Neuropeptide VGF in Antidepressant-Induced Neurogenesis and Mood Disorders

描述(申请人提供)：在成年哺乳动物的海马体中，新神经元的产生及其与神经元网络的整合受到突触活动的影响。神经肽VGF在促进海马区神经发生和在行为模型中作为抗抑郁剂样剂的新作用已被证明。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广泛的认识，最近又有研究表明BDNF促进神经前体细胞的神经发生。VGF还可以增强突触的活性和学习，似乎需要BDNF信号来影响突触的活性。因此，虽然VGF和BDNF对突触活动和神经发生的影响已被阐明，但所有这些成分之间的联系尚未建立起来。VGF是否需要BDNF信号和突触活动来影响神经发生尚不清楚。我们假设神经肽VGF调节BDNF途径和下游突触活性，以刺激成年海马神经发生，这是VGF抗抑郁药样作用所需的。这项提议的第一个目的将检验这样一个假设，即VGF刺激的神经发生需要突触活动。将确定VGF作用于神经发生的特定阶段，以及VGF是否也在新生细胞的存活中发挥作用。然后，我们将研究活性在VGF诱导的神经发生中的作用。这将通过用VGF刺激神经前体细胞的增殖，然后用药物拮抗剂阻断突触活性来实现，以确定这种活性是否对VGF诱导的神经发生是必要的。第二个目标将检验这样一个假设，即VGF的抗抑郁药样作用需要VGF诱导的神经发生。用X射线照射消融海马区的增殖群，观察VGF对照射后小鼠行为的影响。第三个目的是研究VGF对神经发生的影响是否通过BDNF信号介导。BDNF受体的激活将在体外使用分子方法被阻止，并在体内使用转基因小鼠来确定VGF是否需要BDNF信号来促进神经发生。VGF和BDNF如何相互作用以调节神经发生的机制将通过生物化学和分子操作来研究。具体地说，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，这些过程对大脑功能有很大影响。了解神经肽如何影响神经发生，将揭示与神经发生和/或活动有关的疾病的潜在机制，如抑郁症、癫痫、中风和神经退行性疾病。此外，神经肽VGF可能是一种调节干细胞增殖的方法，具有治疗潜力。 公共卫生相关性：成人大脑中新神经元的诞生，特别是在海马体中，被称为成人神经发生，被认为在许多疾病的发病机制和治疗中发挥作用，包括抑郁症、癫痫、中风和神经退行性疾病。了解VGF等神经肽和神经营养因子等生长因子如何协同作用促进神经发生和影响行为，将有助于深入了解神经疾病的潜在机制，并提供新的药物靶点。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. PUBLIC HEALTH RELEVANCE: The birth of new neurons in the adult brain especially in the hippocampus, termed adult neurogenesis, is thought to play a role in the pathogenesis and treatment of a number of disorders including depression, epilepsy, stroke and neurodegenerative diseases. Understanding how neuropeptides such as VGF and growth factors such as neurotrophins work in concert to enhance neurogenesis and affect behavior will thus lend insight into the mechanisms underlying neurological disease and provide new drug targets. In addition, the neuropeptide VGF may represent a way to regulate proliferation of stem cells which has therapeutic potential.