Neural Mechanisms of Anorexia

描述（由申请人提供）：这些实验的长期目标是定义负责大鼠厌食症的神经网络的组织。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厌食症中起着关键作用。主要的假设是，下丘脑外侧区和下丘脑室旁核包含的神经元构成一个？喂养行为控制器？在这里，不同的进食刺激汇聚在一起，控制驱动进食的核心回路。我们的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。三个假设将通过具体的目标来解决。它们是：1)信息编码伏隔核壳(ACBsh)-muscimol和2-脱氧-d -葡萄糖驱动的进食在LHA和PVH中聚集到相同的神经元上；2) ACBsh-muscimol喂养需要后脑或表达NPY-Y1受体的下丘脑（mediobasal hypothalamus， MBH）神经元的输入才能完全表达；3)后脑或MBH中表达NPY-Y1受体的神经元向PVH和LHA的投射是水反馈所必需的。实验将采用两种方法：首先，对对照和厌食症动物的ACBsh-muscimol和2-脱氧-d -葡萄糖驱动的喂养结构进行细粒度分析；其次，一种新的免疫细胞化学重合检测（基于Fos和磷酸化erk /2的不同积累和降解率），揭示了两种趋同的进食刺激激活的神经元。利用皂苷基免疫毒性损伤来控制神经回路，破坏后脑上升的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，影响这两种技术的喂养类型显然是可分离的。总的来说，这个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。

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.