Deconstructing the sertonin system in the mouse brain

项目总结 5-羟色胺是一种进化上保守的神经递质，调节兴奋性和 抑制性神经元遍布整个哺乳动物的大脑，因此对不同方面的 生理和行为。影响5-羟色胺系统的药物已被用于治疗许多脑部疾病 精神障碍包括抑郁、焦虑和创伤后应激障碍。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团中，但轴突横跨整个脑干。 大脑。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了解 功能。 我们最近的研究表明，中缝背核(DR)5-羟色胺神经元可能由平行的 具有不同的投影模式、输入偏差、生理响应特性和 行为功能。例如，DR 5-羟色胺神经元投射到眼眶前额叶皮质和中央 杏仁核具有不同的侧化模式，从 不同的大脑区域，对惩罚做出相反的反应，并具有不同的促进作用 积极应对和焦虑行为。单细胞转录图谱显示，DR 5-羟色胺神经元包括7种转录类型，与附近的4种转录类型不同 中缝中缝(MR)5-羟色胺神经元。我们关于抵押映射的未公布数据进一步表明 DR和MR 5-羟色胺神经元的侧支模式多种多样、复杂，但却是刻板的。 在这里，我们建议使用多种方法的组合，包括5-羟色胺的病毒遗传途径。 投射到特定大脑区域的神经元，轴突侧化模式的全脑映射，在 原位转录和投射分型，化学遗传和光遗传操作，纤维光度学 以及基于神经像素的生理记录和统计建模。具体地说，我们将完成 侧支映射将5-羟色胺神经元划分为特定的子系统。我们将确定 5-羟色胺系统子集的行为功能。我们还将描述子集的动态特性 5-羟色胺亚系统及其作用对靶神经元动力学的影响。通过将病毒 通过解剖学、生理学和行为学分析对5-羟色胺亚系统进行遗传解剖，我们的 拟议的研究有可能在我们对本组织的理解方面向前迈出一大步 以及哺乳动物大脑中5-羟色胺系统的功能。

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 Our unpublished data on collateralization mapping further indicated diverse, complex, yet stereotyped collateralization patterns of DR and MR serotonin neurons.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.