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。其基本原理是，了解这些网络是如何构建的，并在导致动物厌食症的不利挑战中相互作用，将有助于我们开始考虑大脑如何参与临床重要的厌食症。越来越多的证据表明，根据动物是否对外源性NPY治疗敏感，可以将其分为两组。实验旨在解决第二组的神经回路和机制。为了实验性地产生厌食症，该项目将使用饮用高渗盐水后的慢性脱水。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。底层回路如何在功能上组织的理论基础是，大脑包含一个由神经网络组成的三方系统，可以刺激、抑制或解除进食。三个假设将通过五个具体目标来解决。这些假设是：1）在脱水过程中，当其组成神经元增加其神经肽的表达时，抑制网络产生厌食症。这些神经元中的一些位于外侧下丘脑（LHA）和终纹床核（BST）。2)在脱水过程中，这种抑制性网络通过掩盖通常刺激进食的含瘦素敏感性NPY的神经网络的作用而产生厌食症。3)来自饮用水的感觉信号激活第三个网络，该网络通过解除对瘦素敏感的刺激网络的输出的抑制来产生补偿性摄食。这第三个网络的组成部分目前尚不清楚。实验将使用特异性靶向LHA和BST的兴奋性毒性损伤、中枢神经肽输注和快速细胞活化标志物的神经解剖学映射。目标是将这些操作和变量与厌食症发展和逆转相关的行为终点相关联。原位杂交将被用来作为一种工具，探索神经肽基因的动力学厌食症，作为一个神经解剖学探针澄清电路组织，并监测兴奋性病变的程度。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. The rationale is that understanding how these networks are constructed and interact during the adverse challenges that cause anorexia in animals will help us begin considering how the brain is involved with clinically-important anorexias. Increasing evidence suggests that animal anorexias can be categorized into two groups depending on whether or not they are sensitive to exogenous NPY treatment. Experiments are designed to address the neural circuits and mechanisms underlying the second group. 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 theoretical basis for how underlying circuits are functionally organized is that the brain contains a tripartite system of neural networks that either stimulates, inhibits or disinhibits feeding. Three hypotheses will be addressed by five specific aims. These hypotheses are: 1) An inhibitory network generates anorexia during dehydration when its constituent neurons increase their expression of anorexic neuropeptides. Some of these neurons are located in the lateral hypothalamus (LHA) and bed nucleus of the stria terminalis (BST). 2) During dehydration this inhibitory network generates anorexia by masking the effects of a leptin-sensitive NPY-containing neural networks that normally stimulate eating. 3) Sensory signals derived from drinking water activate a third network that generates compensatory feeding by disinhibiting the output of the leptin-sensitive stimulatory network. The constituents of this third network are currently unknown. Experiments will use excitotoxic lesions specifically targeted to the LHA and BST, central neuropeptide infusions, and neuroanatomical mapping of markers of rapid cellular activation. The goal is to correlate these manipulations and variables to behavioral end points associated with anorexia development and reversal. In situ hybridization will be used as a tool for exploring the dynamics of neuropeptide genes during anorexia, as a neuroanatomical probe for clarifying circuit organization, and for monitoring the extent of the excitotoxic lesions. 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.