Functional mapping of the parabrachial nucleus: from gastrointestinal topography to satiety

臂旁核的功能图谱：从胃肠道地形到饱腹感

• 批准号: 10604684
• 负责人: Kiersten Ruda
• 金额: $ 6.95万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-14 至 2024-12-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10604684
• 关键词: Address; Affect; Anatomy; Anesthesia procedures; Architecture; Area; Axon; Behavior; Behavioral; Body Weight; Brain; Brain Stem; Calcitonin Gene-Related Peptide; Calcitonin Receptor; Calcium; Chronic; Consumption; Data; Eating; Environment; Esophagus; Esthesia; Exhibits; Fasting; Feeding behaviors; Food; Future; Gastrointestinal tract structure; Genes; Homeostasis; Image; Individual; Ingestion; Interoception; Knowledge; Lateral; Lead; Link; Liquid substance; Malaise; Maps; Measurement; Measures; Mechanical Stimulation; Mediating; Metabolic Diseases; Methods; Mus; Nature; Neurons; Nucleus solitarius; Nutrient; Obesity; Oral cavity; Organ; Pathway interactions; Pattern; Physiological; Population; Presynaptic Terminals; Protocols documentation; Research; Role; Satiation; Sensory; Signal Transduction; Site; Small Intestines; Stimulus; Stomach; Stretching; Testing; Thalamic structure; Time; Training; Upper digestive tract structure; Visceral; Visceral pain; Work; awake; cell type; dimensional analysis; energy balance; experimental study; feeding; food consumption; gastrointestinal; hindbrain; imaging approach; in vivo; in vivo imaging; multimodality; neural; new therapeutic target; novel; optogenetics; parabrachial nucleus; preference; prodynorphin; response; spinal pathway; therapeutic target; transcriptomics; two-photon

Project Summary/Abstract Interoception, the sensing of signals from internal organs, is crucial to achieving homeostasis in unpredictable environments. For instance, appropriate food intake relies on accurate estimation of future energy balance, which in turn relies on gastrointestinal (GI) signals like nutrient content or stomach stretch. A key brain area that assesses visceral state is the lateral parabrachial nucleus (LPBN) in the brainstem. Visceral information is routed to the LPBN by several convergent pathways, including the nucleus of the solitary tract (NTS), which relays signals from vagal afferents to LPBN. Despite this anatomical roadmap, we lack a comprehensive picture of the functional architecture and GI sensory preferences in the LPBN and its NTS inputs. This information is crucial to understanding how representations of body signals associated with fasted, fed, and feeding states are formed, and how they regulate energy balance. To address this gap in knowledge, I propose to assess the functional organization of GI representations and their relation to natural feeding. I will further test if specific NTS cell types mediate the relay of these visceral signals to the LPBN. I will accomplish these aims with a novel method of two-photon imaging in the hindbrain that tracks hundreds of LPBN neurons across days. In Aim 1, I will measure visceral sensory preferences in the LPBN in response to mechanical stimulation and nutrient delivery across regions of the GI tract. These measurements will allow me to determine the spatial organization of LPBN, including testing the presence of a viscerotopic map of internal organs. Next, I will relate these recordings to activity in the LPBN during ingestion, visceral malaise, and across fasted and fed states. I will test the hypothesis that a wave of neural activation in LPBN across many seconds during natural feeding tracks a putative map of the GI tract. In Aim 2, I will determine how specific inputs from the NTS contribute to feeding-related and satiety state-related activity in LPBN. Specifically, I will repeat the stimuli of Aim 1 while recording from calcitonin receptor-expressing (Calcr) neurons of the NTS that have been shown to signal physiological satiety. I will measure when individual axons of these inputs to LPBN (CalcrNTS->PBN) are active, as well as record LPBN responses to the above stimuli while CalcrNTS->PBN axons are silenced. These experiments will demonstrate how a key pathway relays GI state and other satiety information to the LPBN to regulate behavior and interoception. The proposed research will lay the groundwork for understanding how interoceptive signals from the GI tract lead to satiety sensations, influence feeding behaviors, and ultimately regulate energy balance. This knowledge will pave the way for future efforts combining in vivo imaging with spatial transcriptomics to identify specific cell types and subregions within the LPBN as therapeutic targets for obesity and other metabolic disorders.

项目总结/摘要 内感受，即对来自内部器官的信号的感知，对于实现体内平衡至关重要。 不可预测的环境。例如，适当的食物摄入依赖于对未来的准确估计。 能量平衡，这反过来又依赖于胃肠道（GI）信号，如营养成分或胃伸展。一 评估内脏状态的关键脑区是脑干中的臂旁外侧核（LPBN）。内脏 信息通过包括孤束核在内的几条会聚通路传递到LPBN (NTS)LPBN是迷走神经传入信号的传递途径。尽管有这样的解剖学路线图， LPBN及其NTS的功能结构和GI感觉偏好的综合图 输入。这些信息对于理解身体信号的表征是如何与 与禁食，进食和进食状态的形成，以及它们如何调节能量平衡。为了解决这个 在知识的差距，我建议评估地理标志的代表性和他们的关系， 自然喂养。我将进一步测试特定的NTS细胞类型是否介导了这些内脏信号向神经元的传递。 LPBN。我将通过一种新颖的方法来实现这些目标，即在后脑中进行双光子成像， 数百个LPBN神经元。在目标1中，我将测量LPBN中的内脏感觉偏好， 对机械刺激的反应和跨胃肠道区域的营养输送。这些测量 将允许我确定LPBN的空间组织，包括测试内脏定位的存在， 内部器官图接下来，我将把这些记录与摄入期间LPBN的活动联系起来，内脏 在禁食和进食状态下，我将检验一个假设，即LPBN中的神经激活波 在自然进食期间的许多秒内跟踪胃肠道的推定地图。在目标2中，我将确定 NTS的特定输入如何促进LPBN中的进食相关和饱足状态相关活动。 具体来说，我将重复Aim 1的刺激，同时从降钙素受体表达（Calcr） NTS的神经元已经被证明是生理饱腹感的信号。我将测量单个轴突 LPBN的这些输入（CalcrNTS->PBN）是活跃的，以及记录LPBN对上述刺激的反应， CalcrNTS->PBN轴突沉默。这些实验将展示一个关键途径如何传递GI状态， 其他饱腹感信息的LPBN调节行为和内感受。这项研究将奠定 了解来自胃肠道的内感受信号如何导致饱腹感的基础， 影响进食行为，并最终调节能量平衡。这些知识将为 未来的努力结合体内成像与空间转录组学，以确定特定的细胞类型， LPBN内的亚区作为肥胖症和其他代谢紊乱的治疗靶点。