Functional characterization and rescue of depressive behaviors following adolescent social isolation and re-socialization

项目摘要 抑郁症是世界范围内残疾的主要原因，将影响美国约20%的人。 在他们的有生之年。虽然抑郁症的病因学是广泛的、复杂的和高度异质性的， 患者在NIH定义的积极效价领域（包括动机、奖励）中始终表现出缺陷 敏感性和目标导向的行动，其失调会产生标志性缺陷，如动机丧失， 快感缺乏、反刍和行为不稳定。抑郁症终生风险的一个重要决定因素是 在青春期经历的社会逆境，一个神经发育时期，其特征是广泛的 前额叶皮层（PFC）的变化。我们发展了一个社会逆境模型， 隔离青少年小鼠，然后将它们重新安置在年轻成年人的社会群体中，从而使我们能够隔离 社会逆境的长期后果，即使在社会环境正常化之后。 与人类一样，小鼠青春期的隔离会产生类似抑郁的行为， 这是一段艰难的时期。先前被隔离的小鼠表现出类似快感缺失的行为， 以牺牲PFC依赖的目标导向行为为代价的习惯。在神经生物学的层面上， 树突棘修剪失败，大脑中兴奋性突触的主要部位，导致棘 在成年期过度表达。这表明这些神经元中的兴奋性转变，这与 腹内侧PFC（vmPFC），在抑郁症患者中过度活跃，其活动可以 通过脑深部电刺激（DBS）成功抑制抑郁症。 我们还发现，Rho激酶（ROCK）抑制，操纵树突状细胞的形状和流动性， 脊柱，具有抗抑郁作用。然而，这种类似治疗的作用是否是由 神经元同种型ROCK 2和vmPFC中的抑制仍然未知。在目标1中，我将测试 这一假说认为，青少年时期的社会孤立史会导致大脑皮层的长期功能改变。 可以通过ROCK 2抑制来校正的vmPFC。我会用神经解剖追踪，离体全细胞 膜片钳电生理学和位点选择性病毒介导的基因沉默，以确定和纠正长- 青春期社会隔离对vmPFC电路连接、vmPFC神经元的长期影响 电生理学和抑郁相关行为。在目标2中，我将利用细胞类型特异性，全基因组 转录谱分析和利用基因集富集分析来确定社会隔离的长期影响 对成年期基因表达的影响。我将重点介绍第五层神经元，它们遭受树突状细胞的破坏。 脊柱高密度隔离后。我的发现可能会为抗抑郁药物的开发提供新的线索， 这是迫切需要的，因为目前可用的抗抑郁药仅在约50%的患者中提供缓解， 并且不改变疾病。了解抑郁行为的病因学机制 对于为这数百万患者开发更有效的靶向治疗至关重要。

PROJECT SUMMARY Depressive disorders are the leading cause of disability worldwide, and will affect ~20% of people in the U.S. within their lifetimes. Although depression symptomatology is extensive, complex, and highly heterogeneous, patients consistently exhibit deficits in NIH-defined, positive valence domains including motivation, reward sensitivity, and goal-directed action, dysregulation of which produce hallmark deficits such as amotivation, anhedonia, rumination, and behavioral inflexibility. A significant determinant of lifetime risk for depression is social adversity experienced during adolescence, a neurodevelopmental period characterized by extensive changes in the prefrontal cortex (PFC). We have developed a model of social adversity in which we socially isolate adolescent mice, and then re-house them in social cohorts as young adults, thus allowing us to isolate the long-term consequences of social adversity, even after normalization of the social milieu. As in humans, isolation during adolescence in mice produces depression-like behaviors that persist beyond the period of adversity itself. Previously isolated mice exhibit anhedonic-like behavior and develop inflexible habits at the expense of PFC-dependent, goal-directed behaviors. At the neurobiological level, they suffer failures in the pruning of dendritic spines, the primary sites of excitatory synapses in the brain, resulting in spine over-expression in adulthood. This suggests an excitatory shift in these neurons, which is particularly relevant in the ventromedial PFC (vmPFC), which is hyper-active in depressed patients and whose activity can be successfully suppressed by deep-brain stimulation (DBS) to treat depression. We also find that Rho-kinase (ROCK) inhibition, which manipulates the shape and mobility of dendritic spines, has antidepressant-like actions. However, whether this therapeutic-like effect is specifically mediated by inhibition of the neuronal isoform, ROCK2, and in the vmPFC, remains unknown. In Aim 1, I will test the hypothesis that a history of social isolation during adolescence results in long-term functional alterations in the vmPFC that can be corrected by ROCK2 inhibition. I will use neuroanatomical tract-tracing, ex vivo whole-cell patch clamp electrophysiology, and site-selective viral-mediated gene silencing to identify and correct the long- term consequences of social isolation during adolescence on vmPFC circuit connectivity, vmPFC neuronal electrophysiology, and depression-related behaviors. In Aim 2, I will leverage cell-type specific, genome-wide transcriptional profiling and utilize gene set enrichment analysis to identify the long-term effects of social isolation during adolescence on gene expression in adulthood. I will focus on layer V neurons, which suffer from dendritic spine hyper-density following isolation. My findings may provide new leads for antidepressant drug development, which is desperately needed as currently available antidepressants only confer remission in ~50% of patients, and are not disease-modifying. Understanding the mechanisms underlying the etiology of depressive behaviors is essential for the development of more effective, targeted therapies for these millions of patients.