Nucleus Accumbens-Mediated Feeding: Output Pathways

描述（由申请人提供）：过去几年收集的大量证据令人信服地表明，伏隔核壳（AcbSh）中的gaba能回路在控制食物摄入中起着重要作用。例如，向AcbSh注射GABA激动剂会导致大量且非常具体的摄食增加，考虑到AcbSh通常被认为对动机或奖励机制产生普遍影响，这是一个令人惊讶的结果。AcbSh操纵产生的影响的大小和特异性表明，AcbSh喂养效应背后的神经回路病理可能在某些人类饮食失调中发挥作用，并且该回路可能是开发治疗食物摄入和体重紊乱的新方法的有希望的目标。拟议的研究项目的长期目标是确定和描述通过AcbSh产生摄食行为变化的神经回路。我们的基本工作假设是，AcbSh通过有效调节分布但偏侧的结构网络中的神经活动来影响进食，这些结构网络包括内侧腹侧白球（VPm）、外侧（LH）、弓形（Arc）和室旁（PVN）下丘脑区域。拟议的实验涉及使用互补的神经解剖学，行为学，药理学和分子技术，以更好地了解通过电路的信息流以及每个结构对acbsh介导的喂养表达的功能贡献。具体来说，我们建议检查这些结构的兴奋性毒性病变改变单侧acbsh内注射muscimol引起的食物摄入的数量和模式的能力。这些研究将使用“同侧-对侧破坏”（ICD）设计进行，这将使我们能够避免在这类研究中通常遇到的许多解释困难。由于在AcbSh内注射muscimol会在上述所有结构中诱导强烈的Fos表达，我们也将使用ICD设计来确定这些结构的病变如何改变由AcbSh内注射产生的神经元激活模式。我们还将确定由acbsh内muscimol激活的LH神经元是否直接向Arc或PVN投射。进一步的研究将检验脑内注射食欲素和神经肽Y拮抗剂是否会改变摄食反应，以及向VPm注射双管碱是否会诱导Fos的表达和摄食，类似于在AcbSh注射肌肉素后所见。肥胖和饮食失调的流行使这些情况成为一个主要的公共卫生问题，治疗这些疾病的进展取决于我们对控制进食的大脑机制的详细了解。这些研究结果将使我们更清楚地了解调节摄食行为的大脑机制的功能组织，并可能为发现有效的治疗方法以减少人类摄食失调造成的痛苦提供关键信息。

DESCRIPTION (provided by applicant): A body of evidence assembled over the past several years indicates persuasively that GABAergic circuits in the nucleus accumbens shell (AcbSh) play an important role in the control of food intake. For example, injections of GABA agonists into the AcbSh result in a large and very specific increase in feeding, a surprising result given that the AcbSh is often assumed to exert a generalized influence on motivational or reward mechanisms. The magnitude and specificity of the effects produced by AcbSh manipulations suggest both that pathology of the neural circuitry underlying the AcbSh feeding effects may play a role in some human eating disorders, and that this circuit may be a promising target for the development of novel approaches to the treatment of disturbances in food intake and body weight. The long-term goal of the proposed research project is to identify and characterize the neural circuits through which the AcbSh produces changes in Feeding behavior. Our fundamental working hypothesis is that the AcbSh affects feeding by potently regulating neural activity in a distributed, but lateralized, network of structures that includes the medial ventral pallidum (VPm), and the lateral (LH), arcuate (Arc), and paraventricular (PVN) hypothalamic regions. The proposed experiments involve the use of complementary neuroanatomical, behavioral, pharmacological, and molecular techniques to better understand the flow of information through the circuit and the functional contribution of each structure to the expression of AcbSh-mediated feeding. Specifically, we propose to examine the ability of excitotoxic lesions of each of these structures to modify the amount and pattern of food intake elicited by unilateral intra-AcbSh injections of muscimol. These studies will be carried out using an "ipsilateral-contralateral disruption" (ICD) design which will allow us to avoid many of the interpretative difficulties usually encountered in studies of this type. Because intra-AcbSh injections of muscimol induce intense Fos expression in all of the structures listed above, we will also use the ICD design to determine the manner in which lesions of these structures alter the patterns of neuronal activation produced by the intra- AcbSh injections. We will also establish whether LH neurons activated by intra-AcbSh muscimol project directly to the Arc or PVN. Additional studies will examine whether the feeding response can be altered by intracerebral injections of orexin and neuropeptide Y antagonists, and whether bicuculline injections into the VPm induce Fos expression and feeding similar to that seen after muscimol injections in the AcbSh. The prevalence of obesity and eating disorders has made these conditions a major public health concern and progress in treating them depends on our having a detailed understanding of the brain mechanisms controlling feeding. The results of these investigations will allow us to understand more clearly the functional organization of brain mechanisms that regulate feeding behavior and may provide information critical to the effort to discover effective treatments to reduce the suffering caused by dysregulation of feeding in humans.