Deconstructing brainstem circuits for visceral senses

项目摘要/摘要 严格控制代谢动态平衡的能力对动物的生存至关重要。内心的感觉紧张 系统监控器官的状态，提供反馈信号，使大脑保持动态平衡 通过执行行为和生理反应。例如，系统检测并编码 控制进食行为的胃肠道信号指示进食食物的质量和数量， 消化生理学和全身新陈代谢。调节失调的内部感觉系统，监测 消化系统会导致各种疾病，包括肥胖、糖尿病和厌食症。内心的感官 脑干中的门户，孤束核(NTS)，接受来自胃肠道的输入， 呼吸和心血管系统通过迷走神经和其他神经/体液通路。反过来, NTS投射到不同的高级大脑区域，产生我们对饱腹感、饥饿感、恶心的感知， 以及内脏疼痛。尽管内部感觉系统在健康和疾病中很重要，但神经回路是如何 处理内脏信号来调节行为和生理的研究还很少。解开高度纠缠的 相互连接的脑干神经元需要对解剖、感觉编码和 了解调节个体内脏感官的回路元件的NTS网络的功能。在Dr。 斯蒂芬·利伯勒斯的实验室，我最初的博士后工作破译了身体暗示的感官表征 NTS。在这个提议中，目标是确定内部感觉信息在被处理后是如何 NTS被分成下游的大脑区域，控制行为和生理的特定方面。首先， 将研究组织NTS投射的神经解剖学(目标1)。第二，发自内心的 每个投射传递的线索将使用NTS投射神经元的活体钙成像来确定 (目标2)。最后，NTS投射在控制行为和自主神经生理学中的功能作用将是 建立，重点是调节生理饱足的途径(目标3)。在此提案中进行研究 将在斯蒂芬·利伯勒斯博士的指导下进行，他是内脏感觉研究的先驱 使用遗传方法在迷走神经中的神经元，Clifford Saper博士，神经解剖学的领先科学家 以及神经控制方面的专家Bradford Lowell博士和Eleftheria Maratos-Flier博士 食欲和能量代谢。这一建议将建立一个NTS投射神经元的功能图谱。 内脏感官，提供我们对新陈代谢背后的神经回路的理解 为代谢和内脏感觉障碍开发有针对性的治疗的动态平衡和策略。

PROJECT SUMMARY/ABSTRACT The ability to tightly control metabolic homeostasis is critical for animal survival. The internal sensory nervous system monitors the status of organs, providing feedback signals that enable the brain to maintain homeostasis by executing behavioral and physiological responses. For example, the system detects and encodes gastrointestinal cues signaling the quality and quantity of food ingested during a meal to control feeding behavior, digestive physiology, and whole-body metabolism. Dysregulation of internal sensory systems that monitor the digestive system can lead to various diseases, including obesity, diabetes, and anorexia. The internal sensory gateway in the brainstem, the nucleus of the solitary tract (NTS), receives inputs from the gastrointestinal, respiratory, and cardiovascular systems through the vagus nerve and other neural/humoral pathways. In turn, the NTS projects to diverse higher-order brain regions to generate our perceptions of satiety, hunger, nausea, and visceral pain. Despite the importance of internal sensory systems in health and disease, how neural circuits process visceral signals to regulate behavior and physiology is vastly understudied. Disentangling the highly interconnected brainstem neurons requires a comprehensive analysis of the anatomy, sensory coding, and function of the NTS network to understand the circuit components that mediate individual visceral senses. In Dr. Stephen Liberles’ lab, my initial postdoctoral work deciphered the sensory representations of bodily cues in the NTS. In this proposal, the goal is to determine how internal sensory information, after being processed in the NTS, is sorted into downstream brain regions to control specific aspects of behavior and physiology. First, the neuroanatomical logic by which NTS projections are organized will be investigated (Aim 1). Second, visceral cues transmitted by each projection will be determined using in vivo calcium imaging of NTS projection neurons (Aim 2). Last, the functional roles of NTS projections in controlling behavior and autonomic physiology will be established, with the focus on pathways that mediate physiological satiation (Aim 3). Research in this proposal will be conducted under the guidance of Dr. Stephen Liberles, who pioneered the study of viscerosensory neurons in the vagus nerve using genetic approaches, Dr. Clifford Saper, a leading scientist in the neuroanatomy of the viscerosensory system, and Drs. Bradford Lowell and Eleftheria Maratos-Flier, experts in neural control of appetite and energy metabolism. This proposal will establish a functional atlas of NTS projection neurons in visceral senses, providing insights into our understanding of the neuro-circuitry underlying metabolic homeostasis and strategies to develop targeted treatments for metabolic and viscerosensory disorders.