The brain's reward circuitry is critically involved in regulating mood-related behaviors such as depression and aggression. However, we currently possess a remarkably limited understanding of the molecular and circuit based mechanisms that govern how these reward systems are subverted in neuropsychiatric disorders. We, and others, have previously shown that the nucleus accumbens (NAc), a key hub within the reward system, is a critical regulator of social reward behaviors. This dissertation will explore the two separate, but intrinsically connected, social behavioral states of depression and aggression, and in turn attempt to elucidate putative intracellular and circuit based mechanisms that govern how the NAc modulates these behaviors. Through the use of social defeat stress, in which an aggressive dominant mouse antagonizes a non-aggressive submissive mouse, we can identify the mechanisms that govern both the development of depression-like behaviors (in the subordinate mouse) and the motivation to attack (in the dominant mouse). Specifically, in Chapter 1, I will present an introduction on reward circuitry and synaptic plasticity. In Chapter 2 I will detail the animal model, chronic social defeat stress, which we use to study both depression and aggression-like behaviors in mice. In Chapter 3 I will present data on the role of structural plasticity within the nucleus accumbens, governed by epigenetic regulation of small RhoGTPase Rac1 transcription, on driving the development of depression-related behaviors and social avoidance. In Chapter 4, nucleus accumbens projections to the lateral habenula will be shown to play a critical role in governing the motivational component of aggressive behavior. Lastly, in Chapter 5 I will present future directions for both projects. Although this dissertation presents data spanning both depression and aggression-related behavioral domains, one clear commonality is that the NAc functions as a critical integrator of reward-related social behaviors, and understanding the mechanisms guiding this plasticity may help to establish novel therapeutic strategies for treating mood-related disorders.
|Advisor:||Russo, Scott J.|
|Commitee:||Baxter, Mark, Han, Ming-Hu, Hurd, Yasmin, Moron-Concepcion, Jose, Nestler, Eric J., Schaefer, Anne|
|School:||Icahn School of Medicine at Mount Sinai|
|School Location:||United States -- New York|
|Source:||DAI-B 77/08(E), Dissertation Abstracts International|
|Keywords:||Aggression, Depression, Lateral habenula, Motivation, Nucleus accumbens, Stress|
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