NE contributions to Lateral habenula control of action evaluation under chronic stress

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Project Summary The process of selecting an action, evaluating, and storing the outcome to inform future responses requires the basal ganglia (BG) and extended circuits such as the lateral habenula (LHb). Indeed, perturbed LHb activity is observed in multiple human neurological disorders where action selection is impaired. This includes major depressive disorders where disrupted activity patterns in the LHb are causally related to depression-like phenotypes. Despite its critical function in action selection/outcome evaluation, the contributions of specific neuron types within the LHb to these processes in both health and disease remain incompletely understood. Previously, we defined genetically distinct neuronal subtypes within the LHb using whole transcriptome single-cell sequencing. Further, we developed a variation of a 2-armed bandit behavioral task (2ABT) that allows for manipulation and observation of LHb circuit dynamics in vivo. Utilizing these tools, we aim to study LHb activity and contribution to a behavior that requires updating action selection in uncertain contexts based on previous reward history. It is our overarching hypothesis that distinct, genetically defined LHb neuronal subtypes encode the action, the outcome, or both to differentially control action selection behavior. Stress leads to increased errors in decision making in uncertain contexts and stress or depressed patients show decreased learning rates following negative outcomes. Stressed and anxious individuals also show aversion to uncertainty, selecting more certain but less profitable outcomes rather than uncertain outcomes with higher overall profitability. Stress is a major risk factor for depressive disorder development and is known to disrupt LHb activity patterns. Increased norepinephrine (NE) signaling in the brain is a hallmark of stress response, activating in parallel with the HPA-axis contributing to both central and peripheral effects of psychosocial stress. NE stress response is known to differ between males and females. In the LHb, NE is known to contribute to states of both arousal and anxiety. Additionally, we have found differential expression of adrenergic receptors (ARs) in LHb neuronal subtypes. Consequently, we surmise LHb serves as a hub for the interaction of stress, anxiety and depressive disorders during decision making. We further hypothesize that perturbed activity in LHb neuronal subtypes underlie stress induced alterations in action selection. We will examine these hypotheses in 3 aims. In Aim 1A we will determine which genetically defined subfields encode the action, the outcome, or both during a 2ABT. In this way we will define LHb contributions to action selection. In Aim 1B we will utilize the unpredictable chronic mild stress induced anhedonia and the 2ABT to examine how chronic stress affects LHb and NE signaling during action selection. Finally in Aim 2 we will examine specific ARs in the LHb during the 2ABT. During 2ABT tasks, we predict learning of negative outcomes will be encoded by NE signaling in the LHb. Together, these aims will elucidate the mechanism by which the LHb modulates action evaluation in health and under chronic stress in male and females.