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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，大脑的功能。腹侧被盖区神经元的异质性早已被认识，但针对该系统的治疗策略仍然基于整体观点。最近基于遗传学的方法的进展提供了新的方法来解决分子调节这些细胞内在特性的途径，这些内在特性是它们独特功能的基础并可能赋予独特的药理学敏感性。使用单核RNA测序，我们在特定的细胞类型中定义了独特的遗传特征， to their其functional功能.具体地说，我们鉴定了离子通道亚基，在多巴胺亚群中表达，赋予独特的电生理特性，我们推测，这种必需的电压门控钾通道导致了这些细胞的内在兴奋性。我们还定义了这些细胞。我们将利用遗传学和药理学相结合的方法，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。除了特定人群的遗传特征外，我们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，但这种受体的功能及其细胞内信号在这一过程中，背景情况仍不清楚。为了解决这个问题，我们将使用药理学和和分子遗传学方法来了解与此相关的细胞内信号传导，多巴胺受体，在多巴胺神经元内赋予其功能。总的来说，这项提案将为多巴胺的分子药理学提供重要的新见解亚群