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.