Investigation into the role of lateral hypothalamus GABA and glutamate relative dynamics in encoding affective valence and modulating motivated behaviors

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Project Summary/ Abstract Multiple diseases in humans can be traced to maladaptive reward circuit function including drug addiction, which costs the United States over 740 billion dollars annually and causes an incalculable amount of human suffering. Understanding the neural mechanisms that contribute to affective valence and reward behaviors may facilitate the discovery of therapies to reduce the rate and severity of addiction and other disorders that stem from reward circuitry. Decades of research demonstrates that the lateral hypothalamus (LHA) is a critical brain region within the reward circuit. Electrically stimulating the LHA can powerfully reinforce behavior and that lesioning the LHA reduces motivation across a broad range of behaviors. Recent research into genetically- defined populations of LHA neurons have found that interspersed populations of LHA cells signal in response to rewarding events and can produce independent behaviors. Interpreting results in the literature is hindered due to the fact that experiments into genetically-defined populations of cells have been conducted across different labs and behavioral procedures. This proposal seeks to determine the signaling dynamics of multiple LHA subpopulations during emotionally salient events and to determine the casual role of these signals in mediating reward behavior. During this training period I will learn cutting-edge techniques including collection and analysis of single cell calcium imaging in behaving mice and causal manipulations of defined populations of neurons. In Aim 1, we will record the activity of genetically defined populations of LHA cells during emotionally salient events. These experiments will reveal the signaling dynamics of multiple populations of LHA cells and will inform our understand of how these populations contribute to reward. In Aim 2, we will determine the role of signaling within these populations in mediating reward behavior. These experiments will allow us to understand the causal effect of signaling within LHA subpopulations and will contribute to a theoretical understanding of how the LHA contributes to reward behavior. Altogether, the results of this project will enhance our understanding of how interspersed populations signal in response to emotional salient events and how these signals causally shape behavior. The work I will conduct during my training period will contribute to a greater understanding of neuronal processing of reward may inform future research into interventions to treat addiction and other diseases of reward circuitry.