Striatal glutamatergic plasticity and junk-food induced enhancements in cue-triggered food-craving

纹状体谷氨酸可塑性和垃圾食品诱导线索触发的食物渴望增强

• 批准号: 10617336
• 负责人: Carrie Ferrario
• 金额: $ 54.49万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-03 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617336
• 关键词: Address; Adult; Affect; Alzheimer' s Disease; Amygdaloid structure; Behavior; Behavioral; Behavioral Mechanisms; Blinking; Brain; Breeding; Cardiovascular Diseases; Cells; Clinical; Cognitive; Communities; Consumption; Corpus striatum structure; Cues; Data; Development; Diet; Eating; Excision; Exposure to; Female; Food; Foundations; Functional Magnetic Resonance Imaging; Future; Glutamate Receptor; Glutamates; Goals; Health; Human; Link; Malignant Neoplasms; Measures; Medial; Mediating; Metabolic; Metabolic dysfunction; Modeling; Motivation; National Institute of Diabetes and Digestive and Kidney Diseases; Neurobiology; Neurons; Neurophysiology - biologic function; Neurosciences; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Nucleus Accumbens; Obesity; Obesity Epidemic; Permeability; Persons; Physiology; Play; Population; Pre-Clinical Model; Predisposition; Prefrontal Cortex; Prevention strategy; Process; Rat Transgene; Rattus; Reporting; Research; Resistance; Rewards; Role; Signal Transduction; Slice; Smell Perception; Source; Specificity; Strategic Planning; Synaptic Transmission; System; Testing; Transgenic Organisms; United States National Institutes of Health; Weight; Weight Gain; Work; adult obesity; brain behavior; cardiovascular disorder risk; cell type; craving; evidence base; food consumption; food craving; insight; male; motivated behavior; neural; neurobehavioral; novel strategies; obese person; obesity prevention; optogenetics; patch clamp; pharmacologic; pre-clinical; prevent; preventable death; programs; response; sex; therapy development; tool; transmission process; treatment strategy

PROJECT SUMMARY: 40% of U.S. adults are obese. Obesity produces type II diabetes, which increases the risk for cardiovascular disease, many cancers, and Alzheimer's. The NIH strategic plan for obesity research provides “a blueprint (to) encourage the research community to examine the epidemic of obesity from diverse perspectives…in order to develop and evaluate new prevention and treatment strategies”. Further, the NIDDK Cognitive and Clinical Neuroscience of Obesity Program was formed to promote studies of “non-homeostatic brain-behavior mechanisms (to prevent) obesity”. This proposal directly addresses these needs by using novel approaches to understand differences in neural function and behavior in preclinical obesity models. In people, exposure to cues associated with food (food cues), like the smell of brownies or a blinking donuts sign, increases food craving and the amount of food consumed. Obese people report stronger craving and eat larger portions in response to food cues. Further, increases in activity of the nucleus accumbens (NAc) triggered by food cues predict future weight gain inability to lose weight. Thus in people, enhanced neurobehavioral responses to food cues contribute to obesity. But, the mechanism underlying this enhanced neurobehavioral reactivity is unknown. Our long-term goal is to understand the neurobehavioral mechanisms that underlie enhanced cue-triggered `cravings' that contribute to obesity. AMPA type glutamate receptors (AMPAR) provide the main source of excitation to the NAc, and NAc activity is required for cue-triggered motivation in non-obese rats. My lab has found that that cue-triggered food-seeking is stronger in obesity-susceptible males and females prior to obesity and that consumption of a sugary, fatty `junk-food' diet enhances excitatory transmission within the NAc. Our objectives here are to determine the role of NAc glutamatergic plasticity in cue-triggered food-seeking after junk- food exposure, and the degree to which junk-food-induced glutamate plasticity occurs in specific circuits and NAc cell types. These studies address significant gaps in our current understanding of diet-induced plasticity that drives obesity. Our studies will provide key insights into the neural basis of cue-triggered motivation and help delineate behavioral processes and specific circuits involved in both sexes, and as a function of obesity- susceptibility. Eating is often initiated by food cues and eating in response to food cues contributes to human obesity. Thus, this work inform treatment by providing a better understanding of the neurobiological underpinnings of cue-triggered motivation in relevant preclinical models.

项目摘要：40% 的美国成年人肥胖。肥胖会产生 II 型糖尿病，从而增加 心血管疾病、多种癌症和阿尔茨海默氏症的风险。 NIH 肥胖研究战略计划 提供了“鼓励研究界从不同角度审视肥胖流行情况的蓝图” 观点......以便开发和评估新的预防和治疗策略”。此外，NIDDK 肥胖认知和临床神经科学项目的成立是为了促进“非稳态”的研究 （预防）肥胖的大脑行为机制”。该提案通过使用新颖的方法直接解决了这些需求 了解临床前肥胖模型中神经功能和行为差异的方法。在人们看来， 接触与食物相关的线索（食物线索），例如布朗尼蛋糕的气味或闪烁的甜甜圈标志，会增加 对食物的渴望和消耗的食物量。肥胖者的食欲更强烈，吃的份量也更大 对食物暗示的反应。此外，食物信号引发的伏隔核（NAc）活动增加 预测未来体重增加无法减肥。因此，在人类中，对食物的神经行为反应增强 暗示会导致肥胖。但是，这种神经行为反应性增强的机制尚不清楚。 我们的长期目标是了解增强提示触发背后的神经行为机制 导致肥胖的“渴望”。 AMPA型谷氨酸受体（AMPAR）提供主要来源 NAc 的兴奋，而 NAc 活性是非肥胖大鼠线索触发动机所必需的。我的实验室有 研究发现，在肥胖易感人群中，在肥胖之前，线索触发的食物寻求能力更强 食用含糖、高脂肪的“垃圾食品”饮食会增强 NAc 内的兴奋性传递。我们的 这里的目标是确定 NAc 谷氨酸可塑性在垃圾后线索触发的食物寻找中的作用 食物暴露，以及垃圾食品引起的谷氨酸可塑性在特定电路中发生的程度和 NAc 细胞类型。这些研究解决了我们目前对饮食引起的可塑性的理解中的重大差距 导致肥胖。我们的研究将为线索触发动机和动机的神经基础提供重要见解 帮助描绘两性的行为过程和特定回路，并作为肥胖的函数- 易感性。进食通常是由食物暗示引发的，而根据食物暗示而进食有助于人类 肥胖。因此，这项工作通过提供对神经生物学的更好理解来为治疗提供信息 相关临床前模型中提示触发动机的基础。