Studies Of Central Nervous System Functional Anatomy

功能神经解剖学部分结合分子和神经解剖学方法来识别与精神健康、传染病和药物滥用问题相关的神经系统功能的动态方面。我们实验室目前的目标是探索中枢神经系统（CNS）和免疫系统之间的相互作用，在动物遭受压力，炎症刺激，或感染。我们的方法是识别由免疫挑战诱导的大脑中的细胞和分子成分，并进一步表征分子，解剖和功能水平的反应。使用组织化学技术绘制了关键的解剖通路和相关的神经递质/受体系统。原位杂交组织化学（ISHH）用于定位和量化神经递质、细胞因子、受体、转录因子和即时早期基因的mRNA表达，用于研究免疫、药理、生理或外科干预的适应性变化。免疫组织化学和双标记技术用于表征显示诱导免疫信号分子mRNA表达的细胞表型。我们已经1)在大脑中绘制了急性给药脂多糖（一种细菌内毒素）的免疫反应图，2)绘制了可能涉及在整个大脑中传递免疫信号的脑脊液和间质液流动途径图，3)显示了免疫刺激（脂多糖）在进入血脑屏障后的行为，4)建立了慢性免疫系统激活（锥虫寄生虫感染）的模型，5)显示了在免疫和非免疫生理挑战条件下神经元和非神经元细胞中I类主要组织相容性复合体（MHC） mRNA的激活；6)绘制了在中央给药白介素-1 （IL-1）后导致全脑胶质细胞激活的级联事件。在急性和慢性挑战中被诱导的基因转录物包括IL-1、IL-6、IL-12、肿瘤坏死因子- α (tnf - α)、IL-1受体拮抗剂（IL-1ra）、IL-1转换酶（ICE）、转化生长因子β (tgf - β)和其他免疫信号分子，如抑制因子κ B （IkappaB）、诱导型环氧合酶（COX-2）和诱导型一氧化氮合酶（iNOS）。mrna在特定细胞类型（内皮细胞、小胶质细胞、星形胶质细胞和脑膜）和特定模式（在血管、脉络膜丛和心室周围器官中高水平表达）中被诱导。我们认为先天免疫反应的一个重要功能组成部分涉及中枢产生的细胞因子。正在进行的新项目探索适应性免疫反应中大脑和免疫系统之间的相互作用。实验模型包括在Lewis大鼠中产生抗神经元自身免疫反应，以及在小鼠中使用移植的骨髓干细胞（包括脑小胶质细胞在内的免疫系统的祖细胞）开始工作。

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. The current objective of our laboratory is to explore the interaction between the central nervous system (CNS) and the immune system in animals that are subjected to stress, inflammatory stimuli, or infections. Our approach is to identify cellular and molecular components in the brain induced by immunological challenges and to further characterize the responses at molecular, anatomical, and functional levels. Key anatomical pathways and relevant neurotransmitter/receptor systems are mapped using histochemical techniques. In situ hybridization histochemistry (ISHH) is used to localize and quantify mRNA expression of neurotransmitters, cytokines, receptors, transcription factors, and immediate-early genes in studies of adaptive changes to immunological, pharmacological, physiological, or surgical interventions. Immunohistochemistry and double-label techniques are used to characterize the phenotypes of the cells that show induced mRNA expression of immune signaling molecules. We have 1) mapped in the brain the immune response to acute administration of lipopolysaccharide, a bacterial endotoxin, 2) mapped the cerebrospinal and interstitial fluid flow pathways that may be involved in conveying immune signals throughout the brain, 3) shown how an immune stimulus (lipopolysaccharide) behaves once inside the blood-brain barrier, 4) developed a model of chronic immune system activation (trypanosome parasite infection), 5) shown activation of class I major histocompatibility complex (MHC) mRNA in both neuronal and non-neuronal cells under conditions of immune and non-immune physiological challenges, and 6) mapped the cascade of events leading to brain-wide glial activation following central administration of interleukin-1 (IL-1). Gene transcripts shown to be induced in acute and chronic challenges include IL-1, IL-6, IL-12, tumor necrosis factor-alpha (TNF-alpha), IL-1 receptor antagonist (IL-1ra), IL-1 converting enzyme (ICE), transforming growth factor beta (TGF-beta), and other immune signaling molecules such as inhibitory factor kappa B (IkappaB), inducible cyclooxygenase (COX-2), and inducible nitric oxide synthase (iNOS). The mRNAs are shown to be induced in specific cell types (endothelia, microglia, astrocytes, and meninges) and in specific patterns (high levels of expression in the blood vessels, choroid plexus and circumventricular organs). We propose that an important functional component of the innate immune response involves centrally produced cytokines. New projects underway explore interactions between the brain and the immune system during adaptive immune responses. Experimental models include the development of an antineuronal autoimmune response in Lewis rats and the initiation of work in mice using transplanted bone marrow stem cells, which are the progenitor cells of the immune system, including brain microglia.