Sunbola_Research_FIN - Principal Investigator/Program Director(Last First Middle Monteggia Lisa Research Plan a Summary of the Parent Grant The

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Principal Investigator/Program Director (Last, First, Middle ): Monteggia, Lisa Research Plan a. Summary of the Parent Grant The central research focus of our laboratory is to understand the molecular mechanisms underlying depression and antidepressant efficacy. Recent studies have suggested that brain-derived neurotrophic factor (BDNF) plays a role in depression and antidepressant-like behavioral effects. BDNF expression is decreased in the hippocampus, a brain region implicated in the pathophysiology of depression, by exposure to stress, a factor implicated in depression in some individuals. Conversely, multiple classes of antidepressants, as well as electroconvulsive therapy (ECT), increase BDNF expression in the hippocampus in a time course consistent with the therapeutic action of these drugs. BDNF, the most prevalent growth factor in the brain, can then exert alterations in neuronal plasticity through specific signaling pathways. However, a clear link between the role of endogenous BDNF and ‘depression-like’ behavior and in the behavioral responses to antidepressant drugs remains unclear. The goals of the parent grant are to investigate whether the loss of BDNF produces changes in ‘depressive- like’ behavior and antidepressant responses, and whether chronic antidepressant treatment exerts effects on synaptic plasticity in a BDNF dependent manner. The research plan for this minority candidate, Sunbola Ashimi, will allow her to examine the requirement for BDNF in mediating antidepressant efficacy and to identify key downstream targets for antidepressants. These studies will provide insights into the fundamental mechanisms underlying the role of BDNF in disease and in the treatment of depression as well as provide a solid research experience for the candidate. b. Proposed Research Plan Ms. Sunbola Ashimi is currently pursuing her Ph.D. degree in my laboratory. Her project focuses on the role of BDNF in mediating ‘depression-like’ behavior and antidepressant efficacy. There is much indirect evidence suggesting a link between BDNF and depression/antidepressant efficacy that has collectively led to the neurotrophic hypothesis of depression. This hypothesis states that the loss of BDNF may contribute to hippocampal alterations that underlie aspects of depression, while antidepressants may mediate some of their therapeutic effects by increasing BDNF in this brain region. A major gap of this hypothesis, however, is the lack of direct evidence that loss of endogenous BDNF can itself lead to depression-like behavior or to an attenuated response to antidepressants. We have generated inducible BDNF knockout (KO) mice in which this neurotrophic factor can be selectively deleted in broad forebrain regions in a temporal dependent manner. These mice are viable and show no obvious ‘depression- like’ phenotype as measured in the Forced Swim Test (FST), a paradigm that responds to acute antidepressant treatment but is nonetheless widely used as it reliably predicts antidepressants that are efficacious in human.
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This note was uploaded on 03/26/2008 for the course CHEM 237 taught by Professor Yu-chinli during the Fall '07 term at Texas A&M.

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Sunbola_Research_FIN - Principal Investigator/Program Director(Last First Middle Monteggia Lisa Research Plan a Summary of the Parent Grant The

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