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.

项目摘要 提高对过度摄入卡路里所涉及的神经生物系统的理解是 对于开发新的肥胖症预防和治疗策略至关重要。传统上，该领域一直专注于 在下丘脑和脑干底物上，这些底物控制着对 能源短缺。除了研究这些经典的喂养中心外，识别这些系统也是至关重要的 高级大脑区域通过它来调节奖励驱动的食物寻找和消费，基于 学习、激励和享乐认知因素。该项目将海马体(HPC)作为一个关键的 大脑底物整合记忆过程和与摄食相关的信号来调节条件食物- 动机行为，包括与卡路里摄入过多和肥胖有关的食欲反应。我们的重点是 位于两个交叉于摄食行为和记忆的HPC亚区：腹侧HPC CA1(CA1v)和 背侧CA3(CA3d)。我们在上一个资金周期的发现确定了CA1v预测的作用 内侧前额叶皮质(MPFC)、下丘脑外侧区(LHA)和外侧隔区(LS)为通路 在功能上与取食行为相关1-3。目标1的实验将推动这些发现，以确定角色 HPC依赖联想学习任务中三条HPC投射通路(CA1v&Gt；mPFC、LHA、LS)的比较 与过多的卡路里摄取有关，并基于绝对不同的食物相关刺激， 包括[1]内感能量状态线索、[2]外部语境线索和[3]基于社会的嗅觉线索。 除了上述食欲联想记忆过程外，依赖HPC的膳食- 相关的情节记忆(回忆谁、什么、何时和哪里围着一顿饭)强烈地影响着 摄食行为4-8只。上一个资金周期的结果确定了一条神经通路，通过它 胃肠(GI)迷走神经传入神经(VAN)信号，传统上在饮食大小的背景下进行研究 控制，促进HPC依赖的记忆9。我们的初步结果支持假设[1] 胃源性激素Ghrelin通过GI van信号作用于促进与饮食相关的情节记忆，以及 [2]内侧隔(MS)胆碱能信号是连接胃肠道VAN信号和HPC功能的中继器。 这些假设在Aim 2实验中使用了最先进的创新组合进行了研究 方法学，包括基于体内纤维光度学的新型基因编码荧光成像 用于乙酰胆碱(ACh)10，11和胃扩张依赖的电刺激的传感器。广度 这些腹侧和背侧HPC通路通过共享侧支投射汇合到该区域，和/或 在利用神经通路追踪方法的目标3实验中，检查了常见的下游靶点。 要[1]将CA1v预测的宣传品和二阶投影映射到mPFC、LHA和LS，并[2]确定 编码GIvan信号的CA3d神经元的下游投射。这三个方面的总体结果 相互关联的AIMS将识别出将记忆和摄食行为结合在一起的新型神经系统。