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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：
10349478
负责人：
LARRY S ZWEIFEL
金额：
$ 33.92万
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 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10349478
关键词：
3&apos Untranslated Regions Acute Address Anatomy Anxiety Behavior Behavioral Brain CRISPR/Cas technology Code Corpus striatum structure Cre driver Cues Data Dependence Disease Disease susceptibility Dissection Dopamine Electrophysiology (science)Emotional Enterobacteria phage P1 Cre recombinase Enzymes Etiology Fright Functional disorder Genes Genetic Genetic Heterogeneity Genetic Techniques Glutamates Goals Heterogeneity Hypothalamic structure Internal Ribosome Entry Site Learning Limbic System Literature Maps Mediating Mental Depression Mental disorders Methods Midbrain structure Motivation Mus Neurons Neuropeptide Receptor Neuropeptides Neurotransmitters Nucleus Accumbens Output Pathway interactions Pattern Periodicity Play Population Post-Traumatic Stress Disorders Precision therapeutics Production Property Prosencephalon Regulation Rewards Role Scanning Schizophrenia Signal Transduction Slice Substance Use Disorder Symptoms Synapses System Techniques Testing Therapeutic Tyrosine 3-Monooxygenase Ventral Tegmental Area Viral autism spectrum disorder base cell type dopamine system dopaminergic neuron experimental study gain of function gamma-Aminobutyric Acid genetic approach in vivo insight integrated circuit loss of function motivational processes nerve supply nervous system disorder neuropsychiatric disorder novel novel strategies optogenetics rabies viral tracing receptor

项目摘要

Project Summary Dopamine neurons of the ventral tegmental area (VTA) provide essential modulatory signals to the forebrain limbic system and cortex to facilitate learning and motivational processes. Disruptions in dopamine signaling are broadly implicated in mental illness and likely contribute to a spectrum of behavioral dysfunction through distinct cortico-limbic pathways. The heterogeneity of dopamine neurons in the VTA has long been appreciated, but therapeutic strategies targeting the system are still based on a monolithic perspective. Recent advances in mapping the input/output relationships of distinct dopamine pathways have attempted to resolve the basic organization of the VTA, but have yielded little in the way of establishing how specialized subdivisions might be organized. Unraveling the basic anatomical and functional organization of the VTA is essential if precision therapeutics are to be achieved for treating specific behavioral dysfunctions. We hypothesized that the dopamine system in the VTA can be organized based on peptidergic modulation to gate information through specific output pathways. We have mapped the projections of dopamine neurons in the VTA that express distinct neuropeptide receptors and discovered a remarkable specialization of these outputs. Here we propose to establish the basic electrophysiological, anatomical, and behavioral function of these pathways using novel Cre driver mouse lines in combination with advanced techniques in viral-based circuit dissection. We will also establish novel methods for the genetic characterization of these subpopulations. Successful completion of our proposed aims will provide novel insight into the basic organization of the VTA dopamine system and establish a framework for cracking the dopamine code.

项目概要腹侧被盖区 (VTA) 的多巴胺神经元为前脑提供重要的调节信号边缘系统和皮层促进学习和动机过程。多巴胺信号传导中断广泛与精神疾病有关，并可能通过以下方式导致一系列行为功能障碍独特的皮质边缘通路。长期以来，VTA 中多巴胺神经元的异质性一直被认为是赞赏，但针对该系统的治疗策略仍然基于整体观点。最近的在绘制不同多巴胺通路的输入/输出关系方面的进展试图解决 VTA 的基本组织，但在建立专业化程度方面收效甚微。可能会组织细分。解开 VTA 的基本解剖和功能组织是如果要实现治疗特定行为功能障碍的精准治疗，这一点至关重要。我们假设 VTA 中的多巴胺系统可以基于肽能调节来组织以门控信息通过特定的输出途径。我们绘制了多巴胺神经元的投影图 VTA 表达不同的神经肽受体，并发现这些输出的显着特化。在这里，我们建议建立这些的基本电生理、解剖和行为功能使用新型 Cre 驱动小鼠系与基于病毒的电路中的先进技术相结合的途径解剖。我们还将建立新的方法来表征这些亚群的遗传特征。成功完成我们提出的目标将为 VTA 的基本组织提供新的见解多巴胺系统并建立破解多巴胺密码的框架。