The neurologic basis of depression and response to antidepressant treatment remain uncertain. Recent evidence suggests that the brain derived neurotrophic factor (BDNF) is increased by administration of various classes of antidepressant treatments and BDNF infusion into the brain has antidepressant effects in animal models. Furthermore, BDNF's role in acute regulation of synaptic transmission and synaptic plasticity in the hippocampus and other areas, implicates a role in learning and memory paradigms. The proposed studies will examine the role of BDNF in the adult brain in depression and response to antidepressant treatments. These studies will also screen BDNF deficient mice for deficits in two learning and memory paradigms. We hypothesize that mice lacking BDNF in the brain will exhibit increased susceptibility stress effects in animal models of depression and that these mice will be less susceptible to beneficial effects of anitidepressant therapy. We further hypothesize that mice lacking BDNF in the brain will exhibit deficits in learning and memory paradigms. Finally, we will examine the role of BDNF in support of monoaminergic and serotonergic projections in the adult brain. These studies will enhance our understanding of the pathophysiology of depression and mechanisms of antidepressant action. This knowledge may lead to new therapeutic targets in depression. Experiments examining the role of BDNF in spatial and emotional learning and memory will further our understanding of how neurotrophic factors can influence learning and memory and may lead to new therapeutic considerations in clinical disorders of memory such as Alzheimer's disease. To date, studies examining the role of BDNF in behavioral paradigms have been difficult due to the early postnatal lethality and sensory abnormalities of constitutive BDNF knockout mice. Our approach will be to make use of brain-directed, inducible BNDF knockout mice that have been generated in the Nestler laboratory. This system avoids developmental and peripheral effects of traditional knockout approaches. We also propose to make use of focal injection of Cre-expressing AAV vectors into flox-BDNF mice to assess the specific brain subregions involved with greater temporal specificity. ? ?
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