Neuropeptide VGF in Antidepressant-Induced Neurogenesis and Mood Disorders

描述（由申请人提供）：在成年哺乳动物海马中，新神经元的产生及其融入神经元网络受到突触活动的影响。神经肽VGF在促进海马神经发生和行为模型中作为抗抑郁样药物的新作用已被证明。生长因子脑源性神经营养因子（BDNF）在突触可塑性中的作用已经得到了很好的认识，最近BDNF在神经祖细胞中促进神经发生的研究已经得到证实。VGF也增强突触活动和学习，似乎需要BDNF信号来影响突触活动。因此，虽然VGF和BDNF对突触活动和神经发生的影响已被阐明，但这些成分之间的联系尚未建立。VGF在神经发生中的作用是否需要BDNF信号和突触活性尚不清楚。我们假设神经肽VGF调节BDNF通路和下游突触活性，刺激成人海马神经发生，这是VGF抗抑郁样作用所必需的。这项提议的第一个目的是验证VGF刺激神经发生需要突触活动的假设。VGF作用于神经发生的具体阶段将被确定，并将探讨VGF是否也在新生细胞的存活中起作用。然后研究活性在vgf诱导的神经发生中的作用。这将通过用VGF刺激神经祖细胞增殖，然后用药物拮抗剂阻断突触活性来完成，以确定活性是否对VGF诱导的神经发生是必要的。第二个目标将检验VGF诱导的神经发生是VGF抗抑郁作用所必需的假设。采用x射线辐照法切除海马的增殖群，观察VGF对小鼠行为的影响。第三个目的是研究VGF对神经发生的影响是否由BDNF信号介导。BDNF受体的激活将在体外通过分子方法和在体内通过转基因小鼠来确定VGF是否需要BDNF信号来进行神经发生。VGF和BDNF相互作用调控神经发生的机制将通过生化和分子操作进行研究。具体而言，VGF是否直接结合或激活BDNF受体将被研究。重要的是，分泌的神经肽如VGF对神经营养因子功能的影响尚不清楚。这些相互作用将允许神经系统网络对包括神经发生在内的过程施加更精细的控制，这极大地影响了大脑功能。了解神经肽如何影响神经发生将揭示神经发生和/或活动相关疾病的潜在机制，如抑郁症、癫痫、中风和神经退行性疾病。此外，神经肽VGF可能是一种调节干细胞增殖的方法，具有治疗潜力。

DESCRIPTION (provided by applicant): In the adult mammalian hippocampus, production of new neurons and their integration into the neuronal network is influenced by synaptic activity. Novel roles for the neuropeptide VGF in enhancing neurogenesis in the hippocampus and as an antidepressant-like agent in behavioral models have been demonstrated. The effect of the growth factor brain-derived neurotrophic factor (BDNF) in synaptic plasticity has been well recognized and more recently the promotion of neurogenesis in neural progenitor cells by BDNF has been demonstrated. VGF also enhances synaptic activity and learning and appears to require BDNF signaling for its effects on synaptic activity. Therefore, while the effects of VGF and BDNF on synaptic activity and neurogenesis have been elucidated, a connection between all of these components has not been made. Whether VGF requires BDNF signaling and synaptic activity for its effects on neurogenesis is not known. We hypothesize that the neuropeptide VGF regulates the BDNF pathway and downstream synaptic activity to stimulate adult hippocampal neurogenesis required for VGF's antidepressant-like actions. The first aim of this proposal will test the hypothesis that VGF stimulated neurogenesis requires synaptic activity. The specific stage of neurogenesis which VGF acts upon will be determined and whether VGF also plays a role in survival of newborn cells will be explored. Then the role of activity in VGF-induced neurogenesis will be studied. This will be accomplished by stimulating proliferation of neural progenitor cells with VGF and then blocking synaptic activity with pharmacological antagonists to see if activity is necessary for VGF-induced neurogenesis. The second aim will test the hypothesis that VGF-induced neurogenesis is required for the antidepressant-like effects of VGF. The proliferating population of hippocampus will be ablated using x-ray irradiation and then the effect of VGF on behavior in the irradiated mice will be assayed. The third aim will study if the effect of VGF on neurogenesis is mediated by BDNF signaling. BDNF receptor activation will be blocked in vitro using molecular approaches and in vivo using genetically modified mice to determine if VGF requires BDNF signaling for neurogenesis. The mechanism of how VGF and BDNF interact to regulate neurogenesis will be studied using biochemical and molecular manipulations. Specifically, whether VGF directly binds or activates the BDNF receptor will be studied. Importantly, the influence of secreted neuropeptides such as VGF on neurotrophin function is not known. These interactions would allow the nervous system network to exert a finer level of control over processes including neurogenesis which greatly impact brain function. Understanding how neuropeptides influence neurogenesis will reveal mechanisms underlying disorders in which neurogenesis and/or activity have been implicated such as depression, epilepsy, stroke and neurodegenerative disease. In addition, the neuropeptide VGF may represent a way to regulate proliferation of stem cells which has therapeutic potential.