NEURAL MECHANISMS OF ANOREXIA

厌食症的神经机制

• 批准号: 7105430
• 负责人: Alan G Watts
• 金额: $ 27.77万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-06 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7105430
• 关键词: anorexia; behavior test; body water dehydration; brain mapping; chemoreceptors; corticotropin releasing factor; hypothalamus; immunocytochemistry; in situ hybridization; laboratory rat; leptin; neuroanatomy; neuropeptide Y; neurotensin; orexin; psychophysiology; sensory mechanism; sensory signal detection; thalamus; thirst regulatory center

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.

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。其基本原理是，了解这些网络在导致动物厌食症的不利挑战中是如何构建和相互作用的，将有助于我们开始考虑大脑是如何参与临床重要的厌食症的。越来越多的证据表明，动物厌食症可分为两类，取决于它们是否对外源性NPY治疗敏感。实验的目的是研究第二组背后的神经回路和机制。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。这种文档完备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，厌食症很快就会逆转。潜在回路如何在功能上组织的理论基础是，大脑包含一个刺激、抑制或去抑制进食的三方神经网络系统。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，抑制网络的组成神经元增加厌食性神经肽的表达，从而产生厌食症。其中一些神经元位于下丘脑外侧（LHA）和终纹床核（BST）。2)在脱水过程中，这种抑制网络通过掩盖含有瘦素敏感的npy神经网络的作用而产生厌食症，这种神经网络通常会刺激进食。3)饮水产生的感觉信号激活了第三个网络，该网络通过解除对瘦素敏感刺激网络的抑制而产生代偿性摄食。这第三个网络的组成部分目前尚不清楚。实验将使用特异性针对LHA和BST的兴奋性毒性病变，中枢神经肽输注，以及快速细胞激活标记物的神经解剖图谱。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联系起来。原位杂交将作为一种工具来探索神经肽基因在厌食症期间的动态，作为一种神经解剖学探针来澄清电路组织，并监测兴奋性毒性病变的程度。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。