Higher-Order Neural Control of Food Intake

食物摄入的高阶神经控制

• 批准号: 9335572
• 负责人: Scott Edward Kanoski
• 金额: $ 2.89万
• 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 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335572
• 关键词: Adult; Appetite Depressants; Appetite Stimulants; Association Learning; Automobile Driving; Basic Science; Behavior; Behavioral; Biological; Brain; Brain region; Chemicals; Cholecystokinin; Chronic; Communication; Cues; Data; Deafferentation procedure; Development; Diet; Eating; Energy Intake; Exposure to; Feeding behaviors; Food; Frequencies; Gastrointestinal Physiology; Gastrointestinal tract structure; Genetic; Health; Health Care Costs; Hippocampal Formation; Hormones; Individual; Injection of therapeutic agent; Learning; Medial; Mediating; Memory; Methodology; Methods; Neural Inhibition; Neural Pathways; Neurobiology; Neurons; Neurosecretory Systems; Nucleus solitarius; Obesity; Operative Surgical Procedures; Overweight; Pathway interactions; Pattern; Peptides; Peripheral; Pharmacologic Substance; Pharmacological Treatment; Pharmacotherapy; Physiological; Predisposition; Prevalence; Process; Publishing; RNA Interference; Receptor Signaling; Regulation; Research; Rewards; Role; Satiation; Short-Term Memory; Signal Transduction; Site; Stimulus; Stomach; Synapses; System; Techniques; Testing; Tracer; United States; Vagotomy; Vagus nerve structure; Viral Vector; Visceral; Visual; Work; bariatric surgery; base; biological systems; designer receptors exclusively activated by designer drugs; effective therapy; energy balance; experience; feeding; gastrointestinal; ghrelin; ghrelin receptor; glucagon-like peptide; hindbrain; innovation; insight; learned behavior; neural circuit; neurochemistry; neuronal circuitry; neuroregulation; neurotransmission; novel; novel strategies; obesity treatment; preference; receptor; reduced food intake; relating to nervous system; research study; sensory input; social; targeted treatment

 DESCRIPTION (provided by applicant): Adults in the United States today are consuming ~500 kcal per day more compared to adults in 1980, a phenomenon underlying the fact that obesity prevalence in the U.S. has increased by 75% in the past 30 years. Both the size of an individual meal and the frequency of meal or snack initiation are heavily influenced by previous experience and by exposure to external food-associated stimuli (e.g., visual, olfactory) that can override biological satiation and satiety cues. Therefore, the development of effective pharmacological treatments for obesity requires a better understanding of the neurobiological systems that integrate previous experience with external and internal cues to control food intake. Novel pilot data presented in this proposal implicate the hippocampal formation (HPF), particularly its ventral subregion (HPFv), in this type of "higher-order" regulation of feeding behavior. HPFv neurons influence food intake, in part, by processing neuroendocrine signals that inform about energy status. Meal size, meal frequency, and overall food intake are increased when receptors for the gut-derived hormone ghrelin (GHS-1RA) are activated on HPFv neurons. On the other hand, average meal size and overall food intake are potently reduced following activation of HPFv receptors for GLP-1, a GI- and hindbrain-secreted satiation peptide. In addition to neuroendocrine signals, HPF neurons receive gastrointestinal (GI) visceral information from ascending vagus nerve-hindbrain neural pathways. Our pilot data show that HPFv neurons are activated by peripheral cholecystokinin (CCK), a satiation peptide that reduces meal size via vagus nerve signaling. Other pilot data show that subdiaphragmatic vagotomy impairs HPF-dependent spatial working memory. Collectively, these novel findings indicate that HPF neurons are impacted by various physiological cues that inform about energy status. Experiments will expand these findings using behavioral, neuroanatomical, genetic (RNA-interference), surgical, and other methodologies to determine whether, [Aim I] endogenous HPFv GHS-R1A or GLP-1R signaling increases or decreases (respectively) meal size, meal frequency, and overall energy balance, and [Aim II] whether ablated GI vagus afferent signaling negatively impacts HPF-dependent appetitive learning processes related to food procurement. Additional experiments [Aim III] utilize neuroanatomical analyses to characterize the bi- directional, multisynaptic communication between HPFv and hindbrain neurons. The functional relevance of these neural pathways to feeding behavior will be tested using newly-developed techniques for monosynaptic neural inhibition (designer receptors exclusively activated by designer drugs). Overall our approach utilizes multiple levels of analysis to explore our hypothesis that the HPF is a critical neural locus for integrating previous experience with external food cues and internal visceral cues to control higher-order aspects of feeding. Results from proposed experiments have strong potential to deepen understanding of the neurochemical and neuroanatomical systems controlling excessive feeding behavior.

 描述（由申请人提供）：与 1980 年的成年人相比，今天的美国成年人每天消耗的热量多了约 500 kcal，这一现象是美国肥胖患病率在过去 30 年中增加了 75% 的原因之一。每顿饭的份量以及开始进餐或吃零食的频率都很大程度上受到以前的经验和接触外部食物相关刺激（例如视觉、嗅觉）的影响，这些刺激可以超越生物饱腹感和饱腹感线索。因此，开发有效的肥胖药物治疗方法需要更好地了解神经生物学系统，将先前的经验与外部和内部线索相结合以控制食物摄入。该提案中提出的新试验数据表明海马结构（HPF），特别是其腹侧亚区（HPFv），参与了这种进食行为的“高阶”调节。 HPFv 神经元部分通过处理告知能量状态的神经内分泌信号来影响食物摄入。当 HPFv 神经元上的肠源性激素生长素释放肽 (GHS-1RA) 受体被激活时，进餐量、进餐频率和总体食物摄入量都会增加。另一方面，GLP-1（一种胃肠道和后脑分泌的饱足肽）的 HPFv 受体激活后，平均膳食量和总体食物摄入量显着减少。除了神经内分泌信号外，HPF 神经元还接收来自上行迷走神经-后脑神经通路的胃肠道 (GI) 内脏信息。我们的试验数据显示，HPFv 神经元被外周胆囊收缩素 (CCK) 激活，CCK 是一种饱腹感肽，可通过迷走神经信号传导减少膳食量。其他试点数据表明，膈下迷走神经切断术会损害 HPF 依赖性空间工作记忆。总的来说，这些新发现表明 HPF 神经元受到各种有关能量状态的生理线索的影响。实验将使用行为、神经解剖、遗传（RNA 干扰）、外科和其他方法来扩展这些发现，以确定[目标 I]内源性 HPFv GHS-R1A 或 GLP-1R 信号传导是否（分别）增加或减少进餐量、进餐频率和总体能量平衡，以及[目标 II]消融的胃肠道迷走神经传入信号是否会对 HPF 依赖性食欲产生负面影响 与食品采购相关的学习过程。其他实验 [目标 III] 利用神经解剖学分析来表征 HPFv 和后脑神经元之间的双向、多突触通讯。这些神经通路与进食行为的功能相关性将使用新开发的单突触神经抑制技术（仅由设计药物激活的设计受体）进行测试。总的来说，我们的方法利用了多个层次的分析 探索我们的假设，即 HPF 是一个关键的神经位点，用于将先前的经验与外部食物线索和内部内脏线索相结合，以控制进食的高阶方面。所提出的实验结果具有很大的潜力，可以加深对控制过度进食行为的神经化学和神经解剖系统的理解。