Neural Mechanisms of Anorexia

厌食症的神经机制

• 批准号: 7794966
• 负责人: Alan G Watts
• 金额: $ 36.51万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-06 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7794966
• 关键词: Address; Affect; Animals; Anorexia; Back; Behavior; Biological Neural Networks; Cereals; Deglutition; Dehydration; Deoxyglucose; Detection; Development; Environment; Equilibrium; Feeding behaviors; Gene Expression; Goals; Hypothalamic structure; Individual; Insulin; Lateral Hypothalamic Area; Leptin; Lesion; Location; Maintenance; Maps; Mastication; Metabolic; Modeling; Motor; Motor output; Muscimol; Network-based; Neurons; Nucleus Accumbens; Pattern; Phase; Play; Population; Rattus; Resolution; Role; Sensory; Site; Stimulus; Structure; Structure of nucleus infundibularis hypothalami; Techniques; Telencephalon; Time; Transduction Gene; Water; Work; base; cell type; clinically relevant; design; feeding; fundamental research; ghrelin; hindbrain; network models; neural circuit; neuromechanism; neuropeptide Y-Y1 receptor; novel; paraventricular nucleus; relating to nervous system; research study; response; restraint

DESCRIPTION (provided by applicant): The long-term goal of these experiments is to define the organization of the neural networks responsible for anorexia in rats. In particular, studies will focus on interactions between the telencephalon, and the hypothalamus and hindbrain, since the telencephalon likely plays a critical role in clinically-relevant anorexias. The main hypothesis is that the lateral hypothalamic area and the paraventricular nucleus of the hypothalamus contain neurons that constitute a ?feeding behavior controller?, and are sites where distinct feeding stimuli converge to control the core circuits that drive feeding. The goal is to determine the locations of the points of convergence, and to explore how these are affected during anorexia. Three hypotheses will be addressed by the specific aims. They are: 1) Information encoding nucleus accumbens shell (ACBsh)-muscimol and 2-deoxy-D-glucose-driven feeding converges onto the same neurons in the LHA and PVH; 2) ACBsh-muscimol feeding requires input from either the hindbrain or NPY-Y1 receptor expressing neurons in the mediobasal hypothalamus (MBH) for full expression; 3) projections from either the hindbrain or NPY-Y1 receptor expressing neurons in the MBH to the PVH and LHA are required for water-back feeding. Experiments will use two approaches: first, a fine-grained analysis of the structure of ACBsh-muscimol and 2-deoxy-D-glucose-driven feeding in control and anorexic animals; second, a novel immunocytochemical coincidence detection (based on the differential accumulation and degradation rates of Fos and phosphorylated-ERK/2) that reveals neurons that are activated by two convergent feeding stimuli. Circuits will be manipulated using saporin-based immunotoxic lesions that destroy either the ascending catecholaminergic neurons from the hindbrain, or NPY-Y1 receptor expressing neurons in the MBH. Importantly, the types of feeding that are impacted these two techniques are clearly dissociable. Collectively, the experiments in this project are designed to make major contributions towards elucidating the organization and function of the neural circuits responsible for anorexia in animals in a way that will ultimately help to clarify the neural substrates of clinically important anorexias.

描述（由申请人提供）：这些实验的长期目标是确定导致大鼠厌食症的神经网络的组织。特别是，研究将重点关注端脑、下丘脑和后脑之间的相互作用，因为端脑可能在临床相关的厌食症中发挥着关键作用。主要假设是下丘脑的外侧区和室旁核包含构成“摄食行为控制器”的神经元，并且是不同摄食刺激汇聚以控制驱动摄食的核心回路的部位。目标是确定汇聚点的位置，并探索这些汇聚点在厌食症期间如何受到影响。具体目标将解决三个假设。它们是：1）信息编码伏隔核壳（ACBsh）-蝇蕈醇和2-脱氧-D-葡萄糖驱动的喂养汇聚到LHA和PVH中的相同神经元上； 2) ACBsh-蝇蕈醇喂养需要来自后脑或中基底下丘脑 (MBH) 中表达 NPY-Y1 受体的神经元的输入才能完全表达； 3) 水回喂养需要从后脑或 MBH 中表达 NPY-Y1 受体的神经元到 PVH 和 LHA 的投射。实验将使用两种方法：首先，对对照动物和厌食动物的ACBsh-蝇蕈醇和2-脱氧-D-葡萄糖驱动的喂养进行细粒度分析；其次，一种新颖的免疫细胞化学符合检测（基于 Fos 和磷酸化 ERK/2 的差异积累和降解率），揭示了被两种汇聚摄食刺激激活的神经元。将使用基于皂草素的免疫毒性损伤来操纵电路，这些损伤会破坏后脑的上行儿茶酚胺能神经元或 MBH 中表达 NPY-Y1 受体的神经元。重要的是，受这两种技术影响的喂养类型显然是不相关的。总的来说，该项目的实验旨在为阐明动物厌食症的神经回路的组织和功能做出重大贡献，最终有助于阐明临床上重要的厌食症的神经基础。