Neuromodulation of Brain States

项目总结 包括多巴胺、去甲肾上腺素和5-羟色胺在内的单胺在进化上是保守的。 神经递质调节整个大脑的兴奋性和抑制性神经元的活动， 因此对生理和行为的各个方面都是必不可少的。单胺类药物异常 系统导致许多大脑疾病，包括精神分裂症、抑郁症和帕金森氏症 疾病。我们最近开发了病毒遗传工具来确定输入、输出和输入-输出 在整个小鼠大脑的规模上的给定神经元群体的关系，并发现 蓝斑去甲肾上腺素神经元和中脑的输入输出结构比较 多巴胺神经元。在这里，我们应用这些工具来研究背侧中缝的组织和功能 (DR)5-羟色胺系统，它为前脑提供主要的5-羟色胺能输入，调节不同的 。 功能和大脑状态，包括情绪、冲动、焦虑以及饥饿和口渴。 使用狂犬病介导的跨突触跟踪，我们之前定义了整个 然而，我们未发表的工作揭示了DR-5-羟色胺和DR-GABA神经元的群体 DR 5-羟色胺系统中存在相当大的异质性，这表明它由平行的亚 输入、输出和神经递质表型不同的系统。我们建议每个DR 5-羟色胺 子系统可以执行归因于DR-5-羟色胺神经元的不同功能的特定子集。 我们计划完成我们对DR 5-羟色胺亚单位的解剖组织的描述 系统，解决了每个子系统的轴突如何划分整个系统的投影的问题 DR 5-羟色胺系统，以及每个DR-5-羟色胺子系统的输入输出关系是什么。这些 将为未来对DR-5-羟色胺神经元的所有研究奠定基础。我们还建议将行为 这些子系统的一个子集通过操纵和记录5-羟色胺神经元亚型的功能 已知的焦虑和抑郁状态涉及5-羟色胺以及新的行为模式。 最后，因为之前的研究和我们自己未发表的数据表明，血清素与 和口渴，我们将探索5-羟色胺调节口渴的电路和细胞机制 使用我们基于我们开发的技术建立的定量和灵敏分析的行为 以获得口渴激活神经元的遗传途径。解剖学、生理学和 这里提出的关于遗传、投射和活动定义的神经元群体的行为研究将 有助于将复杂的5-羟色胺系统分解为特定的子系统，并促进我们对 5-羟色胺如何调节各种生理功能和行为。

PROJECT SUMMARY The monoamines, which include dopamine, norepinephrine, and serotonin, are evolutionarily conserved neurotransmitters that modulate the activity of excitatory and inhibitory neurons throughout the entire brain, and are thus essential for diverse aspects of physiology and behavior. Abnormalities of monoamine systems contribute to numerous brain disorders including schizophrenia, depression, and Parkinson's disease. We recently developed viral-genetic tools to determine the input, output, and input–output relationships of a given neuronal population at the scale of the entire mouse brain, and discovered contrasting input–output architectures between locus coeruleus norepinephrine neurons and midbrain dopamine neurons. Here, we apply these tools to study the organization and function of the dorsal raphe (DR) serotonin system, which provides major serotoninergic input to the forebrain to regulate diverse . functions and brain states including mood, impulsivity, anxiety, as well as hunger and thirst. Using rabies-mediated trans-synaptic tracing, we previously defined the input architecture to the entire populations of DR-serotonin and DR-GABA neurons However, our unpublished work revealed considerable heterogeneity within the DR serotonin system and suggests that it consists of parallel sub- systems that differ in input, output, and neurotransmitter phenotypes. We propose that each DR serotonin sub-system may carry out a specific subset of the diverse functions ascribed to the DR-serotonin neurons. We plan to complete our characterization of the anatomical organization of the DR serotonin sub- systems, addressing the questions of how axons of each sub-system divide up the projections of the entire DR serotonin system, and what is the input–output relationship for each DR serotonin sub-system. These will lay a foundation for all future studies of DR-serotonin neurons. We also propose to identify behavioral functions of a subset of these sub-systems by manipulating and recording serotonin neuron subtypes in anxiety- and depression-like states known to involve serotonin, as well as new behavioral paradigms. Finally, because previous studies and our own unpublished data suggest a strong link between serotonin and thirst, we will explore the circuit and cellular mechanisms by which serotonin regulates thirst-motivated behavior using quantitative and sensitive assays we have established based on a technique we developed to gain genetic access of thirst-activated neurons. The integration of anatomical, physiological, and behavioral studies on genetic-, projection-, and activity-defined neuronal populations proposed here will help dissect the complex serotonin system into specific sub-systems and advance our understanding of how serotonin modulates diverse physiological functions and behaviors.