramine: a comparative analysis of mRNA levels in brain areas involved in HPA axis control following short-term and long-term administration in normal and stressed rats. Mol. Psychiatry, 2001; 6: 547-564.
Patchev, A., Fischer, D., Wolf, S., Herkenham, M., Gotz, F., Gehin, M., Chambon, P., Patchev, V., and Almeida, O. Insidious adrenocortical insufficiency underlies neuroendocrine dysregulation in TIF-2 deficient mice. FASEB J., 21: 231-238, 2007
Schloesser, R.J., Lehmann, M., Martinowich, K., Manji, H.K., Herkenham, M. Environmental enrichment requires adult neurogenesis to facilitate the recovery from psychosocial stress. Mol. Psychiatry, 15: 1152-1163, 2010.
Lehmann, M.L. and Herkenham, M. Environmental enrichment confers stress resiliency to social defeat through an infralimbic cortex-dependent neuroanatomical pathway. J. Neuroscience, 31: 6159-6173, 2011
Brady, L. S., Whitfield, H. J. Jr., Fox, R. J., Gold, P. W., and Herkenham, M. Long-term imipramine administration increases mineralocorticoid receptor mRNA in the hippocampus and decreases corticotropin-releasing hormone mRNA in the hypothalamus of rats. J. Clin. Invest., 87: 831-837, 1991.
Butterweck, V. Winterhoff, H. and Herkenham, M. St. John's wort, hypericin, and imipramine: a comparative analysis of mRNA levels in brain areas involved in HPA axis control following short-term and long-term administration in normal and stressed rats. Mol. Psychiatry, 2001; 6: 547-564.
Patchev, A., Fischer, D., Wolf, S., Herkenham, M., Gotz, F., Gehin, M., Chambon, P., Patchev, V., and Almeida, O. Insidious adrenocortical insufficiency underlies neuroendocrine dysregulation in TIF-2 deficient mice. FASEB J., 21: 231-238, 2007
Schloesser, R.J., Lehmann, M., Martinowich, K., Manji, H.K., Herkenham, M. Environmental enrichment requires adult neurogenesis to facilitate the recovery from psychosocial stress. Mol. Psychiatry, 15: 1152-1163, 2010.
Lehmann, M.L. and Herkenham, M. Environmental enrichment confers stress resiliency to social defeat through an infralimbic cortex-dependent neuroanatomical pathway. J. Neuroscience, 31: 6159-6173, 2011
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