This competitive renewal application seeks support to continue our preclinical and clinical studies concerning the neurobiology of corticotropin-releasing factor (CRF) and its role in the pathophysiology of major depression. Considerable evidence from a number of investigators using different experimental approaches has accrued in the last decade consistent with the hypothesis that CRF mediates the endocrine, behavioral and autonomic responses of mammals to stress. Preclinical investigations focus on stress-associated alterations in CRF neurons, CRF receptors and CRF signal transduction, interactions of CRF with neurons in the locus coeruleus and nearby parabrachial nucleus, and the modification of these observed effects by treatment with anxolytic and antidepressant drugs. In addition, the effects of stress in neonatal rats on subsequent stress responsiveness of CRF neurons and CRF signal transduction in adult rats is proposed. The preclinical studies utilize behavioral, neurochemical and electrophysiological measures. One focus of the clinical studies is an analysis of CRF neuronal systems in postmortem brain tissue of depressed suicide victims. In both the preclinical studies and the postmortem studies, the following measures are obtained: CRF concentrations, CRF mRNA levels, CRF receptor binding and CRF signal transduction. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most well-- documented findings in major depression. Therefore another focus of the clinical studies proposed is to determine the relationship between pituitary and adrenal gland enlargement, as assessed by magnetic resonance imaging (MRI) and computed tomography (CT), respectively, the attenuated ACTH response to CRF and elevations in CSF CRF concentrations. These studies will provide further information on the role of CRF in the CNS, and in particular the role of hypersecretion of CRF in the pathophysiology of major depression. Such studies have important implications for the development of novel treatments for major depression and perhaps anxiety disorders.

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National Institute of Mental Health (NIMH)
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Clinical Neuroscience Review Committee (CNR)
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Emory University
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Flandreau, Elizabeth I; Ressler, Kerry J; Owens, Michael J et al. (2012) Chronic overexpression of corticotropin-releasing factor from the central amygdala produces HPA axis hyperactivity and behavioral anxiety associated with gene-expression changes in the hippocampus and paraventricular nucleus of the hypothalamus. Psychoneuroendocrinology 37:27-38
Pariante, Carmine M; Nemeroff, Charles B (2012) Unipolar depression. Handb Clin Neurol 106:239-49
Hanson, Nicola D; Nemeroff, Charles B; Owens, Michael J (2011) Lithium, but not fluoxetine or the corticotropin-releasing factor receptor 1 receptor antagonist R121919, increases cell proliferation in the adult dentate gyrus. J Pharmacol Exp Ther 337:180-6
Hanson, Nicola D; Owens, Michael J; Boss-Williams, Katherine A et al. (2011) Several stressors fail to reduce adult hippocampal neurogenesis. Psychoneuroendocrinology 36:1520-9
Bonne, Omer; Gill, Jessica Mary; Luckenbaugh, David A et al. (2011) Corticotropin-releasing factor, interleukin-6, brain-derived neurotrophic factor, insulin-like growth factor-1, and substance P in the cerebrospinal fluid of civilians with posttraumatic stress disorder before and after treatment with paroxetine. J Clin Psychiatry 72:1124-8
Gutman, David A; Owens, Michael J; Thrivikraman, K V et al. (2011) Persistent anxiolytic affects after chronic administration of the CRFýýý receptor antagonist R121919 in rats. Neuropharmacology 60:1135-41
Coplan, Jeremy D; Abdallah, Chadi G; Kaufman, Joan et al. (2011) Early-life stress, corticotropin-releasing factor, and serotonin transporter gene: a pilot study. Psychoneuroendocrinology 36:289-93
Martin, Elizabeth I; Ressler, Kerry J; Jasnow, Aaron M et al. (2010) A novel transgenic mouse for gene-targeting within cells that express corticotropin-releasing factor. Biol Psychiatry 67:1212-6
Gatt, Justine M; Nemeroff, Charles B; Schofield, Peter R et al. (2010) Early life stress combined with serotonin 3A receptor and brain-derived neurotrophic factor valine 66 to methionine genotypes impacts emotional brain and arousal correlates of risk for depression. Biol Psychiatry 68:818-24
Martin, Elizabeth I; Ressler, Kerry J; Binder, Elisabeth et al. (2010) The neurobiology of anxiety disorders: brain imaging, genetics, and psychoneuroendocrinology. Clin Lab Med 30:865-91

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