Food Restriction, AMPA Receptor Trafficking, and Binge Eating

食物限制、AMPA 受体贩运和暴饮暴食

• 批准号: 8921173
• 负责人: Kenneth D Carr
• 金额: $ 20.87万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8921173
• 关键词: AMPA Receptors; Agonist; Animal Model; Behavior; Behavior Therapy; Behavioral; Binge Eating; Chronic; Cocaine; Consumption; Cues; Data; Development; Diet; Dopamine Agonists; Dopamine Receptor; Drug Addiction; Eating Disorders; Electron Microscopy; Extinction (Psychology); Feeding behaviors; Food; Future; Gene Expression; Glutamates; Health; Hyperactive behavior; Hyperphagia; Intake; Laboratories; Laboratory Animals; Learning; Mediating; Microinjections; Modeling; Molecular; Nucleus Accumbens; Pathology; Pharmaceutical Preparations; Phosphorylation; Play; Population; Prosencephalon; Rattus; Receptor Signaling; Recording of previous events; Research; Resistance; Rewards; Risk Factors; Role; Signal Transduction; Societies; Stress; Sucrose; Synapses; Synaptic plasticity; Testing; base; cell preparation; density; experience; feeding; food restriction; insight; motivated behavior; neuroadaptation; novel strategies; postsynaptic; preference; prevent; psychostimulant; receptor; research study; response; restoration; synaptic function; trafficking

DESCRIPTION (provided by applicant): Dieting periods are common in the history of binge eaters, and cycling between food restriction (FR) and free feeding is a strong predictor of overeating palatable food in response to stress. In past studies, we have observed that chronic FR induces neuroadaptations that increase intracellular signaling and gene expression downstream of D-1 dopamine (DA) receptor stimulation in nucleus accumbens (NAc). Behaviorally, FR subjects display enhanced rewarding effects of DA receptor agonists and psychostimulant drugs, enhanced acquisition of cocaine conditioned place preference, and resistance to extinction of a place preference acquired during a prior ad libitum fed state. In ligt of evidence that drug addiction represents a "hijacking" of the neurocircuitry that mediates appetitively motivated behavior, the enhanced responsiveness to drugs and associated cues during FR likely reflect exploitation of neuroadaptations that normally promote foraging, reward-related learning, and ingestive behavior during periods of food scarcity. Yet, recent developments in Western societies, including prevalent dieting and an abundance of supranormally rewarding energy-dense food, present a set of conditions with potential to ingrain another type of maladaptive behavior, namely, excessive reward-driven feeding. Severe dieting often leads to loss of control and is an established risk factor for binge pathology. The pathogenic role of FR in the development of binge eating has been modeled in laboratory animals by alternating periods of FR with access to palatable food; however, the mechanistic basis of the relationship between FR and binge eating is unknown. In the preliminary data for this project we have shown that administration of a D-1 agonist, or brief intake of 10% sucrose, increase NAc phosphorylation of the glutamatergic AMPA receptor GluA1 subunit on Ser845 with a greater effect in FR than AL rats. Moreover, the enhanced rewarding effect of the D-1 agonist in FR rats was reversed by microinjection of a GluA1 antagonist in NAc shell. Using sucrose, we found that seven consecutive daily 5-min episodes of intake increased GluA1 abundance in the NAc postsynaptic density (PSD), and quantitative electron microscopy revealed an increased intraspinous GluA1 population. Comparing ad libitum fed (AL) and FR rats, it was found that neither FR nor episodic sucrose intake altered levels of GluA1 or GluA2 in the NAc whole cell preparation, suggesting no alteration in synthesis or degradation of these AMPAR subunits. However, sucrose increased GluA1 and GluA2 abundance in the PSD with a greater effect in FR than AL rats. These findings are important because AMPARs mediate enduring forms of synaptic plasticity and behavior modification. Thus, in a recent preliminary study we obtained results consistent with the hypothesis that episodic sucrose intake during FR increases sucrose consumption after AL access to food has been restored. Consequently, the hypothesis to be tested in this project, is that episodic intake of sucrose during FR increases the trafficking of AMPARs to the NAc PSD, and this is the molecular basis of increased sucrose-directed behavior that is expressed when subjects have returned to AL feeding. Experiments of Aim 1 test the prediction that episodic intake of sucrose during FR enhances development of binge-like intake and sucrose-conditioned hyperactivity following restoration of AL feeding. Experiments of Aim 2 test the prediction that episodic intake of sucrose during FR increases AMPAR abundance in NAc PSD in a manner that correlates with behavioral expression of sucrose-directed behavior. Experiments of Aim 3 capitalize on results obtained in Aims 1 and 2 to conduct a representative test of the prediction that interference with AMPAR trafficking during episodic sucrose intake in FR rats prevents future expression of excessive sucrose-directed behavior. By elucidating the synaptic changes induced by food restriction, and investigating their involvement in the acquisition of excessive sucrose-directed behavior, this project has the potential to illuminate risk factors, mechanisms, and novel approaches to preventing and treating binge type eating disorders.

描述（由申请人提供）：节食期在暴饮暴食者的历史中很常见，在食物限制（FR）和自由进食之间循环是应对压力时过度食用可口食物的有力预测因素。在过去的研究中，我们已经观察到，慢性FR诱导的神经适应，增加细胞内信号和基因表达的D-1多巴胺（DA）受体刺激的下游在丘脑核（NAc）。在行为上，FR科目显示增强的DA受体激动剂和精神兴奋剂药物的奖励效果，增强收购可卡因条件性位置偏好，并抵抗灭绝的位置偏好收购在先前的自由进食状态。有证据表明，药物成瘾代表了对调节食欲动机行为的神经回路的“劫持”，FR期间对药物和相关线索的增强反应可能反映了对神经适应的利用，这些神经适应通常促进食物短缺期间的觅食、奖励相关学习和摄食行为。然而，西方社会最近的发展，包括普遍的节食和大量的超正常奖励能量密集的食物，提出了一套条件，有可能根深蒂固的另一种类型的适应不良行为，即过度奖励驱动的喂养。严重的节食往往会导致失控，是一个既定的风险因素狂欢病理。FR在暴饮暴食发展中的致病作用已在实验室动物中通过FR与获得可口食物的交替时期进行建模;然而，FR与暴饮暴食之间关系的机制基础尚不清楚。在这个项目的初步数据中，我们已经表明，D-1激动剂的管理，或短暂摄入10%蔗糖，增加NAc磷酸化的丝氨酸845上的谷氨酸能AMPA受体GluA 1亚基与更大的影响，在FR比AL大鼠。此外，增强的奖励作用的D-1激动剂在FR大鼠被逆转的GluA 1拮抗剂在NAc壳中微量注射。使用蔗糖，我们发现，连续7天每天5分钟的摄入量增加GluA 1丰度的NAc突触后密度（PSD），和定量电子显微镜显示增加的棘内GluA 1人口。比较自由采食（AL）和FR大鼠，结果发现，无论是FR还是间歇性蔗糖摄入量改变的水平，GluA 1或GluA 2的NAc全细胞制剂，这表明没有改变这些AMPAR亚基的合成或降解。然而，蔗糖增加了GluA 1和GluA 2丰度在PSD与更大的影响，FR比AL大鼠。这些发现很重要，因为AMPAR介导突触可塑性和行为改变的持久形式。因此，在最近的一项初步研究中，我们得到的结果与假设一致，即在FR期间的情景性蔗糖摄入增加了AL获得食物后的蔗糖消耗。因此，在本项目中要检验的假设是，在FR期间间歇性摄入蔗糖会增加 这可能是AMPAR向NAc PSD的运输，并且这是当受试者恢复AL喂养时表达的增加的蔗糖定向行为的分子基础。目的1的实验测试了FR期间蔗糖的间歇性摄入增强了AL喂养恢复后暴食样摄入和蔗糖条件性多动的发展的预测。目的2的实验测试了FR期间蔗糖的间歇性摄入以与蔗糖定向行为的行为表达相关的方式增加NAc PSD中AMPAR丰度的预测。目的3的实验利用目的1和2中获得的结果进行预测的代表性测试，即在FR大鼠中间歇性蔗糖摄入期间干扰AMPAR运输防止未来过度蔗糖定向行为的表达。通过阐明食物限制引起的突触变化，并调查它们参与获得过度蔗糖定向行为，该项目有可能阐明风险因素，机制和预防和治疗暴食型饮食失调的新方法。