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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH086499-03
Application #
8213766
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Winsky, Lois M
Project Start
2010-04-01
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$419,513
Indirect Cost
$172,013
Name
Icahn School of Medicine at Mount Sinai
Department
Neurosciences
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Foglesong, Grant D; Huang, Wei; Liu, Xianglan et al. (2016) Role of Hypothalamic VGF in Energy Balance and Metabolic Adaption to Environmental Enrichment in Mice. Endocrinology 157:983-96
Choi, Soon Gang; Wang, Qian; Jia, Jingjing et al. (2016) Characterization of Gonadotrope Secretoproteome Identifies Neurosecretory Protein VGF-derived Peptide Suppression of Follicle-stimulating Hormone Gene Expression. J Biol Chem 291:21322-21334
Lin, Wei-Jye; Jiang, Cheng; Sadahiro, Masato et al. (2015) VGF and Its C-Terminal Peptide TLQP-62 Regulate Memory Formation in Hippocampus via a BDNF-TrkB-Dependent Mechanism. J Neurosci 35:10343-56
Sadahiro, Masato; Erickson, Connor; Lin, Wei-Jye et al. (2015) Role of VGF-derived carboxy-terminal peptides in energy balance and reproduction: analysis of "humanized" knockin mice expressing full-length or truncated VGF. Endocrinology 156:1724-38
Fargali, Samira; Garcia, Angelo L; Sadahiro, Masato et al. (2014) The granin VGF promotes genesis of secretory vesicles, and regulates circulating catecholamine levels and blood pressure. FASEB J 28:2120-33
Fairbanks, Carolyn A; Peterson, Cristina D; Speltz, Rebecca H et al. (2014) The VGF-derived peptide TLQP-21 contributes to inflammatory and nerve injury-induced hypersensitivity. Pain 155:1229-37
Jiang, Cheng; Salton, Stephen R (2013) The Role of Neurotrophins in Major Depressive Disorder. Transl Neurosci 4:46-58
Lin, Wei-Jye; Salton, Stephen R (2013) The regulated secretory pathway and human disease: insights from gene variants and single nucleotide polymorphisms. Front Endocrinol (Lausanne) 4:96
Fargali, Samira; Scherer, Thomas; Shin, Andrew C et al. (2012) Germline ablation of VGF increases lipolysis in white adipose tissue. J Endocrinol 215:313-22
Fargali, Samira; Sadahiro, Masato; Jiang, Cheng et al. (2012) Role of neurotrophins in the development and function of neural circuits that regulate energy homeostasis. J Mol Neurosci 48:654-9

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