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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.

项目摘要腹侧被盖区（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，以促进学习和动机的过程。多巴胺信号传导中断与精神疾病有着广泛的联系，并可能导致一系列的行为功能障碍，不同的皮质边缘通路腹侧被盖区多巴胺神经元的异质性一直被认为是这是值得赞赏的，但靶向该系统的治疗策略仍然基于整体观点。最近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以组织细分。揭开腹侧被盖区的基本解剖和功能组织，如果要实现用于治疗特定行为功能障碍的精确疗法，则这是必不可少的。我们假设腹侧被盖区的多巴胺系统可以基于肽能调节来组织，通过特定的输出路径。我们已经绘制了大脑中多巴胺神经元的投射图 VTA表达不同的神经肽受体，并发现这些输出的显着专业化。在这里，我们建议建立基本的电生理，解剖和行为功能，这些在基于病毒的电路中使用新型Cre驱动小鼠线与先进技术相结合的途径解剖我们还将建立新的方法，这些亚群的遗传特征。成功地完成我们提出的目标将提供新的见解的基本组织的VTA 多巴胺系统，并建立一个框架，破解多巴胺密码。