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

项目摘要：40%的美国成年人肥胖。肥胖会导致II型糖尿病， 心血管疾病、多种癌症和老年痴呆症的风险。美国国立卫生研究院肥胖研究战略计划 提供了“一个蓝图，鼓励研究界从不同的角度研究肥胖症的流行。 .以便制定和评估新的预防和治疗战略”。此外，NIDDK 肥胖症的认知和临床神经科学计划的形成是为了促进“非稳态”的研究， 大脑行为机制（以防止）肥胖”。该提案通过使用新颖的 了解临床前肥胖模型中神经功能和行为差异的方法。在人身上， 暴露于与食物相关的线索（食物线索），如布朗尼的气味或闪烁的甜甜圈标志，增加 食物的渴望和食物的消耗量。肥胖的人报告更强烈的渴望和吃更大的部分， 对食物线索的反应此外，由食物线索触发的丘脑核（NAc）活动的增加 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 暗示导致肥胖。但是，这种增强的神经行为反应的机制尚不清楚。 我们的长期目标是了解增强线索触发的神经行为机制 导致肥胖的“渴望”。AMPA型谷氨酸受体（AMPAR）提供了谷氨酸的主要来源。 兴奋的NAc，和NAc活动所需的线索触发的动机在非肥胖大鼠。我的实验室 他们发现，在肥胖之前，易患肥胖症的男性和女性， 而食用含糖、高脂肪的“垃圾食品”会增强NAc内的兴奋性传递。我们 这里的目标是确定NAc神经元可塑性在垃圾后线索触发的食物寻找中的作用， 食物暴露，以及垃圾食物诱导的谷氨酸可塑性在特定回路中发生的程度， NAc细胞类型。这些研究解决了我们目前对饮食诱导的可塑性理解的重大空白 导致肥胖我们的研究将为线索触发动机的神经基础提供关键的见解， 有助于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线索引发的，而对食物线索的反应有助于人类的健康。 肥胖因此，这项工作通过提供对神经生物学的更好理解来告知治疗。 相关临床前模型中线索触发动机的基础。

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.