Neural Mechanisms of Anorexia

描述(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，研究将集中在端脑与下丘脑和后脑之间的相互作用，因为端脑可能在临床相关厌食症中发挥关键作用。主要的假设是，下丘脑外侧区和下丘脑室旁核含有神经元，这些神经元构成了一个摄食行为控制器，是不同的摄食刺激汇聚在一起控制驱动摄食的核心电路的地方。目标是确定汇聚点的位置，并探索这些点在厌食症期间是如何受到影响的。具体目标将涉及三个假设。它们是：1)编码伏隔核壳(ACBsh)-蝇香酚和2-脱氧-D-葡萄糖驱动的摄食的信息汇聚到LHA和PVH中的相同神经元；2)ACBsh-Muscimol摄食需要来自后脑或表达NPY-Y1受体的下丘脑(MBH)神经元的全部表达；3)回水摄食需要从后脑或表达MBH的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，细粒度分析ACBsh-Muscimol和2-Deoxy-D-葡萄糖驱动的对照组和厌食症动物的摄食结构；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的差异积累和降解率)，揭示神经元被两种趋同的摄食刺激激活。电路将使用基于皂苷的免疫毒性损伤来操作，这种损伤要么破坏后脑上升的儿茶酚胺能神经元，要么破坏MBH中表达NPY-Y1受体的神经元。重要的是，影响这两种技术的喂养类型显然是分开的。总而言之，本项目中的实验旨在为阐明导致动物厌食症的神经回路的组织和功能做出重大贡献，最终将有助于阐明临床上重要厌食症的神经基础。

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.