Higher-Order Neural Control of Food Intake

食物摄入的高阶神经控制

• 批准号: 8861570
• 负责人: Scott Edward Kanoski
• 金额: $ 37.1万
• 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/8861570
• 关键词: Adult; Appetite Depressants; Association Learning; Automobile Driving; Basic Science; Behavior; Behavioral; Biological; Brain; Brain region; Chemicals; Cholecystokinin; Chronic; Communication; Cues; Data; Deafferentation procedure; Designer Drugs; Development; Diet; Eating; Energy Intake; Exposure to; Feeding behaviors; Food; Frequencies; Gastrointestinal Physiology; Gastrointestinal tract structure; Genetic; 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; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacological Treatment; 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; Tetragastrin; Tracer; United States; Vagotomy; Vagus nerve structure; Viral Vector; Visceral; Visual; Work; bariatric surgery; base; biological systems; 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; public health relevance; receptor; 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(申请人提供)：与1980年的成年人相比，今天的美国成年人每天多消耗约500千卡的热量，这一现象背后的原因是美国的肥胖率在过去30年里增加了75%。个体进餐的大小和进餐或零食开始的频率都受到先前经验和与食物相关的外部刺激(如视觉、嗅觉)的严重影响，这些刺激可以超越生物饱足感和饱腹感的暗示。因此，开发有效的肥胖症药物治疗方法需要更好地了解神经生物系统，这些系统将先前的经验与外部和内部线索结合起来，以控制食物摄入量。这项建议中提出的新的先导数据表明，海马体结构(HPF)，特别是其腹侧亚区(HPFV)，参与了这种“更高级别”的摄食行为调节。HPFV神经元影响食物摄入量，部分是通过处理告知能量状态的神经内分泌信号。当胃肠衍生激素Ghrelin(GHS-1RA)受体在HPFV神经元上被激活时，进食量、进餐频率和总食物摄入量都会增加。另一方面，在激活GLP-1的HPFV受体后，平均进食量和总食物摄入量显著减少。GLP-1是一种由GI和后脑分泌的饱满肽。除了神经内分泌信号外，HPF神经元还从迷走神经-后脑神经通路接收胃肠(GI)内脏信息。我们的实验数据显示，HPFV神经元被外周胆囊素(CCK)激活，CCK是一种通过迷走神经信号减少进食大小的饱满肽。其他实验数据显示，隔膜下迷走神经切断术损害了HPF依赖的空间工作记忆。总而言之，这些新的发现表明，HPF神经元受到各种生理线索的影响，这些线索告知能量状态。实验将使用行为学、神经解剖学、遗传学(RNA干扰)、外科和其他方法来扩展这些发现，以确定内源性HPFV GHS-R1a或GLP-1R信号是否(分别)增加或减少进食大小、进餐频率和总体能量平衡，以及[目标II]切断GI迷走神经传入信号是否对与食物采购相关的HPF依赖的食欲学习过程产生负面影响。其他实验[目标III]利用神经解剖学分析来描述HPFV和后脑神经元之间的双向、多突触通信。这些神经通路与摄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(设计者受体仅由设计者药物激活)来测试。总体而言，我们的方法利用了多层次的分析 为了探索我们的假设，即HPF是将先前的经验与外部食物线索和内部内脏线索相结合，以控制喂养的高级方面的关键神经位置。拟议中的实验结果有很大的潜力加深对控制过度摄食行为的神经化学和神经解剖系统的理解。