Higher-Order Neural Control of Food Intake

食物摄入的高阶神经控制

• 批准号: 10297005
• 负责人: Scott Edward Kanoski
• 金额: $ 51.25万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10297005
• 关键词: Acetylcholine; Adult; Appetite Stimulants; Appetitive Behavior; Basic Science; Behavioral; Behavioral Mechanisms; Biological; Brain; Brain Stem; Brain region; Categories; Chemicals; Cholecystokinin; Cholinergic Receptors; Chronic; Cognitive; Consumption; Cues; Data; Desire for food; Development; Dorsal; Eating; Energy Intake; Episodic memory; Feeding behaviors; Fiber; Food; Funding; Genetic Recombination; Health Care Costs; Hippocampus (Brain); Hormones; Hypothalamic structure; Image; Incentives; Intestines; Lateral; Lateral Hypothalamic Area; Learning; Link; Maps; Medial; Mediating; Memory; Memory impairment; Methodology; Neural Pathways; Neurobiology; Neurons; Neurosciences; Nutrient; Obesity; Overweight; Palate; Pathway interactions; Photometry; Population; Prefrontal Cortex; Prevention strategy; Process; RNA Interference; Research; Rewards; Role; Satiation; Signal Transduction; Stimulus; Stomach; Synapses; System; Technology; Vagus nerve structure; Viral; afferent nerve; base; biological systems; cholinergic; classical conditioning; cognitive process; effective therapy; energy balance; experience; experimental study; feeding; gastrointestinal; ghrelin; ghrelin receptor; gut-brain axis; hedonic; improved; in vivo; innovation; knock-down; memory process; memory recall; motivated behavior; multimodality; neural circuit; neuroregulation; neurotransmission; novel; novel strategies; obesity prevention; obesity treatment; receptor binding; reduced food intake; relating to nervous system; response; sensor; social; treatment strategy

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.

项目概要 提高对与过量热量消耗有关的神经生物学系统的理解是 对于制定新的肥胖预防和治疗策略至关重要。传统上该领域重点关注 下丘脑和脑干底物控制响应食物摄入而发生的“稳态” 能源短缺。除了研究这些经典的喂养中心之外，识别系统也很重要 高阶大脑区域通过它来调节奖励驱动的食物寻求和消费 学习、激励和享乐认知因素。该项目将海马体 (HPC) 视为关键的 大脑基质整合记忆过程和喂养相关信号来调节调理食物 动机行为，包括与过多热量摄入和肥胖相关的食欲反应。我们的重点 位于与进食行为和记忆相交的两个 HPC 子区域：腹侧 HPC CA1 (CA1v) 和 背侧 CA3 (CA3d)。我们在上一个融资周期中的发现确定了 CA1v 预测目标的作用 内侧前额皮质 (mPFC)、外侧下丘脑区 (LHA) 和外侧隔膜 (LS) 作为通路 与进食行为 1-3 功能相关。目标 1 实验将推进这些发现以确定其作用 HPC 依赖的联想学习任务中的三个 HPC 投影路径（CA1v -> mPFC、LHA、LS） 与过多的热量摄入有关，并且基于完全独立的食物相关刺激， 包括[1]内感受能量状态线索、[2]外部情境线索和[3]基于社会的嗅觉线索。 除了上述食欲联想记忆过程之外，HPC 依赖的膳食- 相关的情景记忆（回忆一顿饭的人物、事件、时间和地点）对 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，通过该通路 胃肠 (GI) 迷走传入神经 (VAN) 信号传导，传统上是根据膳食量进行研究 控制，促进 HPC 依赖性记忆 9. 我们的初步结果支持以下假设：[1] 胃源性激素胃饥饿素通过 GI VAN 信号发挥作用，促进与膳食相关的情景记忆，以及 [2] 内侧隔膜（MS）胆碱能信号是连接GI VAN信号和HPC功能的中继。 这些假设在 Aim 2 实验中使用最先进的创新组合进行了研究 方法论，包括基于体内光纤光度测定的新型荧光基因编码成像 乙酰胆碱 (ACh) 10,11 和胃扩张依赖性电 VAN 刺激传感器。程度 这些腹侧和背侧 HPC 通路通过共享的侧支投射汇聚到其中，和/或 在利用神经通路追踪方法的 Aim 3 实验中检查常见的下游目标 [1] 将 CA1v 投影的并行投影和二阶投影映射到 mPFC、LHA 和 LS，并且 [2] 识别 编码 GI VAN 信号的 CA3d 神经元的下游投射。这三项的总体结果 相互关联的目标将识别出与记忆和进食行为相交叉的新型神经系统。