STUDIES OF CENTRAL NERVOUS SYSTEM FUNCTIONAL ANATOMY

中枢神经系统功能解剖学研究

• 批准号: 6162848
• 负责人: M HERKENHAM
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6162848
• 关键词: biological signal transduction; blood brain barrier; brain mapping; cannabinoids; corticotropin releasing factor; cytokine; cytokine receptors; drug receptors; growth factor receptors; hypothalamic pituitary axis; immunocytochemistry; in situ hybridization; interleukin 1; lipopolysaccharides; long term potentiation; neurochemistry; neuroendocrine system; neuropeptides; neuropharmacologic agent; neurotransmitter metabolism; neurotransmitter receptor; neurotrophic factors; nuclear factor kappa beta; tumor necrosis factor alpha

The Section on Functional Neuroanatomy combines molecular and neuroanatomical methods to identify dynamic aspects of nervous system function that relate to issues of mental health, infectious disease, and drug abuse. Drug and neurotransmitter receptors are mapped using in vitro ligand binding and autoradiography. In situ hybridization histochemistry (ISHH) is used to localize and quantify mRNA expression of neuropeptides, monoamine transporters and synthesizing enzymes, cytokines, receptors, transcription factors, and immediate-early genes in studies of adaptive changes to pharmacological, physiological, or surgical interventions. 1) We used neuroanatomical localization techniques to study the pathways by which peripheral immune signals (cytokines) transduce a signal at the blood-brain barrier and gain access to the brain to induce CNS production of immune molecules. We propose that this mechanism is part of an amplification process in the immune-to-brain signaling pathways. These putative transduction processes have been examined in both acute (lipopolysaccharide administration) and chronic (trypanosome infection) paradigms. We have used ISHH of IkappaB mRNA to track the brain's immune response. IkappaB is the controlling molecule in the NF-kappaB transcription factor signaling pathway in immune cells. We proposed that this pathway exists in brain, and we have localized and identified the cell types expressing IkappaB message following acute and chronic immune challenges. We are also showing that the brain responds to a peripheral immune challenge by generating its own cytokines. Messages shown to be induced in acute and chronic challenges include interleukin-1 (IL-1), tumor necrosis factor-alpha, IL-1 receptor antagonist, and IL-1 converting enzyme (ICE). 2) Cells expressing the nervous system cannabinoid receptor (CB1) are marked by ISHH in the brainstem, spinal cord, and dorsal root ganglia (DRG). In the DRG, identification of nociceptive cells of the C-fiber type is achieved by labeling for substance P mRNA. From single- and double-label experiments, we have determined that only 15% of the substance P mRNA expressing cells are also CB1 mRNA expressing. Similar kinds of studies are planned for spinal cord (where enkephalin-and GABA-positive cells will be co-localized) and brainstem (where norepinephrine and serotonin will be co-localized).

功能神经解剖学部分结合了分子和 神经解剖学方法，以确定神经系统的动态方面 与心理健康、传染病和 吸毒 药物和神经递质受体的映射使用在 体外配体结合和放射自显影。 原位杂交 组织化学（ISHH）用于定位和定量mRNA表达 神经肽，单胺转运蛋白和合成酶， 细胞因子、受体、转录因子和即刻早期基因 在药理学、生理学或 手术干预。 1)我们用神经解剖学定位 研究外周免疫信号传递途径的技术 （细胞因子）信号在血脑屏障和增益 进入大脑以诱导CNS产生免疫分子。 我们 我认为，这种机制是一个放大过程的一部分， 免疫到大脑的信号通路。 这些假定的转导 已经在急性（脂多糖）和急性（脂多糖）中检查了这些过程。 施用）和慢性（锥虫感染）范例。 我们有 使用IkappaB mRNA的ISHH来追踪大脑的免疫反应。 IkappaB 是NF-κ B转录因子的控制分子 免疫细胞中的信号通路。 我们认为这条途径 在大脑中，我们已经定位并鉴定了表达 急性和慢性免疫挑战后的IkappaB信息。 我们 还表明大脑对外周免疫攻击的反应是 产生自己的细胞因子 显示在急性和急性期诱导的信息， 慢性挑战包括白细胞介素-1（IL-1）、肿瘤坏死 α因子、IL-1受体拮抗剂和IL-1转化酶 （ICE）. 2)表达神经系统大麻素受体的细胞 (CB1)在脑干、脊髓和背根中有ISHH标记 神经节（DRG）。 在背根神经节中， C-纤维类型通过标记P物质mRNA来实现。 从单身- 和双标记实验，我们已经确定，只有15%的 表达P物质mRNA的细胞也表达CB 1 mRNA。 类似 计划对脊髓进行各种研究（脑啡肽和 GABA阳性细胞将共定位）和脑干（其中 去甲肾上腺素和5-羟色胺将共定位）。