Isolation of brain reward circuits using peptidergic systems

项目摘要 腹侧被盖区(VTA)的多巴胺神经元为前脑提供必要的调制信号 边缘系统和皮质，以促进学习和动机过程。多巴胺信号转导中断 广泛地与精神疾病有关，并可能通过以下途径导致一系列行为障碍 明显的皮质-边缘通路。长期以来，VTA内多巴胺神经元的异质性一直是 感谢，但针对该系统的治疗策略仍然基于单一的观点。近期 绘制不同多巴胺通路的输入/输出关系的进展试图解决 VTA的基本组织，但在确定专业程度方面收效甚微 细分可能会被组织起来。VTA的基本解剖和功能组织是 如果要实现精确治疗来治疗特定的行为功能障碍，这是必不可少的。我们 假设VTA中的多巴胺系统可以基于对GATE的多肽能调制来组织 通过特定的输出路径获取信息。我们绘制了多巴胺神经元在大脑中的投射图 VTA表达不同的神经肽受体，并发现这些输出具有显著的专一性。 在这里，我们建议建立基本的电生理、解剖学和行为功能 在基于病毒的电路中使用新型Cre驱动鼠系与先进技术相结合的途径 解剖。我们还将建立新的方法来描述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。

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.