Neural Mechanisms of Anorexia

描述（由申请方提供）：这些实验的长期目标是确定大鼠厌食症的神经网络组织。特别是，研究将集中在端脑，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脑下垂体中起着关键作用。主要的假设是，下丘脑外侧区和室旁核的下丘脑含有神经元，构成一个？进食行为控制器？，并且是不同的进食刺激汇聚以控制驱动进食的核心回路的部位。目标是确定收敛点的位置，并探索厌食症如何影响这些点。三个假设将解决的具体目标。它们是：1）编码核壳（ACBsh）-蝇蕈醇和2-脱氧-D-葡萄糖驱动的摄食的信息会聚到LHA和PVH中的相同神经元上; 2）ACBsh-蝇蕈醇摄食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以完全表达; 3）背水反馈需要从中脑或MBH中表达NPY-Y1受体的神经元投射到PVH和LHA。实验将使用两种方法：第一，ACBsh-蝇蕈醇和2-脱氧-D-葡萄糖驱动的喂养在控制和哺乳动物中的结构的细粒度分析;第二，一种新的免疫细胞化学符合检测（基于Fos和磷酸化ERK/2的差异积累和降解速率），揭示了由两种会聚喂养刺激激活的神经元。将使用基于皂草素的免疫毒性损伤来操纵回路，所述损伤破坏来自后脑的上行儿茶酚胺能神经元或MBH中的NPY-Y1受体表达神经元。重要的是，这两种技术所影响的喂养类型显然是不可分离的。总的来说，本项目中的实验旨在为阐明动物厌食症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重要厌食症的神经基质。

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.