Food Restriction, AMPA Receptor Trafficking, and Binge Eating

描述(申请人提供)：节食期在暴食者的历史上很常见，在限食(FR)和自由喂养之间循环是一个强烈的预测因素，可以预测在压力下过量食用美味的食物。在过去的研究中，我们已经观察到慢性FR诱导神经适应，增加伏核(NAC)D-1多巴胺(DA)受体刺激下游的细胞内信号和基因表达。在行为上，FR受试者表现出DA受体激动剂和精神刺激剂的增强奖励效应，增强了对可卡因条件性位置偏爱的获得，并抵抗了在先前自由摄取状态下获得的位置偏爱的消退。有证据表明，药物成瘾代表着对调节食欲行为的神经回路的“劫持”，在FR过程中对药物和相关线索的反应增强可能反映了神经适应的利用，这种神经适应通常促进在食物匮乏时期的觅食、与奖励相关的学习和摄取行为。然而，西方社会最近的发展，包括普遍的节食和大量超乎寻常的高能量食物，带来了一系列条件，可能会根深蒂固地根深蒂固另一种不适应行为，即过度奖励驱动的进食。严重的节食往往会导致失控，是狂欢病理的既定风险因素。FR在暴饮暴食发展中的致病作用已在实验室动物中通过交替使用FR和美味食物来模拟；然而，FR与暴饮暴食之间关系的机制基础尚不清楚。在本项目的初步数据中，我们已经表明，给予D-1激动剂或短暂摄入10%蔗糖，可增加Ser845上谷氨酸能AMPA受体GluA1亚单位的NAC磷酸化，对FR的影响比AL大鼠更大。此外，NAC壳内微量注射GluA1拮抗剂可逆转D-1激动剂对FR大鼠增强的奖赏效应。使用蔗糖，我们发现连续七次每天5分钟的摄入增加了NAC突触后密度(PSD)中GluA1的丰度，定量电子显微镜显示棘内GluA1数量增加。比较自由采食(AL)大鼠和FR大鼠，发现FR和间歇性摄入蔗糖都不会改变NAC全细胞制剂中GluA1或GluA2的水平，这表明这些AMPAR亚单位的合成或降解没有改变。然而，蔗糖增加了PSD大鼠GluA1和GluA2的丰度，对FR大鼠的影响比AL大鼠更大。这些发现很重要，因为AMPAR介导了持久形式的突触可塑性和行为改变。因此，在最近的一项初步研究中，我们获得了与假设一致的结果，即在AL恢复获得食物后，FR期间的间歇性蔗糖摄入量增加了蔗糖的摄入量。因此，在这个项目中要检验的假设是，在FR期间间歇性摄入蔗糖会增加 AMPAR被运输到NAC PSD，这是当受试者回到AL喂养时表达的蔗糖导向行为增加的分子基础。Aim 1的实验验证了在恢复AL喂养后，FR期间间歇性摄入蔗糖促进暴饮式摄入和蔗糖条件性多动的发展的预测。Aim 2的实验验证了这一预测，即在FR期间间歇性摄入蔗糖会增加NAC PSD中AMPAR的丰度，其方式与蔗糖导向行为的行为表达相关。AIM 3的实验利用在AIMS 1和AIMS 2中获得的结果，对以下预测进行了代表性测试：在FR大鼠发作性蔗糖摄入期间干扰AMPAR运输可以防止未来表达过度的蔗糖导向行为。通过阐明食物限制引起的突触变化，并调查它们在获得过量蔗糖导向行为中的参与，本项目有可能阐明风险因素、机制和预防和治疗暴食型饮食障碍的新方法。

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.