Opioid modulation of neural encoding of motivation and reward

阿片类药物对动机和奖励神经编码的调节

基本信息

批准号：
8431774
负责人：
Sharif A. Taha
金额：
$ 35.8万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2017-02-28
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Our long-term goal is to understand the contribution of neural reward circuits to control of food intake during normal consumption as well as in pathologies that incorporate binge eating. We are specifically interested in how opioid signaling within reward circuits, particularly in the shell of the nucleus accumbens (sNAcc), mediates binge-like food intake. Stimulation of mu opioid receptors (MORs) in the sNAcc induces voracious feeding and sNAcc opioid receptor and ligand expression is altered in rat models of diet-induced binge eating. However, the mechanisms through which sNAcc MOR stimulation causes hyperphagia, and how diet-induced changes in this circuit contribute to binge eating behavior, remain poorly understood. In previous studies, we characterized two firing patterns in sNAcc neurons that we hypothesize play important and distinct roles in processing of taste hedonics and controlling appetitive food-seeking behavior. Our data suggests that the first of these firing patterns encodes palatability, while the second serves to permissively gate food-seeking behavior (and subsequent consumption) through a disinhibition mechanism. In the present proposal, we will test the hypothesis that distinct effects of sNAcc MOR stimulation on these firing patterns act to increase palatability-induced hyperphagia and food-seeking appetitive behaviors through signaling in segregated anatomical pathways. We further hypothesize that diet-induced binge eating arises specifically through sensitization of opioid signaling in the neural pathway mediating appetitive food-seeking, rather than through changes in pathways processing palatability. To address these hypotheses, we will use a combination of in vivo electrophysiological and pharmacological approaches to characterize the effects of sNAcc MOR manipulations on firing in efferent targets of the sNAcc. We will investigate interactions between the sNAcc and target regions using simultaneous electrode array recordings and cross-correlation techniques to characterize functional connectivity between these regions. Finally, we will characterize electrophysiological and pharmacological changes occurring in this circuit in a rat model of diet-induced binge eating. We anticipate that these experiments will provide important insights into the mechanisms underlying hyperphagia caused by sNAcc MOR stimulation and diet-induced binge eating. These experiments will lead to greater understanding of neural-circuit mechanisms underlying compulsive food intake, and are thus highly relevant in developing novel therapeutic interventions for eating disorders such as bulimia nervosa.

描述（由申请人提供）：我们的长期目标是了解神经奖励回路对正常消费期间以及融合暴饮暴食的病理中对食物摄入的贡献。我们特别对奖励电路中的阿片类药物信号传导感兴趣，尤其是在伏隔核（SNACC）的外壳中，会介导类似暴饮暴食的食物摄入量。在饮食引起的暴饮暴食大鼠模型中，SNACC中的MU阿片受体（MOR）刺激诱导的喂养和SNACC阿片受体和配体表达会改变。但是，SNACC刺激导致倍率的机制以及该电路中饮食引起的变化如何导致暴饮暴食行为的机制，对饮食行为有差异。在先前的研究中，我们表征了SNACC神经元中的两种射击模式，我们假设我们在处理口味享乐者和控制食欲的行为方面起着重要而独特的作用。我们的数据表明，这些射击模式中的第一个编码可口性，而第二种则可以通过消除抑制作用机制允许地寻求食物寻求食物的行为（以及随后的消费）。在本提案中，我们将测试以下假设：SNACC刺激对这些发射模式的明显影响可起作用可通过在分离的解剖途径中发出信号传导来增加对可儿童诱导的食欲和寻求食物的食欲。我们进一步假设，饮食引起的暴饮暴食是通过在介导食欲寻求食物的神经通路中的阿片类药物信号传导的敏化而出现的，而不是通过处理可口的途径的变化。为了解决这些假设，我们将使用体内电生理学和药理学方法的组合来表征SNACC MOR操纵对SNACC传出靶标发射的影响。我们将使用同时的电极阵列记录和互相关技术来研究SNACC和目标区域之间的相互作用，以表征这些区域之间的功能连通性。最后，我们将在饮食引起的暴饮暴食大鼠模型中表征该电路中发生的电生理和药理变化。我们预计，这些实验将为SNACC Mor刺激和饮食引起的暴饮暴食所引起的心晶状体的基础机制提供重要的见解。这些实验将导致对强迫性食物摄入的神经信流机制有更多的了解，因此在开发新的治疗干预措施（例如神经性贪食症）方面高度相关。