The Neural Basis of Social Stress-Induced Depression
Despite the increased prevalence of major depressive disorders (MDD) and the continued investment into identifying effective cures, long-term treatments are generally required for this disease and are often ineffective. Those experiencing depression display a common but often variable set of symptoms: muted responses to pleasurable stimuli (anhedonia), psychomotor impairment, disruptions in sleep patterns, retraction from social interaction. While the behavioral changes associated with depression in human patients have been well-studied, there is relatively little known about the changes in neural circuitry underlying these behavioral phenotypes. In particular, the dysregulation of distinct brain areas may cause different symptoms in MDD. For example, brain areas underlying impaired social interaction in depressed patients may differ from those underlying helplessness. Using a combination of novel approaches we have recently developed and adapted, we will identify the neural circuits underlying distinct symptoms of depression, an important step towards understanding the neural mechanisms of depression and providing better therapeutic strategies for treating this mental disorder.
Repeated social defeat stress in rodents induces long-lasting behavioral changes similar to the diverse symptoms seen in patients with MDD including impaired social interaction, lack of motivation, helplessness and anhedonia. Using the social defeat stress paradigm we will anatomically and functionally dissect the distinct neural circuits mediating various stress-induced behaviors in mice to better understand the mechanistic changes in the brain accompanying MDD in human patients. For this purpose, we will use cutting edge techniques developed in this lab and others, including viral-mediated anatomical tracing, optogenetic manipulations in behaving animals, electrophysiology, and in vivo imaging in freely-moving animals, in order to parse the neural circuits and mechanisms underlying depression. Specifically, we will focus on the ventral pallidum (VP), a major components of reward circuitry, an area that has been implicated in many reward-related behaviors linked to depression, yet whose circuitry and physiological profiles have received only rudimentary characterization. Our preliminary investigations reveal that a subset of VP neurons mediate aversive behaviors and modulation of these neurons reverse social stress-induced depressive behaviors; more interestingly, optogenetic modulation of VP neurons projecting to different targets has distinct behavioral effects. Thus, we will focus on the cell type- and projection-specific roles of VP circuitry in social defeat stress-induced depressive behavior. Completion of these studies will represent an important advance towards understanding the neural mechanisms underlying neuropsychiatric disorders and developing more effective treatments.