Isolation of brain reward circuits using peptidergic systems

使用肽能系统分离大脑奖励回路

基本信息

批准号：
10748560
负责人：
LARRY S ZWEIFEL
金额：
$ 41.72万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-15 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10748560
关键词：
Address Affective Association Learning Behavior Behavioral Brain Calcium Calcium Signaling Cells Cholecystokinin Clustered Regularly Interspaced Short Palindromic Repeats Corticotropin-Releasing Hormone Receptors Coupled Cre driver Cues Decision Making Disease susceptibility Dopamine Electrophysiology (science)Endowment Foundations Functional disorder Genes Genetic Genetic Heterogeneity Heterogeneity Ion Channel Learning Link Literature Mental disorders Methods Molecular Molecular Genetics Motivation Mus Mutagenesis Neurokinin B Neuromedin K Receptor Neurons Neuropeptide Receptor Neuropeptides Neurotransmitters Nuclear RNA Nucleus Accumbens Pathway interactions Pharmacology Play Population Property Psychological reinforcement Receptor Gene Receptor Signaling Regulation Rewards Role Signal Pathway Signal Transduction Stimulus Symptoms System Techniques Therapeutic Uncertainty Ventral Tegmental Area Viral Voltage-Gated Potassium Channel addiction cell type differential expression dopamine system dopaminergic neuron genetic approach genetic signature in vivo in vivo calcium imaging insight mesolimbic system motivated behavior nervous system disorder neuronal excitability neuropsychiatric disorder novel strategies optogenetics pharmacologic receptor receptor function response segregation therapeutic development transcriptome sequencing

项目摘要

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.

项目摘要神经递质多巴胺提供了一个重要的调节信号，可促进无数大脑功能。长期以来，VTA中神经元的异质性一直受到赞赏，但针对系统的治疗策略仍基于单片的观点。最近的基于遗传学的方法的进步提供了解决分子的新方法调节这些细胞的内在特性的途径，这些细胞具有不同的功能并可能赋予独特的药理敏感性。使用单个核RNA测序，我们在特定的细胞类型中定义了独特的遗传特征，我们假设有助于达到他们的功能。具体而言，我们确定了不同的离子通道亚基在多巴胺亚群中表达，赋予独特的电生理特性我们假设的基本电压门控钾通道有助于这些细胞的固有兴奋性。我们还定义了独特的电路连接这些细胞。我们将利用遗传学和药理方法的结合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专业化。除了特定人群的遗传特征外，我们已经确定了在主要投影子集中表达的神经肽受体亚群。表达该受体的神经元的激活在最小的促进加固，但是该受体及其细胞内信号的功能上下文在很大程度上是未知的。为了解决这个问题，我们将使用药理学的组合和分子遗传学方法是了解与此相关的细胞内信号传导赋予其功能在多巴胺神经元中的受体。总体而言，目的提案将为多巴胺的分子药理学提供重要的新见解亚群。