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.
Depressive disorders are the leading cause of disability in the United States and around the world. The experience of social adversity during adolescence results in permanent changes in the brain, which may prime the emergence of depressive disorders throughout a person?s lifetime. This proposal seeks to better understand the mechanism(s) by which this maladaptive process occurs in order to develop novel therapies for treating depression and depressive behaviors.
