Deconstructing the sertonin system in the mouse brain

项目摘要 5-羟色胺是一种进化上保守的神经递质，其调节兴奋性和兴奋性神经元的活性。 抑制性神经元遍布整个哺乳动物的大脑，因此是必不可少的不同方面， 生理和行为。影响血清素系统的药物已被用于治疗许多大脑 包括抑郁症、焦虑症和创伤后应激障碍在内的疾病。在哺乳动物的大脑中， 5-羟色胺神经元聚集在脑干的中缝核中，但在整个脑干中投射轴突。 个脑袋我们缺乏对5-羟色胺神经元如何组织以实现其多样性的基本理解。 功能协调发展的 我们最近的研究表明，中缝背核（DR）5-羟色胺神经元可能包括平行的 具有不同投影模式、输入偏差、生理响应特性的子系统，以及 行为功能例如，投射到眶额皮质和中枢的DR 5-羟色胺神经元 杏仁核有不同的侧支模式，从杏仁核接收定量偏置的单突触输入， 一组不同的大脑区域，对惩罚做出相反的反应，并在促进 积极应对和焦虑行为。单细胞转录组分析显示，DR 5-羟色胺神经元包括7个转录组类型，不同于附近的4个转录组类型。 中缝正中（MR）5-羟色胺神经元。我们未发表的抵押品映射数据进一步表明， DR和MR 5-羟色胺神经元的多样、复杂但定型的侧支模式。 在这里，我们建议使用多种方法的组合，包括病毒遗传获取血清素 投射到特定脑区的神经元，轴突侧支模式的全脑映射， 原位转录组学和投射组学分型，化学遗传学和光遗传学操作，纤维光度学 和基于神经像素的生理记录，以及统计建模。具体来说，我们将完成 将5-羟色胺神经元划分为特定的子系统。康贝特人将以 5-羟色胺系统子集的行为功能。我们还将描述一个子集的动态特性 以及它们对靶神经元动力学的作用。通过结合病毒 通过解剖学、生理学和行为学分析对血清素子系统进行遗传解剖， 拟议的研究有可能使我们对本组织的了解向前迈出一大步 和哺乳动物大脑中血清素系统的功能。

PROJECT SUMMARY Serotonin is an evolutionarily conserved neurotransmitter that modulates the activity of excitatory and inhibitory neurons throughout the entire mammalian brain and is thus essential for diverse aspects of physiology and behavior. Drugs that impact the serotonin system have been used to treat numerous brain disorders including depression, anxiety, and post-traumatic stress disorder. In the mammalian brain, serotonin neurons are clustered in the raphe nuclei of the brainstem, but project axons across the entire brain. We lack a fundamental understand of how serotonin neurons are organized to achieve their diverse functions. Our recent studies suggested that dorsal raphe (DR) serotonin neurons likely comprise parallel subsystems with distinct projection patterns, input biases, physiological response properties, and behavioral functions. For example, DR serotonin neurons that project to orbitofrontal cortex and central amygdala have distinct collateralization patterns, receive quantitatively biased monosynaptic inputs from a diverse set of brain regions, respond oppositely to punishment, and have distinct functions in promoting active coping and anxiety behaviors, respectively. Single-cell transcriptomic profiling revealed that DR serotonin neurons comprise 7 transcriptomic types, distinct from the 4 transcriptomic types in the nearby median raphe (MR) serotonin neurons. Our unpublished data on collateralization mapping further indicated diverse, complex, yet stereotyped collateralization patterns of DR and MR serotonin neurons. Here we propose to use a combination of approaches, including viral-genetic access of serotonin neurons that project to specific brain regions, whole-brain mapping of axon collateralization patterns, in situ transcriptomic and projectomic typing, chemogenetic and optogenetic manipulations, fiber photometry and Neuropixels-based physiological recordings, and statistical modeling. Specifically, we will complete the collateralization mapping and divide serotonin neurons into specific subsystems. We will determine the behavioral functions of a subset of serotonin systems. We will also characterize the dynamics of a subset of serotonin subsystems and the effect of their action on target neuron dynamics. By combining viral genetic dissection of serotonin subsystems with anatomical, physiological, and behavioral analyses, our proposed studies have the potential to take a major step forward in our understanding of the organization and function of the serotonin system in the mammalian brain.