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，丘脑核壳（AcbSh）中的GABA能回路在控制食物摄入方面发挥重要作用。例如，将GABA激动剂注射到AcbSh中导致进食大量且非常特异性的增加，这是一个令人惊讶的结果，因为AcbSh通常被认为对动机或奖励机制产生普遍影响。AcbSh操作产生的影响的幅度和特异性表明，AcbSh喂养影响的神经回路的病理可能在一些人类饮食失调中发挥作用，并且该回路可能是开发新方法治疗食物摄入和体重紊乱的有前途的目标。拟议研究项目的长期目标是确定和表征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影响喂养的分布，但偏侧，网络结构，包括内侧腹苍白球（VPm），和外侧（LH），弓状（弧），和室旁（PVN）下丘脑区域的神经活动的有力调节。拟议的实验涉及使用互补的神经解剖学，行为，药理学和分子技术，以更好地了解通过电路的信息流和每个结构对AcbSH介导的进食表达的功能贡献。具体而言，我们建议检查这些结构中的每一个的兴奋性毒性病变的能力，以修改单方面内AcbSh注射蝇蕈醇引起的食物摄入量和模式。这些研究将使用“同侧-对侧中断”（ICD）设计进行，这将使我们能够避免在此类研究中通常遇到的许多解释困难。由于AcbSh内注射蝇蕈醇在上述所有结构中诱导强烈的Fos表达，我们还将使用ICD设计来确定这些结构的损伤改变由AcbSh内注射产生的神经元激活模式的方式。我们还将确定是否LH神经元激活内AcbSh蝇蕈醇项目直接到弧或PVN。进一步的研究将检查是否可以通过脑内注射食欲素和神经肽Y拮抗剂来改变摄食反应，以及荷包牡丹碱注射到VPm是否诱导Fos表达和摄食，类似于蝇蕈醇注射后在AcbSh中所见。肥胖和饮食失调的流行使这些疾病成为一个主要的公共卫生问题，治疗它们的进展取决于我们对控制进食的大脑机制的详细了解。这些研究的结果将使我们能够更清楚地了解调节摄食行为的大脑机制的功能组织，并可能为发现有效治疗方法以减少人类摄食失调引起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.