Higher-Order Neural Control of Food Intake

项目摘要 提高对涉及过量热量消耗的神经生物学系统的理解， 对于开发新的肥胖预防和治疗策略至关重要。传统上，该领域的重点是 作用于下丘脑和脑干基质，控制因响应而发生的“稳态”食物摄入 能量不足。除了研究这些典型的摄食中心， 通过这些机制，大脑的高级区域可以调节奖励驱动的食物寻找和消费， 学习、激励和享乐认知因素。本项目研究海马体（HPC）作为一个关键的 大脑基质整合记忆过程和喂养相关信号，以调节条件食物- 动机行为，包括与过量热量摄入和肥胖有关的食欲反应。我们的重点 位于两个HPC子区域，它们与进食行为和记忆相交：腹侧HPC CA 1（CA 1v）和 背侧CA 3（CA 3d）。我们在上一个融资周期的研究结果确定了CA 1v预测的作用， 内侧前额叶皮质（mPFC）、外侧下丘脑区（LHA）和外侧隔（LS）作为通路 与进食行为相关的功能1-3。目标1实验将推进这些发现，以确定作用 在HPC依赖的联想学习任务中，三种HPC投射途径（CA 1v-> mPFC，LHA，LS）的差异 与过量热量摄入有关，并基于分类分离的食物相关刺激， 包括[1]内感受能量状态线索，[2]外部上下文线索，和[3]基于社会的嗅觉线索。 除了上述的食欲联想记忆过程，HPC依赖的膳食- 相关的情景记忆（回忆谁，什么，什么时候，在哪里吃饭）强烈影响 摄食行为4-8.上一个资助周期的结果确定了一条神经通路， 胃肠道（GI）迷走传入神经（货车）信号传导，传统上在膳食量的背景下研究 控制，促进HPC依赖的存储器9.我们的初步结果支持了假设[1]， 胃源性激素胃促生长素通过GI货车信号传导发挥作用，促进与膳食相关的情景记忆，并且 [2]内侧隔（MS）胆碱能信号传导是连接GI货车信号传导和HPC功能的中继。 这些假设在目标2实验中使用最先进的创新组合进行研究。 方法学，包括新的荧光基因编码的基于体内纤维光度计的成像， 用于乙酰胆碱（ACh）10，11和胃扩张依赖性电货车刺激的传感器。程度 这些腹侧和背侧HPC通路通过共享的侧支投射会聚到该位置，和/或 在Aim 3实验中，利用神经通路追踪方法检查了常见的下游靶点 [1]将CA 1v投影的侧支和二阶投影映射到mPFC、LHA和LS，[2]确定 编码GI货车信号传导的CA 3d神经元的下游投射。这三个方面的总体结果 相互关联的目标将确定新的神经系统，交叉记忆和喂养行为。

Project Summary Improved understanding of the neurobiological systems involved in excessive caloric consumption is critical for developing novel prevention and treatment strategies for obesity. Traditionally the field has focused on hypothalamic and brainstem substrates that control `homeostatic' food intake that occurs in response to energy deficits. In addition to studying these classic feeding centers, it is critical to also identify the systems through which higher-order brain regions regulate reward-driven food seeking and consumption based on learned, incentive, and hedonic cognitive factors. This project investigates the hippocampus (HPC) as a critical brain substrate integrating memory processes and feeding-related signals to regulate conditioned food- motivated behavior, including appetitive responses linked with excessive caloric intake and obesity. Our focus is on two HPC subregions that intersect feeding behavior and memory: the ventral HPC CA1 (CA1v) and the dorsal CA3 (CA3d). Our findings from the previous funding cycle identify a role for CA1v projections targeting the medial prefrontal cortex (mPFC), lateral hypothalamic area (LHA), and lateral septum (LS) as pathways functionally relevant to feeding behavior 1-3. Aim 1 experiments will advance these findings to identify the role of three HPC projection pathways (CA1v -> mPFC, LHA, LS) in HPC-dependent associative learning tasks that are relevant to excessive caloric intake and are based on categorically separate food-associated stimuli, including [1] interoceptive energy status cues, [2] external contextual cues, and [3] social-based olfactory cues. In addition to the appetitive associative memory processes described above, HPC-dependent meal- related episodic memory (recalling who, what, when, and where surrounding a meal) powerfully influences feeding behavior 4-8. Results from the previous funding cycle identified a neural pathway through which gastrointestinal (GI) vagus afferent nerve (VAN) signaling, traditionally studied in the context of meal size control, promotes HPC-dependent memory 9. Our preliminary results support the hypotheses that [1] the stomach-derived hormone ghrelin acts via GI VAN signaling to promote meal-related episodic memory, and [2] medial septum (MS) cholinergic signaling is a relay connecting GI VAN signaling and HPC function. These hypotheses are investigated in Aim 2 experiments using an innovative combination of state-of-the-art methodologies, including in vivo fiber photometry-based imaging of novel fluorescent genetically-encoded sensors for acetylcholine (ACh) 10,11 and stomach distention-dependent electrical VAN stimulation. The extent to which these ventral and dorsal HPC pathways converge through shared collateral projections, and/or common downstream targets is examined in Aim 3 experiments that utilize neural pathway tracing approaches to [1] map the collateral and 2nd-order projections of CA1v projections to mPFC, LHA, and LS, and [2] identify downstream projections of CA3d neurons that encode GI VAN signaling. Overall results from these three interconnected aims will identify novel neural systems that intersect memory and feeding behavior.