VGF function in depression and antidepressant treatment

描述(申请人提供)：一般而言，生长因子，特别是脑源性神经营养因子(BDNF)，在神经系统中发挥关键作用，调节神经元的发育和存活、轴突生长、突触发生和突触可塑性。BDNF信号可以改变抑郁行为，大量研究表明，BDNF/TrkB通路在语境恐惧条件反射和空间记忆以及突触可塑性调节中发挥着额外的作用。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，神经营养因子和CREB下游与抑郁和记忆形成有关的候选基因很少被发现。最近的一些研究表明，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NT3快速诱导，在抑郁症和抗抑郁药物治疗的反应中发挥作用。众所周知，VGF衍生的多肽可以调节突触的可塑性、生殖行为和能量平衡。初步和最近发表的研究表明，VGF C端肽具有抗抑郁效果，并通过BDNF依赖的机制调节脑片上海马神经元的电兴奋性，这与VGF基因敲除小鼠在空间和情境恐惧记忆任务中的表现受损以及在强迫游泳和尾部悬挂试验中的抑郁行为一致。为了更好地了解VGF在神经系统中的功能，我们建立了一个带有loxP侧翼(牙线状)VGF基因的小鼠系，使我们能够以组织特异性的方式有条件地去除VGF的表达。在目标1中，我们将使用VGF基因敲除的小鼠模型和包括社交失败和新奇诱导的吞噬减少在内的抑郁范例来研究VGF如何调节抑郁行为，这些范例对慢性但不是急性抗抑郁药物治疗有反应。在目标2中，我们将利用一些抑郁模式来确定VGF的表达是否是抗抑郁药物疗效所必需的，研究条件和生殖系VGF基因敲除小鼠的反应。目的3将确定VGF在发育中的时间和在中枢神经系统中的什么位置发挥调节抑郁行为的功能，利用新的花状VGF系，以及条件VGF消融或局部VGF消融，后者使用靶向输注表达Cre重组酶的腺相关病毒。在目标4中，我们将确定海马神经发生是否需要VGF的表达。总体而言，拟议的实验将使用研究良好的和新产生的小鼠模型来研究VGF和VGF衍生多肽在调节海马突触可塑性、海马神经发生、抑郁行为和抗抑郁药物反应中所起的作用。

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.