PROJECT SUMMARY Survival in dynamic environments demands that behaviors are flexible and adaptive. An organism must make predictions about which actions lead to rewards, calculate how outcomes differ from those predictions (prediction errors), and adapt a behavioral strategy accordingly. Neurons encoding prediction errors can be found throughout many reward-related brain structures, with the highest densities in the VTA and the lateral habenula (LHb). Transcriptional analyses have found the LHb contains a diverse set of intermingled cell types, but at present, it is unknown how prediction error-encoding neurons map onto transcriptionally-defined habenular cell types. Therefore, we lack a genetic cell type framework to identify and selectively manipulate them to better understand their role in behavior. To address this need, this proposal aims to determine how Tac1LHb neurons encode reward parameters, adapt their responses in dynamic environments, and impact behavioral flexibility. Our central hypothesis is that prediction errors trigger activity in Tac1LHb neurons and promote flexible behavior. In Aim 1, we will use population level and single unit recordings to determine how different reward parameters (reward probability, reward history, reward interval, and reward size) modulate Tac1LHb activity at unexpected outcomes. In Aim 2, we will determine the circuit- and synaptic-level mechanisms by which Tac1LHb activity changes with reward history. In Aim 3, we propose to manipulate Tac1LHb activity in a reversal learning task to determine if it is necessary for behavioral flexibility, and to test a theoretical model describing the computational role of Tac1LHb activity in decision-making. The Tac1 gene encodes the neuropeptide Substance P and our proposal will determine the role of peptidergic signaling in synaptic transmission in this circuit, as well as its impact on behavior. Completion of the proposed research program will establish a cell-type resolved view of error-encoding neurons and demonstrate a key role for Tac1LHb neurons in behavioral flexibility. Deficits in behavioral flexibility are a hallmark of several neuropsychiatric disorders, including schizophrenia, ADHD, OCD, and depression. Joint information on cell typology and function has the potential to advance new therapeutic targets to treat maladaptive behavior in these disorders.

PROJECT NARRATIVE The ability to evaluate outcomes and adjust behavior to optimize reward is a fundamental aspect of behavioral flexibility and a key element of survival in a dynamic environment. Our proposal aims to understand how distinct neuronal cell types compute differences between expected outcomes and realized outcomes to guide flexible behavior. Identifying genetic markers for cell types that evaluate outcomes has the potential to facilitate the development of targeted treatments in neuropsychiatric disorders characterized by deficits in flexible behavior.