NEURAL MECHANISMS OF ANOREXIA

厌食症的神经机制

• 批准号: 6642762
• 负责人: Alan G Watts
• 金额: $ 32.5万
• 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 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6642762
• 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(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。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期间相互作用，将有助于我们开始考虑大脑如何参与临床上重要的厌食症。越来越多的证据表明，动物厌食症可以根据它们对外源性NPY治疗是否敏感而分为两组。实验旨在解决第二组背后的神经电路和机制。为了在实验中产生厌食症，该项目将使用饮用高渗盐水后的慢性脱水。这种有据可查的模式的优势是，它的发展和强度可以简单而可靠地控制。此外，当动物喝水时，厌食症很快就会逆转。基本电路的功能组织方式的理论基础是，大脑包含一个由神经网络组成的三部分系统，该系统要么刺激、抑制或抑制进食。三个假设将由五个具体目标来解决。这些假设是：1)抑制网络在脱水过程中，当其组成神经元增加其厌食神经肽的表达时，会产生厌食症。其中一些神经元位于下丘脑外侧核(LHA)和终纹床核(BST)。2)在脱水期间，这个抑制网络通过掩盖正常刺激进食的瘦素敏感的NPY神经网络的影响而产生厌食症。3)来自饮用水的感觉信号激活了第三个网络，该网络通过抑制瘦素敏感刺激网络的输出来产生补偿性摄食。这第三个网络的成员目前尚不清楚。实验将使用专门针对LHA和BST的兴奋毒性损伤，中枢神经肽注射，以及快速细胞激活标志的神经解剖图谱。我们的目标是将这些操作和变量与与厌食症发展和逆转相关的行为终点联系起来。原位杂交将作为探索厌食症期间神经肽基因动态的工具，作为阐明回路组织的神经解剖学探针，并用于监测兴奋性毒性损害的程度。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。