Isolation of brain reward circuits using peptidergic systems

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Project Summary The neurotransmitter dopamine provides an important modulatory signal that facilitates a myriad of brain functions. The heterogeneity of neurons in the VTA has long been appreciated, but therapeutic strategies targeting the system are still based on a monolithic perspective. Recent advances in genetics-based methods have provided new approaches to resolving the molecular pathways that regulate the intrinsic properties of these cells that underlie their distinct functions and likely confer unique pharmacological sensitivities. Using single nuclear RNA sequencing, we defined unique genetic signatures within specific cell types that we hypothesize contributes to their functionality. Specifically, we identified ion channel subunits that are differentially expressed in dopamine subpopulations that confer unique electrophysiological properties to essential voltage-gated potassium channels that we hypothesize contributes to differences in the intrinsic excitability of these cells. We have also defined the unique circuit connectivity of these cells. We will utilize a combination of genetic and pharmacological approaches to understand how the regulation of ion channels and circuit connections contributes to the specialization of these cell types. In addition to the genetic profile of specific populations, we have identified a neuropeptide receptor that is expressed in subsets of the major projection subpopulations. Activation of neurons that express this receptor is minimally sufficient to promote reinforcement, but the function of this receptor and its intracellular signaling in this context remain largely unknown. To address this, we will use a combination of pharmacology and molecular genetics approaches to understand the intracellular signaling associated with this receptor that confers its function within dopamine neurons. Collectively, the aims of this proposal will provide important new insight into the molecular pharmacology of dopamine subpopulations.