Higher-Order Neural Control of Food Intake

 描述（由申请人提供）：与1980年的成年人相比，今天美国的成年人每天消耗约500千卡的热量，这一现象表明美国的肥胖患病率在过去30年中增加了75%。个体膳食的大小和膳食或零食开始的频率都受到先前经验和暴露于外部食物相关刺激（例如，视觉、嗅觉），其可以覆盖生物饱足感和饱足感线索。因此，开发有效的肥胖药物治疗需要更好地了解神经生物学系统，这些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。新的试点数据中提出的建议涉及海马结构（HPF），特别是其腹侧亚区（HPFv），在这种类型的“高阶”调节摄食行为。HPFv神经元影响食物摄入，部分是通过处理神经内分泌信号来告知能量状态。当HPFv神经元上的肠源性激素ghrelin（GHS-1 RA）受体被激活时，膳食量、膳食频率和总食物摄入量都会增加。另一方面，GLP-1（一种GI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有效减少。除了神经内分泌信号外，HPF神经元还接受来自迷走神经-后脑神经通路的胃肠内脏信息。我们的试验数据表明，HPFv神经元被外周胆囊收缩素（CCK）激活，CCK是一种通过迷走神经信号传导减少进食量的饱足肽。其他试点数据表明，蛛网膜下迷走神经切断术损害HPF依赖的空间工作记忆。总的来说，这些新的发现表明，HPF神经元受到各种生理线索的影响，这些生理线索反映了能量状态。实验将利用行为、神经解剖学、遗传学等方法来扩展这些发现。[目的I]内源性HPFv GHS-R1 A或GLP-1 R信号传导是否增加或减少（分别）膳食量、膳食频率和总体能量平衡，以及[目的II]消融的GI迷走神经传入信号是否对与食物获取相关的HPF依赖性食欲学习过程产生负面影响。其他实验[目的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（设计药物专门激活的设计受体）进行测试。总的来说，我们的方法利用了多层次的分析 探讨我们的假设，即HPF是一个关键的神经位点整合以前的经验与外部食物线索和内部内脏线索，以控制高阶方面的喂养。从拟议的实验结果有很强的潜力，以加深了解控制过度摄食行为的神经化学和神经解剖系统。

 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.