This proposal for a Mentored Scientist Development Award focuses on elucidating the role of beta adrenergic receptors (ARs) and the adenylyl cyclase-cyclic cAMP (AC-cAMP) pathway in the pathophysiology of depression and suicide. Several studies suggest that betaAR number is increased in the postmortem brain of suicide subjects; however, the precise mechanism, significance and the cellular/molecular nature of events associated with this increase have not been elucidated. The goals of this study are to examine: 1) if upregulation of betaARs is due to increased rnRNA and/or protein expression of beta1 and/or beta2 ARs; 2) whether this increase is associated with increase transcription rate and/or dysregulated HPA axis; 3) functional consequences of increased betaARs in the AC-cAMP signaling pathway at the level of catalytic and regulatory activities of protein kinase A (PKA) and gene transcription of their specific subunits; 4) functional significance of altered PKA by examining functional characteristics and gene expression of transcription factors and target genes; 5) the localization of these changes at the cellular level in discrete brain areas; and 5) whether these changes are specific to depression.To achieve these goals we propose a series of related human postmortem brain and animal studies. We will study mRNA and protein expression of beta1 and beta2ARs by quantitative RT-PCR, in-situ hybridization and gold-immunolabeling. To examine whether changes in betaARs are associated with alterations in components of the AC- cAMP signaling pathway, we will study [3H]cAMP binding to PKA; total, endogenous and betaAR-mediated PKA activity; mRNA and protein expression of PKA (regulatory and catalytic subunits), CREB, BDNF and phospho-CREB; CREB-DNA binding activity in BAs 8, 9, 10 and hippocampus of suicide victims and age-, postmortem interval-, and gender-matched nonpsychiatric control subjects. We will examine changes in mRNA and protein expression in discrete areas of the brain (layers I-VI of prefrontal cortex and areas CA1-4, dentate gyrus subiculum and area entorhinalis of the hippocampal formation). Further, to examine if the changes in the proposed measures are specific to depression, we will examine the effects of major depression on the proposed measures. To consolidate our human postmortem brain findings, we will study the proposed measures in prefrontal cortex and hippocampus of behaviorally depressed rats. Finally, to examine if these changes are associated with abnormal HPA function we will study the proposed measures in prefrontal cortex and hippocampus of corticosterone-treated rats with and without adrenalectomy. With this proposal the candidate seeks training in 1) Clinical and psychological aspects of mental disorders and suicide, 2) molecular biology, 3) neuroanatomy, 4) animal behavior, and 5) specialized statistical analyses. The rigorous training plan, which integrates strong didactics and multidisciplinary expertise, and the research plan will advance the knowledge of molecular mechanisms associated with depression and suicide and will provide the candidate with the skills needed to achieve independence in this highly complex field.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01MH001836-03
Application #
6528103
Study Section
Special Emphasis Panel (ZMH1-BRB-P (02))
Program Officer
Wynne, Debra K
Project Start
2000-09-01
Project End
2005-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
3
Fiscal Year
2002
Total Cost
$98,275
Indirect Cost
Name
University of Illinois at Chicago
Department
Psychiatry
Type
Schools of Medicine
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Pandey, Ghanshyam N; Dwivedi, Yogesh; Rizavi, Hooriyah S et al. (2009) GSK-3beta gene expression in human postmortem brain: regional distribution, effects of age and suicide. Neurochem Res 34:274-85
Pandey, Ghanshyam N; Ren, Xinguo; Rizavi, Hooriyah S et al. (2008) Brain-derived neurotrophic factor and tyrosine kinase B receptor signalling in post-mortem brain of teenage suicide victims. Int J Neuropsychopharmacol 11:1047-61
Donati, Robert J; Dwivedi, Yogesh; Roberts, Rosalinda C et al. (2008) Postmortem brain tissue of depressed suicides reveals increased Gs alpha localization in lipid raft domains where it is less likely to activate adenylyl cyclase. J Neurosci 28:3042-50
Pandey, Ghanshyam N; Dwivedi, Yogesh; Ren, Xinguo et al. (2007) Cyclic AMP response element-binding protein in post-mortem brain of teenage suicide victims: specific decrease in the prefrontal cortex but not the hippocampus. Int J Neuropsychopharmacol 10:621-9
Pandey, Ghanshyam N; Dwivedi, Yogesh (2007) Noradrenergic function in suicide. Arch Suicide Res 11:235-46
Dwivedi, Y; Rizavi, H S; Pandey, G N (2006) Antidepressants reverse corticosterone-mediated decrease in brain-derived neurotrophic factor expression: differential regulation of specific exons by antidepressants and corticosterone. Neuroscience 139:1017-29
Pandey, Ghanshyam N; Dwivedi, Yogesh; Ren, Xinguo et al. (2006) Regional distribution and relative abundance of serotonin(2c) receptors in human brain: effect of suicide. Neurochem Res 31:167-76
Chen, Hu; Pandey, Ghanshyam N; Dwivedi, Yogesh (2006) Hippocampal cell proliferation regulation by repeated stress and antidepressants. Neuroreport 17:863-7
Dwivedi, Yogesh; Mondal, Amal C; Rizavi, Hooriyah S et al. (2006) Differential and brain region-specific regulation of Rap-1 and Epac in depressed suicide victims. Arch Gen Psychiatry 63:639-48
Dwivedi, Y; Rizavi, H S; Conley, R R et al. (2006) ERK MAP kinase signaling in post-mortem brain of suicide subjects: differential regulation of upstream Raf kinases Raf-1 and B-Raf. Mol Psychiatry 11:86-98

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