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

项目摘要/摘要 内感觉，即对来自内脏器官的信号的感觉，是实现脑内环境平衡的关键 不可预测的环境。例如，适当的食物摄入量依赖于对未来的准确估计 能量平衡，而能量平衡又依赖于胃肠道(GI)信号，如营养含量或胃伸展。一个 评估内脏状态的关键大脑区域是脑干中的臂旁外侧核(LPBN)。发自内心的 信息通过包括孤束核在内的几条汇聚通路传递到下丘脑束核。 (NTS)，它将迷走神经传入的信号传递到LPBN。尽管有这样的解剖路线图，但我们缺乏 LPBN及其NTS的功能结构和GI感官偏好的综合图景 投入。这一信息对于理解身体信号的表征如何关联至关重要 禁食、进食和进食状态的形成，以及它们如何调节能量平衡。要解决这个问题 在知识差距方面，我建议评估GI表征的功能组织及其与 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到 LPBN.我将用一种在后脑追踪的双光子成像的新方法来实现这些目标 几天内有数百个LPBN神经元。在目标1中，我将测量LPBN中的内脏感觉偏好 对机械刺激和跨胃肠道区域的营养输送的反应。这些测量结果 将使我能够确定LPBN的空间组织，包括测试内脏是否存在 内脏器官图。接下来，我将把这些录音与摄取内脏的下丘脑核团的活动联系起来。 萎靡不振，并跨越禁食和美联储的州。我将测试LPBN中一波神经激活波的假设 在自然摄食过程中的几秒钟内，追踪到了一张推定的胃肠道地图。在目标2中，我将决定 来自NTS的特定输入如何有助于LPBN中与摄食相关和与饱足状态相关的活动。 具体地说，我将重复目标1的刺激，同时记录降钙素受体表达(Calcr) 已被证明具有生理饱足感的NTS神经元。我将测量单个轴突何时 其中LPBN(CalcrNTS-&>PBN)的输入是活跃的，并记录LPBN对上述刺激的反应 CalcrNTS-&gt；PBN轴突被沉默。这些实验将演示关键通路如何传递GI状态和 其他饱腹感信息传递给LPBN，以调节行为和内感。这项拟议的研究将 了解来自胃肠道的相互感觉信号是如何导致饱腹感的基础， 影响摄食行为，最终调节能量平衡。这一知识将为 未来的努力结合体内成像和空间转录，以识别特定的细胞类型和 LPBN内的亚区作为肥胖和其他代谢紊乱的治疗靶点。

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.