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

点击翻译按钮获取中文摘要

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.