NEURAL CIRCUITRY OF CYTOKINE-INDUCED ANOREXIA

细胞因子引起的厌食症的神经回路

• 批准号: 6523945
• 负责人: TERESA M REYES
• 金额: $ 4.62万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6523945
• 关键词: albino rat; anorexia; appetite; appetite regulatory center; biological signal transduction; central neural pathway /tract; cytokine receptors; experimental brain lesion; fenfluramine; fos protein; gene expression; hypothalamus; immunocytochemistry; interleukin 1; melanocyte stimulating hormone; neuroanatomy; neuronal transport; neuropeptide Y; neuropeptides; nucleic acid hybridization; paraventricular nucleus; proopiomelanocortin; receptor expression

Loss of appetite is a significant obstacle in the treatment of chronic illnesses, including certain cancers and HIV infection. Pro-inflammatory cytokines released from activated immune cells are prime candidates for mediating this anorexia, yet a complete understanding of the neural pathways and mechanisms involved in this response remains elusive. The overall goal of this proposal is to explore the functional organization of neural circuits that underlie IL-1-induced anorexia. Interleukin-1 (IL-1), a cytokine which can potently inhibit feeding, will be used to model an acute infectious/inflammatory event. The arcuate nucleus (ARC) of the hypothalamus can be accessed directly by circulating macromolecules, expresses IL-1- receptors, and houses peptidergic neurons strongly implicated in the control of feeding. Correlated behavioral (feeding) and functional neuroanatomical (induced patterns of immediate-early gene expression) assays will be used to test a role of IL-1-sensitive ARC neurons in IL-1-induced anorexia. First, a discrete lesioning method will be used to test if the ARC plays a prominent and specific role in IL-1 mediated inhibition of food intake. Next, IL-1 sensitive ARC neurons will be characterized with respect to their expression of IL-1 receptors, and/or neuropeptides implicated in the stimulation and inhibition of appetite. Finally, axonal transport and selective fiber transection methods will be used to identify and characterize behaviorally relevant downstream targets of IL-1-sensitive ARC neurons. Collectively, the proposed studies will serve as a initial step in delineating the circuitry underlying the cytokine-induced feeding inhibitory response.

食欲不足是治疗慢性疾病的重要障碍，包括某些癌症和HIV感染。从活化的免疫细胞释放出的促炎性细胞因子是介导这种厌食症的主要候选者，但对此反应中涉及的神经途径和机制的完全理解仍然难以捉摸。该提案的总体目标是探索IL-1引起的厌食症的神经回路的功能组织。白介素-1（IL-1）是一种可以有效抑制喂养的细胞因子，将用于对急性感染/炎症事件进行建模。 下丘脑的弧形核（ARC）可以通过循环大分子，表达IL-1受体直接进入，并容纳与喂养控制有关的肽肽神经元。相关的行为（进食）和功能性神经解剖学（诱导的即时基因表达）测定法将用于测试IL-1敏感的ARC神经元在IL-1诱导的厌食症中的作用。首先，将使用一种离散的病变方法来测试ARC在IL-1介导的食物摄入抑制中是否起着突出而特定的作用。接下来，IL-1敏感的电弧神经元将以其IL-1受体的表达为特征，以及与刺激和抑制食欲有关的神经肽。最后，轴突传输和选择性纤维横断方法将用于识别和表征IL-1敏感弧神经元的行为相关的下游靶标。总的来说，拟议的研究将作为描述细胞因子诱导的喂养抑制反应的基础电路的第一步。