Higher-Order Neural Control of Food Intake

食物摄入的高阶神经控制

• 批准号: 10640909
• 负责人: Scott Edward Kanoski
• 金额: $ 47.81万
• 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/10640909
• 关键词: Acetylcholine; Adult; Appetite Stimulants; Appetitive Behavior; Association Learning; 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; 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; Pathway interactions; Photometry; Population; Prefrontal Cortex; Prevention strategy; Process; RNA Interference; Receptor Signaling; Research; Rewards; Role; Satiation; Signal Transduction; Stimulus; Stomach; Synapses; System; Technology; Vagus nerve structure; Viral; afferent nerve; biological systems; cholinergic; 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; motivated behavior; multimodality; neural; neural circuit; neuroregulation; neurotransmission; novel; novel strategies; obesity prevention; obesity treatment; receptor binding; reduced food intake; 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 对过度热量消耗涉及的神经生物学系统的了解得到了改善的是 对于制定肥胖症的新型预防和治疗策略至关重要。传统上，该领域集中于 关于控制“稳态”食物摄入的下丘脑和脑干底物，该食物响应于 能源不足。除了研究这些经典的喂养中心外，还必须确定系统 高阶大脑区域通过其中调节奖励驱动的食物，以寻求和消费 学会，激励和享乐认知因素。该项目将海马（HPC）视为关键 脑底物整合记忆过程和喂养相关信号以调节条件食品 - 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 位于两个与进食行为和内存相交的HPC子区域：腹侧HPC CA1（CA1V）和 背CA3（CA3D）。我们以前的资金周期中的发现确定了CA1V预测的作用 内侧前额叶皮层（MPFC），下丘脑面积（LHA）和外侧隔膜（LS）作为途径 与进食行为1-3的功能相关。 AIM 1实验将推进这些发现以确定角色 在HPC依赖性的关联学习任务中 与过量的热量摄入相关，并且基于与食物相关的刺激， 包括[1]互感能量状态提示，[2]外部上下文提示和[3]基于社会的嗅觉提示。 除了上述的食用性关联记忆过程外，HPC依赖性餐 相关的情节记忆（回想谁，什么，何时和周围的饭菜）有力地影响 喂养行为4-8。以前的资金周期的结果确定了一种神经途径 胃肠道（GI）迷走神经（van）信号传统在膳食大小的背景下进行研究 控制，促进HPC依赖性内存9。我们的初步结果支持[1] 胃衍生的激素生长素蛋白通过GI货车信号作用，以促进与进餐相关的情节记忆，并 [2]内侧隔膜（MS）胆碱能信号传导是连接GI货车信号传导和HPC功能的继电器。 在AIM 2实验中研究了这些假设 方法学，包括基于体内纤维光度法的新型荧光遗传编码的成像 乙酰胆碱（ACH）10,11和胃扩张依赖性电型式型刺激的传感器。程度 这些腹侧和背侧HPC途径通过共同的附带预测和/或 在AIM 3实验中检查了常见的下游目标，该实验利用神经途径追踪方法 [1]将CA1V投影的抵押品和二阶投影映射到MPFC，LHA和LS，[2]确定 编码GI货车信号传导的CA3D神经元的下游投影。这三个的总体结果 相互联系的目标将确定与记忆和进食行为相交的新型神经系统。