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

项目总结 抑郁症是世界范围内导致残疾的主要原因，将影响美国约20%的人。 在他们的有生之年。尽管抑郁症的症状是广泛的、复杂的和高度不同的， 患者在NIH定义的正价值域，包括动机、奖励等方面持续表现出缺陷 敏感度和目标导向的行动，它们的失调会产生标志性的缺陷，如运动障碍， 快感缺乏、沉思和行为僵化。抑郁的终生风险的一个重要决定因素是 青春期经历的社会逆境，这是一个神经发育时期，以广泛的 前额叶皮质(PFC)的变化。我们已经建立了一种社会逆境的模式，在这种模式中，我们在社会上 隔离青春期小鼠，然后将它们重新安置在成年后的社会群体中，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也是如此。 与人类一样，在青春期隔离的小鼠会产生类似抑郁的行为，这种行为会持续到 逆境本身的时期。以前隔离的小鼠表现出类似享乐性的行为，并发展为僵硬 以依赖PFC、目标导向的行为为代价的习惯。在神经生物学层面上，他们遭受 大脑中兴奋性突触的主要部位--树突棘修剪失败，导致脊柱 成年期的过度表达。这表明这些神经元发生了兴奋性移位，这在 腹内侧PFC(VmPFC)，在抑郁症患者中高度活跃，其活性可以 成功地通过脑深部刺激(DBS)抑制了抑郁症的治疗。 我们还发现，Rho-Kinase(ROCK)抑制，它操纵树突状细胞的形状和流动性 脊椎，有抗抑郁药一样的作用。然而，这种类似治疗的效果是否由特定的 神经元异构体ROCK2和vmPFC的抑制作用仍不清楚。在目标1中，我将测试 假设青春期的社会孤立史会导致长期的功能改变 可通过抑制ROCK2纠正的vmPFC。我将使用神经解剖束追踪，体外全细胞 膜片钳电生理学和定点选择性病毒介导的基因沉默来识别和纠正长... 青春期社会隔离对vmPFC回路连接性、vmPFC神经元的影响 电生理学和抑郁症相关行为。在目标2中，我将利用特定细胞类型、全基因组 转录图谱分析和利用基因集浓缩分析来确定社会隔离的长期影响 青春期对成年期基因表达的影响。我将重点介绍V层神经元，它们患有树突状细胞 隔离后的脊柱高密度。我的发现可能会为抗抑郁药物的开发提供新的线索， 这是非常需要的，因为目前可用的抗抑郁药只对大约50%的患者有缓解作用， 而且不能治疗疾病。理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、更有针对性的疗法至关重要。

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.