The primary goal of this Program Project Grant renewal is to identify the neurobiological mechanisms that underlie the pathophysiology and treatment of depression. A major strength of this application is the integrated and multi-disciplinary approach, including molecular, biochemical, electrophysiological, and behavioral levels of analysis for each research project. Another strength is the close interaction between the basic and clinical research faculty that allows for efficient and productive transfer of information. This program of research consists of a small Administrative ore, two scientific Cores, and 4 research projects. The Molecular and Transgenic Core is responsible for the breeding and development of mutant mice and for viral vectors that are used to investigate molecular models in the 4 research projects. The Behavioral Core is responsible for testing rodents in standard models of depression and anxiety. This Core is used by the 4 research projects to determine the behavioral phenotype of mutant mice, effects of viral-mediated gene transfer, and responses to systemic and intracerebral drug infusions. Project by Russell will extend our finding that brain derived neurotrophic factor (BDNF) produces an anti- depressant effect in behavioral models of depression This will include molecular, electrophysiological, and behavioral analysis of the intracellular pathways that are regulated by neurotrophic factors in limbic brain regions. Project by Alreja will determine the role of septal pathways in the regulation of hippocampal function by stress and antidepressant treatments, and the molecular, neurochemical, and electrophysiological determinants underlying these effects. Project by Duman is a continuation of our previous studies demonstrating that anti- depressant treatment produces morphological adaptations, most notably increased neurogenesis in adult rodent hippocampus. This project will include the molecular and biochemical analysis of the signal transduction pathways that regulate adult neurogenesis and the behavioral consequences of these effects. Project by Taylor will determine the role of the amygdala and nucleus accumbens and intracellular signaling in these brain regions, in established models of depression and conditioned reward. Funding of this program of research will ensure the continued success of these multidisciplinary studies to identify the molecular and cellular basis of depression, and that could lead to novel therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Program Projects (P01)
Project #
5P01MH025642-30
Application #
6785255
Study Section
Special Emphasis Panel (ZMH1-BRB-S (02))
Program Officer
Desmond, Nancy L
Project Start
1978-07-01
Project End
2007-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
30
Fiscal Year
2004
Total Cost
$1,418,406
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Voleti, Bhavya; Navarria, Andrea; Liu, Rong-Jian et al. (2013) Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses. Biol Psychiatry 74:742-9
Duric, Vanja; Banasr, Mounira; Stockmeier, Craig A et al. (2013) Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects. Int J Neuropsychopharmacol 16:69-82
Duric, Vanja; Duman, Ronald S (2013) Depression and treatment response: dynamic interplay of signaling pathways and altered neural processes. Cell Mol Life Sci 70:39-53
Newton, Samuel S; Fournier, Neil M; Duman, Ronald S (2013) Vascular growth factors in neuropsychiatry. Cell Mol Life Sci 70:1739-52
Fournier, Neil M; Lee, Boyoung; Banasr, Mounira et al. (2012) Vascular endothelial growth factor regulates adult hippocampal cell proliferation through MEK/ERK- and PI3K/Akt-dependent signaling. Neuropharmacology 63:642-52
Fournier, Neil M; Duman, Ronald S (2012) Role of vascular endothelial growth factor in adult hippocampal neurogenesis: implications for the pathophysiology and treatment of depression. Behav Brain Res 227:440-9
Son, Hyeon; Banasr, Mounira; Choi, Miyeon et al. (2012) Neuritin produces antidepressant actions and blocks the neuronal and behavioral deficits caused by chronic stress. Proc Natl Acad Sci U S A 109:11378-83
Voleti, Bhavya; Tanis, Keith Q; Newton, Samuel S et al. (2012) Analysis of target genes regulated by chronic electroconvulsive therapy reveals role for Fzd6 in depression. Biol Psychiatry 71:51-8
Kang, Hyo Jung; Voleti, Bhavya; Hajszan, Tibor et al. (2012) Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat Med 18:1413-7
Li, Nanxin; Liu, Rong-Jian; Dwyer, Jason M et al. (2011) Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 69:754-61

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