Mu-opioid systems in the prefrontal cortex: role in appetitive behavior

描述(由申请者提供)：有人提出，全世界的肥胖率正处于流行病的比例。与这一威胁相关的是与肥胖相关的后遗症，如患2型糖尿病、心脏病和中风的风险增加。考虑到这些统计数据，研究了解参与调节体重和食物摄入相关行为的系统是至关重要的。在我们对基本食欲行为的“高级”皮质控制的理解上有一个明显的差距。为了解决这一差距，我们建议探索内侧前额叶皮质，这是一个富含与“下游”区域的连接的区域，这些区域介导了对摄食行为的动态平衡和享乐控制。与这一目标特别相关的是，我们实验室的初步结果表明，刺激mPFC中的u-阿片受体可以增加缺乏食物和没有缺乏食物的动物的食物摄入量，并促进极度过度活动和运动再摄取的碎片化。令人惊讶的是，人们对PFC阿片类药物的功能作用知之甚少，也很少有研究考察局部PFC阿片类药物操作后的行为影响。因此，我们建议探索这些效应背后的神经药理学和解剖学基础，并调查我们观察到的效应背后的精确行为结构。 与公共健康相关：本提案中概述的工作有可能增强我们对更高层次的认知因素如何影响并可能组织和调节与食物摄入相关的基本动态平衡机制的理解。因此，这项工作可能导致对基本动机和动态平衡过程的“自上而下”的执行控制的新颖和令人兴奋的见解。这项拟议的工作还可能阐明有关前额叶皮质功能的肽控制的重要新知识，这可能对ADHD和精神分裂症等疾病具有深远的翻译意义。

DESCRIPTION (provided by applicant): It has been suggested that obesity rates around the world are at epidemic proportions. Relevant to this threat are the sequelae that are associated with obesity, such as increased risk of developing type 2 diabetes, heart disease, and stroke. With these statistics in mind, research into understanding the systems that are involved in regulating body weight and food intake-associated behaviors is critical. There is a notable gap in our understanding of "higher-order" cortical control of basic appetitive behaviors. To address this gap, we propose to explore the medial prefrontal cortex, an area rich in connections to 'downstream' regions that mediate homeostatic and hedonic control of feeding behavior. Particularly germane to this goal are preliminary results from our lab showing that stimulation of mu-opioid receptors in the mPFC augments food intake in both food- deprived and non-deprived animals, and promotes extreme hyperactivity and fragmentation of motor repetoires. Surprisingly, very little is known about the functional role of PFC opioids and very few studies have examined the behavioral effects following local PFC opioid manipulation. Thus, we propose to explore the neuropharmacology and anatomical substrates underlying these effects, and to investigate the precise behavioral constructs underlying our observed effects. PUBLIC HEALTH RELEVANCE: The work outlined in this proposal has the potential to enhance our understanding of how higher-order cognitive factors impinge upon, and perhaps organize and regulate, basic homeostatic mechanisms related to food intake. Hence, this work could lead to novel and exciting insights into the 'top-down' executive control of basic motivational and homeostatic processes. The proposed work may also elucidate important new knowledge regarding peptide control of prefrontal cortical function, which could have profound translational implications for disorders like ADHD and Schizophrenia.