Investigating how long-term signals modulate brainstem satiation circuits

项目摘要： 每餐的量要仔细控制，以防止过量或不足。直接控制膳食量是 脑干区，如孤束尾侧核（cNTS），直接接收 进食期间来自胃肠道的短期感觉反馈。相反，间接控制，包括 下丘脑回路和瘦素，被假设编码长期能量平衡和调节膳食 通过调节脑干中感受到的这些短期信号的效力来终止。相互作用 这些长期和短期系统之间的关系对于控制食物摄入至关重要，但它是如何 编码在潜在脑干回路动力学中的基因仍然未知。cNTS包含许多细胞 控制食物摄入的类型。在这些细胞类型中，催乳素释放激素（PRLH） 和胰高血糖素（GCG）神经元对于进餐终止特别重要。在我最近的研究中， 这两种细胞类型在清醒行为小鼠中的首次神经记录。我意外地发现这些细胞 在进餐开始时被诸如味觉之类的前馈信号迅速激活。这些技术和 概念上的进步为我创造了一个机会来研究长期存在的问题， 长期能量平衡调节脑干回路以控制进食终止。我在此提议， 通过研究两种长期能量平衡调节剂-Agouti相关肽（AgRP） 神经元和瘦素调节PRLH或GCG神经元动力学或其控制进食行为。一起 这些结果将揭示长期系统如何调节脑干回路来调节膳食量，这是一个重要的问题。 它是整体食物摄入量的重要决定因素，在肥胖等疾病中可能失调。

Project Abstract: The size of a meal is carefully regulated to prevent over- or under-feeding. Direct control of meal size is attributed by brainstem areas, such as the caudal nucleus of the solitary tract (cNTS), that directly receive short-term sensory feedback from the GI tract during feeding. In contrast, the indirect controls, which include hypothalamic circuits and leptin, are hypothesized to encode long-term energy balance and regulate meal termination by modulating the potency of these short-term signals sensed in the brainstem. Interactions between these long-term and short-term systems are critical for the control of food intake, but how it is encoded in the dynamics of the underlying brainstem circuits remains unknown. The cNTS contains many cell types that are involved in controlling food intake. Among these cell types, prolactin releasing hormone (PRLH) and glucagon (GCG) neurons are particularly important for meal termination. In my recent studies, I performed the first neural recordings of these two cell types in awake behaving mice. I found unexpectedly that these cells were rapidly activated at the start of a meal by feedforward signals such as taste. These technical and conceptual advances create an opportunity for me to investigate the longstanding question of how signals of long-term energy balance modulate brainstem circuits to control meal termination. I propose here to address this question by investigating how two regulators of long-term energy balance – Agouti-related peptide (AgRP) neurons and leptin – modulate PRLH or GCG neuron dynamics or their control of feeding behavior. Together these results will reveal how long-term systems modulate brainstem circuits to regulate meal size, which is an important determinant of overall food intake and can be dysregulated in conditions like obesity.