Nucleus Accumbens-Mediated Feeding: Output Pathways

伏隔核介导的喂养：输出途径

• 批准号: 7450921
• 负责人: THOMAS R STRATFORD
• 金额: $ 27.3万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7450921
• 关键词: Affect; Behavioral; Bicuculline; Body Weight; Brain; Brain region; Cell Nucleus; Cells; Condition; Contralateral; Data; Detection; Development; Disease; Disruption; Eating; Eating Disorders; Efferent Pathways; Excitatory Amino Acid Antagonists; Excitotoxic lesion; Feeding behaviors; GABA Agonists; Globus Pallidus; Goals; Human; Hypothalamic structure; Injection of therapeutic agent; Investigation; Ipsilateral; Lateral; Lesion; Medial; Mediating; Molecular; Muscimol; Neurons; Nucleus Accumbens; Numbers; Obesity; Output; Pathology; Pathway interactions; Pattern; Play; Prevalence; Public Health; Research Design; Research Project Grants; Rewards; Role; Site; Specificity; Structure; Structure of nucleus infundibularis hypothalami; Techniques; Third ventricle structure; Work; design; feeding; hypocretin; neural circuit; neuropeptide Y; neurotransmission; novel strategies; paraventricular nucleus; receptor; relating to nervous system; research study; response

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.

描述(申请人提供)：过去几年收集的大量证据令人信服地表明，伏隔核壳内的GABA能回路(AcbSh)在控制食物摄入方面发挥着重要作用。例如，在AcbSh中注射GABA激动剂会导致摄食量的大幅和非常特定的增加，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操作产生的效应的大小和特异性表明，AcbSh摄食效应背后的神经回路的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摄食量和体重失调的新方法的一个有前途的靶点。这项拟议的研究项目的长期目标是识别和描述AcbSh在进食行为中产生变化的神经回路。我们的基本工作假设是，AcbSh通过有效地调节分布在分布但偏侧化的结构网络中的神经活动来影响摄食，该结构网络包括内侧腹侧苍白球(VPM)、外侧(LH)、弓状(Arc)和脑室旁(PVN)区域。拟议的实验涉及使用补充的神经解剖学、行为学、药理学和分子技术，以更好地了解信息在回路中的流动以及每个结构对AcbSh介导的摄食表达的功能贡献。具体地说，我们建议检查这些结构中的每一个的兴奋毒性损伤改变单侧AcbSh内注射麝香酚引起的食物摄入量和模式的能力。这些研究将使用“同侧-对侧干扰”(ICD)设计进行，这将使我们避免在这类研究中经常遇到的许多解释困难。由于AcbSh内注射蝇草酚诱导上述所有结构中强烈的Fos表达，我们还将使用ICD设计来确定这些结构的损伤如何改变AcbSh内注射产生的神经元激活模式。我们还将确定由AcbSh Muscimol内激活的黄体生成素神经元是否直接投射到Arc或PVN。其他研究将检验大脑内注射增食欲素和神经肽Y拮抗剂是否可以改变摄食反应，以及在VPM中注射荷包牡丹碱是否会诱导Fos表达和摄食，类似于AcbSh中注射蝇草酚后的情况。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。这些研究的结果将使我们更清楚地了解大脑调节摄食行为的机制的功能组织，并可能提供至关重要的信息，以努力发现有效的治疗方法，以减少人类摄食失调造成的痛苦。