Growth factors in general, and brain-derived neurotrophic factor (BDNF) in particular, play critical roles in the nervous system to regulate neuronal development and survival, axonal outgrowth, synaptogenesis, and synaptic plasticity. BDNF signaling modifies depressive behavior, and a large number of studies demonstrate additional roles for BDNF/TrkB pathways in contextual fear conditioning and spatial memory, as well as in the regulation of synaptic plasticity. These functions likely depend on genes or gene products that BDNF regulates at the transcriptional, translational or post-translational levels, several via activation of the transcription factor CREB. However, few candidate genes downstream of neurotrophins and CREB that contribute to depression and memory formation have been identified. Several recent studies indicate that VGF, a secreted neuronal protein and peptide precursor that is rapidly induced by the neurotrophins BDNF, NGF and NT3, plays a role in depression and the response to antidepressant treatment. VGF-derived peptides are known to regulate synaptic plasticity, reproductive behavior and energy balance. Preliminary and recently published studies show that VGF C-terminal peptides have antidepressant efficacy, and also regulate hippocampal neuronal electrical excitability in slices via a BDNF-dependent mechanism, consistent with impaired performance of VGF knockout mice in spatial and contextual fear memory tasks and depressed behavior in the forced swim and tail suspension tests. To better understand VGF function in the nervous system we have generated a mouse line with a loxp-flanked (floxed) Vgf gene, allowing us to conditionally ablate VGF expression in a tissue-specific manner. In Aim 1, we will investigate how VGF regulates depressive behavior, using VGF knockout mouse models, and paradigms of depression that include social defeat and novelty induced hypophagia, which are responsive to chronic but not acute antidepressant treatment. In Aim 2 we will utilize a number of depression pardigms to determine whether VGF expression is required for antidepressant efficacy, studying responses in conditional and germline VGF knockout mice. Aim 3 will determine when in development and where in the CNS VGF functions to regulate depressive behavior, taking advantage of the new floxed VGF line, and either conditional VGF ablation or localized VGF ablation, the latter using targeted infusion of adeno-associated virus expressing Cre-recombinase. In Aim 4 we will determine whether VGF expression is required for hippocampal neurogenesis. Overall, the proposed experiments will investigate the roles that VGF and VGF-derived peptides play in the regulation of hippocampal synaptic plasticity, hippocampal neurogenesis, depressive behavior, and the response to antidepressants, using well- studied and newly generated mouse models. PUBLIC HEALTH RELEVANCE: Characterization of the molecules and mechanisms that control emotional behavior and cognition will lead to increased understanding of brain function, mood disorders such as depression, and memory, all clearly impacted by aging and by degenerative diseases including Alzheimer's.