This proposal examines how the regulation of adult neurogenesis produced by repeated antidepressant drug treatment in mice may contribute to behavioral recovery from stress and depression. Major depressive disorder results from convergent underlying genetic predispositions and exposure to environmental stress. Evidence for increases of neurogenesis in the adult dentate gyrus of the hippocampus is a model for changes in neuroplasticity that emerge with chronic treatment with antidepressant drugs and serve as a model for the production of therapeutic effects. Most studies have measured the effects of antidepressants using rodents under routine housing conditions and have ignored the critical role of genetics and stress in contributing to drug treatment effects. We have identified a mouse strain (MRL/MpJ) that shows larger increases in neurogenesis following chronic fluoxetine. Also, the addition of stress hormones augments the effects of fluoxetine on neurogenesis in a non-responder mouse strain (C57BL/6). The central hypothesis of this grant proposal is that genetic predispositions and stress produce a critical role for revealing the effects of chronic antidepressant treatments on hippocampal neurogenesis. The use of flow cytometry as a technique to measure neurogenesis rapidly developed by this laboratory will enable completion of the large number of studies required for investigation of the pharmacology of neurogenesis. The primary goals of this proposal are: 1) demonstrate the critical role of exposure to corticosterone (CORT) in augmenting responses to chronic treatment with antidepressant drugs on neurogenesis and behavior in a responder and non-responder mouse strain;2) show whether environmental stress plays a similar role in causing antidepressant drugs to alter neurogenesis and behavior;and 3) determine whether hippocampal BDNF serves as a mechanism underlying the production these effects by chronic antidepressant drug treatments.

Public Health Relevance

This project examines the convergent role of genetic predispositions and exposure to environmental stress in mouse models regulating the effects of chronic antidepressant drug treatments on hippocampal neurogenesis and behavior. Major depression is an important public health problem because of its severe economic impact and contribution to morbidity from other medical disorders. The results of this project will contribute to identifying mechanisms of vulnerability and resilience to stress and lead to the discovery of novel and more effective antidepressant treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH086599-03
Application #
8267123
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (03))
Program Officer
Winsky, Lois M
Project Start
2010-09-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$396,000
Indirect Cost
$148,500
Name
University of Pennsylvania
Department
Psychiatry
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Robinson, Shivon A; Brookshire, Bethany R; Lucki, Irwin (2016) Corticosterone exposure augments sensitivity to the behavioral and neuroplastic effects of fluoxetine in C57BL/6 mice. Neurobiol Stress 3:34-42
Ho, Nancy; Brookshire, Bethany R; Clark, Janet E et al. (2015) Indomethacin reverses decreased hippocampal cell proliferation in streptozotocin-induced diabetic mice. Metab Brain Dis 30:555-62
Arnold, Steven E; Lucki, Irwin; Brookshire, Bethany R et al. (2014) High fat diet produces brain insulin resistance, synaptodendritic abnormalities and altered behavior in mice. Neurobiol Dis 67:79-87
Browne, Caroline A; Lucki, Irwin (2013) Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants. Front Pharmacol 4:161
Balu, Darrick T; Turner, Jill R; Brookshire, Bethany R et al. (2013) Brain monoamines and antidepressant-like responses in MRL/MpJ versus C57BL/6J mice. Neuropharmacology 67:503-10
Featherstone, Robert E; M Tatard-Leitman, Valerie; Suh, Jimmy D et al. (2013) Electrophysiological and behavioral responses to ketamine in mice with reduced Akt1 expression. Psychopharmacology (Berl) 227:639-49
Carlin, Jesselea; Hill-Smith, Tiffany E; Lucki, Irwin et al. (2013) Reversal of dopamine system dysfunction in response to high-fat diet. Obesity (Silver Spring) 21:2513-21
Vassoler, Fair M; White, Samantha L; Schmidt, Heath D et al. (2013) Epigenetic inheritance of a cocaine-resistance phenotype. Nat Neurosci 16:42-7
Multani, P K; Hodge, R; Estévez, M A et al. (2013) VMAT1 deletion causes neuronal loss in the hippocampus and neurocognitive deficits in spatial discrimination. Neuroscience 232:32-44
Ho, Nancy; Sommers, Marilyn S; Lucki, Irwin (2013) Effects of diabetes on hippocampal neurogenesis: links to cognition and depression. Neurosci Biobehav Rev 37:1346-62

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