Neural Mechanisms of Anorexia

项目总结/摘要 这些实验的长期目标是定义负责神经网络的组织， 特别是，研究将集中在端脑和下丘脑之间的相互作用， 和后脑，因为端脑可能在临床相关的脑下垂体中起关键作用。完成网站 实验性厌食症，该项目将使用慢性脱水后，饮用高渗盐水。 这个有据可查的模型的优点是，它的发展和强度可以简单可靠地 控制。此外，当动物喝水时，厌食症会迅速逆转。主要假设 下丘脑外侧区和室旁核含有神经元 构成了一个进食行为控制器，并且是不同的进食刺激聚集在一起以控制 驱动进食的核心电路目标是确定收敛点的位置， 以探索厌食症期间这些是如何受到影响的。三个假设将解决的具体目标。 它们是：1）编码核壳（ACBsh）的信息-蝇蕈醇和2-脱氧-D-葡萄糖- 驱动进食收敛于LHA和PVH中的相同神经元; 2）ACBsh-蝇蕈醇进食需要 来自中脑或下丘脑中表达NPY-Y1受体的神经元的输入 (MBH)完全表达; 3）来自后脑或NPY-Y1受体表达神经元的投射， 需要MBH到PVH和LHA用于水回输。实验将使用两种方法：第一， ACBsh-蝇蕈醇和2-脱氧-D-葡萄糖驱动的对照中的进食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（基于差异 Fos和磷酸化ERK/2的积累和降解速率），揭示了神经元 由两种集中进食刺激激活。回路将使用基于皂草素的免疫毒性 破坏来自后脑的上行儿茶酚胺能神经元或NPY-Y1受体的病变 在MBH中表达神经元。重要的是，影响这两种技术的喂养类型 很明显是可以分离的总的来说，这个项目中的实验旨在做出重大贡献 旨在阐明动物厌食症的神经回路的组织和功能， 一种最终将有助于阐明临床上重要的脑下垂体的神经基质的方法。项目叙述 饮食失调，特别是神经性厌食症，是临床上的重要问题，其结果很差; 事实上，神经性厌食症是所有精神疾病中最致命的一种。治疗饮食失调 是出了名的困难，药物干预是令人沮丧的无效。拟议的研究 目的是描绘神经回路负责产生一种实验上易于处理的厌食症类型 在动物中，为了开发可以应用于临床相关的神经网络模型， 你好

PROJECT SUMMARY/ABSTRACT The long-term goal of these experiments is to define the organization of the neural networks responsible for anorexiainrats.Inparticular,studieswillfocusoninteractionsbetweenthetelencephalon,andthehypothalamus and hindbrain, since the telencephalon likely plays a critical role in clinically-relevant anorexias. To generate anorexia experimentally, the project will use the chronic dehydration that follows drinking hypertonic saline. This well-documented model has the advantage that its development and intensity can be simply and reliably controlled. Furthermore, the anorexia is quickly reversed when the animal drinks water. 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. PROJECT NARRATIVE Eating disorders, and anorexia nervosa in particular, are significant clinical problems that have poor outcomes; indeed, anorexia nervosa is one of the deadliest of all psychiatric disorders. Treatment of eating disorders is notoriously difficult, with pharmacological intervention being frustratingly ineffective. The proposed studies aim to delineate the neural circuitry responsible for generating an experimentally-tractable type of anorexia in animals, with a view to developing neural network models that can be applied to clinically-relevant anorexias.