VGF function in depression and antidepressant treatment

描述（由申请人提供）：生长因子，特别是脑源性神经营养因子（BDNF），在神经系统中起着调节神经元发育和存活、轴突生长、突触发生和突触可塑性的关键作用。BDNF信号传导改变抑郁行为，大量研究表明BDNF/TrkB通路在情境恐惧条件反射和空间记忆以及突触可塑性调节中的额外作用。这些功能可能依赖于BDNF在转录、翻译或翻译后水平上调节的基因或基因产物，其中一些是通过激活转录因子CREB来调节的。然而，很少有候选基因下游的神经营养因子和CREB，有助于抑郁症和记忆形成已被确定。最近的几项研究表明，VGF是一种分泌的神经元蛋白和肽前体，由神经营养因子BDNF，NGF和NT 3快速诱导，在抑郁症和抗抑郁治疗的反应中起作用。已知VEGF衍生肽调节突触可塑性、生殖行为和能量平衡。初步和最近发表的研究表明，VGF C-末端肽具有抗抑郁功效，并且还通过BDNF依赖性机制调节切片中海马神经元的电兴奋性，这与VGF敲除小鼠在空间和背景恐惧记忆任务中的受损表现以及在强迫游泳和悬尾测试中的抑郁行为一致。为了更好地了解VGF在神经系统中的功能，我们已经产生了一个loxP侧翼（floxed）VGF基因的小鼠品系，使我们能够有条件地消融VGF表达的组织特异性的方式。在目标1中，我们将研究VGF如何调节抑郁行为，使用VGF基因敲除小鼠模型，以及抑郁症的范例，包括社会失败和新奇引起的食欲减退，这是响应于慢性而不是急性抗抑郁药治疗。在目标2中，我们将利用一些抑郁症的范例，以确定是否VGF表达所需的抗抑郁疗效，研究条件和生殖系VGF基因敲除小鼠的反应。目的3将确定何时在发展中以及在CNS中VGF发挥作用以调节抑郁行为，利用新的floxed VGF系，以及条件性VGF消融或局部VGF消融，后者使用表达Cre重组酶的腺相关病毒的靶向输注。在目的4中，我们将确定VGF表达是否是海马神经发生所必需的。总体而言，所提出的实验将使用充分研究和新产生的小鼠模型研究VGF和VGF衍生肽在海马突触可塑性、海马神经发生、抑郁行为和对抗抑郁药的反应的调节中发挥的作用。 公共卫生相关性：控制情绪行为和认知的分子和机制的表征将导致对大脑功能，情绪障碍（如抑郁症）和记忆的理解增加，所有这些都明显受到衰老和退行性疾病（包括阿尔茨海默氏症）的影响。

DESCRIPTION (provided by applicant): 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.