Food Restriction, AMPA Receptor Trafficking, and Binge Eating

描述（由申请人提供）：节食期在暴饮暴食者的历史中很常见，食物限制（FR）和自由喂养之间的循环是对压力反应过度食用美味食物的有力预测。在过去的研究中，我们观察到慢性FR诱导神经适应，增加伏隔核（NAc）中D-1多巴胺（DA）受体刺激下游的细胞内信号传导和基因表达。在行为上，FR受试者表现出增强的DA受体激动剂和精神兴奋剂的奖励作用，增强的可卡因条件下的位置偏好的获得，以及对在先前的自由进食状态下获得的位置偏好的消退的抵抗力。有证据表明，药物成瘾代表了介导食欲驱动行为的神经回路的“劫持”，FR期间对药物和相关线索的增强反应可能反映了在食物短缺期间通常促进觅食、奖励相关学习和摄食行为的神经适应的利用。然而，西方社会最近的发展，包括普遍的节食和大量超常的能量密集食物，呈现出一系列条件，有可能使另一种类型的不适应行为根深蒂固，即过度的奖励驱动进食。严格的节食经常导致失去控制，是暴饮暴食病理的一个确定的危险因素。FR在暴饮暴食发展中的致病作用已在实验室动物中通过FR与获得美味食物的交替期来模拟；然而，FR和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，我们已经表明给药D-1激动剂，或短暂摄入10%的蔗糖，增加了谷氨酸AMPA受体GluA1亚基Ser845上的NAc磷酸化，对FR的影响比AL大。此外，在NAc壳中微量注射GluA1拮抗剂可以逆转D-1激动剂在FR大鼠中增强的奖励作用。使用蔗糖，我们发现连续7次每天5分钟的摄入增加了NAc突触后密度（PSD）中的GluA1丰度，定量电子显微镜显示了突起内GluA1种群的增加。比较随意喂养（AL）和FR大鼠，发现FR和间歇性蔗糖摄入都没有改变NAc全细胞制备中GluA1或GluA2的水平，这表明这些AMPAR亚基的合成或降解没有改变。然而，蔗糖增加了PSD中GluA1和GluA2的丰度，对FR的影响大于AL大鼠。这些发现很重要，因为AMPARs介导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，我们得到的结果与假设一致，即在人工进食恢复后，FR期间间歇性摄入蔗糖会增加蔗糖的消耗。因此，在这个项目中要测试的假设是，在FR期间间歇性摄入蔗糖会增加

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.