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整合到神经元网络中受到突触活动的影响。神经肽VGF在增强海马神经发生中的新作用以及在行为模型中作为抗抑郁剂的新作用已被证实。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被充分认识，并且最近已证实BDNF促进神经祖细胞中的神经发生。VGF还增强突触活动和学习，并且似乎需要BDNF信号传导来影响突触活动。因此，虽然VGF和BDNF对突触活动和神经发生的影响已经阐明，但所有这些成分之间的联系尚未建立。VGF对神经发生的影响是否需要BDNF信号传导和突触活动尚不清楚。我们推测，神经肽VGF调节BDNF通路和下游突触活动，刺激VGF的抗抑郁样作用所需的成年海马神经发生。这个提议的第一个目的是检验VGF刺激神经发生需要突触活动的假设。VGF作用于神经发生的特定阶段将被确定，并且VGF是否也在新生细胞的存活中起作用将被探索。然后将研究活性在VEGF诱导的神经发生中的作用。这将通过用VGF刺激神经祖细胞的增殖，然后用药理学拮抗剂阻断突触活性以观察活性是否是VGF诱导的神经发生所必需的来实现。第二个目的是检验VGF诱导的神经发生是VGF抗抑郁样作用所必需的这一假设。将使用X射线照射来消融海马的增殖群体，然后将测定VGF对照射小鼠的行为的影响。第三个目的是研究VGF对神经发生的影响是否是通过BDNF信号转导介导的。BDNF受体激活将在体外使用分子方法阻断，并在体内使用遗传修饰的小鼠来确定VGF是否需要BDNF信号传导用于神经发生。VGF和BDNF如何相互作用调节神经发生的机制将通过生物化学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，这些过程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/或活动涉及的疾病的潜在机制，如抑郁症，癫痫，中风和神经退行性疾病。此外，神经肽VGF可能代表了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.