Reward Signaling in the Gut-Brain Axis

肠脑轴的奖励信号

• 批准号: 10464137
• 负责人: Molly McDougle
• 金额: $ 1.78万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-29 至 2022-06-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10464137
• 关键词: Ablation; Address; Affect; Afferent Neurons; Animals; Area; Behavior; Behavioral; Bilateral; Body Weight; Brain; Brain Stem; Calories; Cause of Death; Cholecystokinin; Cholecystokinin Receptor; Complex; Corpus striatum structure; Data; Development; Diabetes Mellitus; Diet; Disease; Dopamine; Dorsal; Eating; Fatty acid glycerol esters; Feeding behaviors; Fellowship; Fiber; Fiber Optics; Food; Food Intake Regulation; Food Preferences; Foundations; Functional disorder; Future; Genetic; Goals; Grant; Growth and Development function; Health Care Costs; Heart Diseases; Homeostasis; Impairment; Implant; Infusion procedures; Injections; Intake; Intervention; Knowledge; Lead; Learning; Life Style; Lung diseases; Macronutrients Nutrition; Malignant Neoplasms; Measures; Mediating; Medical; Mentors; Methods; Microdialysis; Modeling; Modernization; Molecular; Molecular Target; Mus; Neurons; Neurotoxins; Nodose Ganglion; Nose; Nutrient; Obesity; Operative Surgical Procedures; Pathway interactions; Peripheral; Phenotype; Physiological; Physiology; Play; Population; Population Heterogeneity; Postdoctoral Fellow; Prevalence; Psychological reinforcement; Quality of life; Recording of previous events; Research; Research Personnel; Rewards; Risk Factors; Role; Satiation; Self Stimulation; Signal Transduction; Stimulus; Stroke; Testing; Therapeutic; Thinness; Time; Training; Vagus nerve structure; Virus; Work; base; career; career development; conditioning; detection of nutrient; experimental study; food environment; gut-brain axis; heart disease risk; lifestyle intervention; neuromechanism; new therapeutic target; optogenetics; preference; recruit; relating to nervous system; response; reward circuitry; skills; success; sugar; symposium; therapeutic target

PROJECT SUMMARY Obesity is not only a leading cause of death in the US, but also a risk factor for nearly all other top causes of death including heart disease, pulmonary disease, stroke, and cancer. Overconsumption of high-fat high-sugar foods is a driver of obesity, but the mechanism for this is unclear. Nodose ganglia (NG) neurons of the vagus nerve transmit post-ingestive signals for fats and sugars from the gut to the brain to regulate food intake and reinforce food choice. Previous studies have demonstrated that vagal activity in response to post-ingestive signals is reduced in obesity, which may lead to increased food intake. To understand how altered macronutrient signaling may lead to obesity requires understanding its basic physiology, which has not been fully elucidated. My preliminary data reveals distinct neuronal populations in the vagus nerve are required for post-ingestive fat or sugar signaling, but whether these signals are sufficient to reinforce conditioned behavior is unclear. I have previously shown that ablation of neurons expressing cholecystokinin receptor (CCKR) affects fat- but not sugar-mediated satiation, indicating CCKR may be a specific marker for fat responsive vagal afferent neurons. Accordingly, I hypothesize that fats and sugars activate phenotypically and functionally distinct vagal ensembles in the gut-brain axis, which are sufficient to reinforce conditioned behavior, and this activation is reduced in obesity. To address these hypotheses, we will use FosTRAP mice, an activity-dependent genetic targeting model, to selectively target vagal sensory neurons that respond to either fat or sugar. In aim 1, we will test whether optogenetic activation of fat or sugar sensing vagal neurons is sufficient to trigger nigrostriatal dopamine release, and for animals to learn to self-stimulate, two hallmarks of reward. In aim 2, we will test the necessity of CCK receptor expressing vagal sensory neurons in fat, but not sugar reward, by performing a flavor-nutrient conditioning experiment with and without selective ablation of vagal afferents expressing CCKR, using the conjugated neurotoxin CCK-Saporin. In aim 3, we will test how high-fat high-sugar diet intake disrupts nutrient sensing by using FosTRAP mice to compare neural responses to intragastric stimuli before and after the onset of obesity within the same animal. This work will for the first time characterize nutrient-specific signaling in the gut-brain reward circuitry in lean and obese conditions for future study and possible therapeutic targets.

项目摘要 肥胖不仅是美国的主要死亡原因，而且是几乎所有其他主要原因的危险因素 死亡，包括心脏病，肺部疾病，中风和癌症。高脂高糖过度消费 食物是肥胖的驱动力，但尚不清楚的机制。迷走神经元的神经元神经元 神经从肠道传播脂肪和糖从肠道到大脑的神经信号，以调节食物摄入量和 加强食物选择。先前的研究表明，迷走神经活动是响应于后期的 肥胖症的信号降低，这可能导致食物摄入量增加。了解如何改变 大量营养素信号传导可能会导致肥胖症，需要了解其基本生理学，这不是 完全阐明。我的初步数据表明，迷走神经中的不同神经元种群需要 产后脂肪或糖信号传导，但是这些信号是否足以增强条件行为 不清楚。我以前已经表明，表达胆囊动蛋白受体（CCKR）的神经元的消融 影响脂肪 - 但不影响糖介导的饱腹感，表明CCKR可能是脂肪反应的特定标记 迷走神经神经元。因此，我假设脂肪和糖在表型上激活 肠道轴上功能上不同的迷走神经合奏，足以加强 条件行为，肥胖症中这种激活减少。为了解决这些假设，我们将使用 FOSTRAP小鼠是一种依赖活性的遗传靶向模型，可选择性地靶向迷走性感觉神经元 回应脂肪或糖。在AIM 1中，我们将测试脂肪还是糖传感迷走神经的光遗传学激活 神经元足以触发黑质纹状体多巴胺释放，并让动物学习自刺激，两个 奖励的标志。在AIM 2中，我们将测试CCK受体表达迷走性感觉神经元的必要性 脂肪，但不是糖奖励，通过进行有选择性的调味剂调节实验，而不是糖奖 使用共轭神经毒素CCK-肉饼蛋白的表达CCKR的迷走神经传入的消融。在AIM 3中，我们将 测试高脂高糖饮食摄入量如何通过使用Fostrap小鼠比较神经来破坏营养感 对同一动物内肥胖发作之前和之后对胃内刺激的反应。这项工作将为 第一次表征在精益和肥胖的肠道奖励电路中营养特异性的信号传导 未来研究的条件和可能的治疗靶标。