Isolation of brain reward circuits using peptidergic systems

项目摘要 神经递质多巴胺提供了一种重要的调节信号，使无数的 大脑功能的变化。VTA内神经元的异质性长期以来一直受到重视，但 针对该系统的治疗策略仍然基于单一的观点。近期 基于遗传学的方法的进展为解决分子生物学问题提供了新的途径 调节这些细胞内在特性的途径，这些特性是它们不同功能的基础 并可能赋予其独特的药理敏感性。使用单核RNA测序， 我们在我们假设的特定细胞类型中定义了独特的遗传特征 他们的功能。具体地说，我们确定了不同的离子通道亚基 在多巴胺亚群中表达，使其具有独特的电生理特性 重要的电压门控性钾通道，我们假设它有助于 这些细胞的内在兴奋性。我们还定义了唯一的电路连通性 这些细胞。我们将利用遗传学和药理学的结合方法来 了解离子通道和电路连接的调节如何有助于 这些细胞类型的特化。除了特定人群的基因图谱外，我们还 已经确定了一种神经肽受体，它在主要投射的亚群中表达 亚群。表达这种受体的神经元的激活最低限度地足以 促进强化，但这个受体的功能和它的细胞内信号在这个 背景在很大程度上仍然不得而知。为了解决这个问题，我们将结合使用药理学 以及分子遗传学方法来理解与此相关的细胞内信号 在多巴胺神经元内提供其功能的受体。总的来说，这一行动的目标是 该提案将为多巴胺的分子药理学提供重要的新见解 亚群。

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.