Regulation of Brain IL-1 & Sickness Responses Following E.coli Challenge

描述（由申请人提供）：促炎细胞因子在大脑中对改变行为和内分泌反应具有强效作用。促炎性细胞因子水平升高介导在多种刺激后观察到的许多行为和内分泌应答，所述刺激包括外周免疫激发、暴露于一些身体/心理应激源、脑损伤和中枢炎性病症如阿尔茨海默病、帕金森病和多发性硬化症。虽然升高的脑细胞因子的生物学效应已经得到很好的表征，但调节脑细胞因子产生的机制在很大程度上仍然未知。本提案的目的是研究外周免疫激发后调节脑细胞因子的诱导和抑制的机制，并建立这种调节对各种行为和内分泌反应的生理重要性，如发热，食物/水摄入量减少，收入/记忆受损，以及下丘脑-垂体-肾上腺（HPA）轴的激活。我们实验室的最新数据表明，<$-肾上腺素受体在脑细胞因子的诱导中起重要作用，并且<$-肾上腺素受体拮抗剂的中枢给药阻断或减弱外周大肠杆菌（E.大肠杆菌）的挑战。有趣的是，β-肾上腺素受体仅在由位于孤束核（NTS）中的去甲肾上腺素能神经元支配的脑区域中介导脑细胞因子产生，而不在主要由位于蓝斑（LC）中的去甲肾上腺素能神经元支配的脑区域中介导脑细胞因子产生。这些数据支持先前发表的工作，证明免疫刺激后，NTS神经元被快速和稳健地激活，而只有LC神经元的亚群被激活。此外，我们提出，LC神经元的激活过程中的免疫反应功能，以抑制NTS的活动。这一假设得到了以下观察结果的支持：证实LC神经元的刺激抑制NTS活性，以及我们的初步数据，即LC投射的损伤导致E.在NTS投射位点中的大肠杆菌挑战。这些数据导致我们目前的假设进行测试，在这个建议，在免疫激发激活NTS中的去甲肾上腺素能神经元诱导细胞因子的产生在离散的脑区通过激活的<$-肾上腺素受体，而激活LC神经元在免疫反应过程中起到抑制NTS的活动。

DESCRIPTION (provided by applicant): Pro-inflammatory cytokines have potent effects in the brain on altering behavioral and endocrine responses. Elevated levels of proinflammatory cytokines mediate many of the behavioral and endocrine responses observed following a variety of stimuli including peripheral immune challenge, exposure to some physical/psychological stressors, brain injury, and central inflammatory conditions such as Alzheimer's, Parkinson's, and multiple sclerosis. While the biological effects of elevated brain cytokines have been well characterized, the mechanisms that regulate brain cytokine production remain largely unknown. The aims of this proposal are to examine the mechanisms that regulate both the induction and inhibition of brain cytokines following a peripheral immune challenge, and establish the physiological importance of this regulation on various behavioral and endocrine responses such as fever, decreased food/water intake, impaired earning/memory, and activation of the hypothalamus-pituitary-adrenal (HPA) axis. Recent data from our laboratory demonstrate that ¿-adrenoceptors play an important role in the induction of brain cytokines, and that central administration of a ¿-adrenoceptor antagonist blocks or attenuates cytokine production following a peripheral Escherichia coli (E. coli) challenge in distinct brain areas. Interestingly, ¿-adrenoceptors only mediate brain cytokine production in brain areas innervated by noradrenergic neurons located in the nucleus of the solitary tract (NTS), and not in brain areas largely innervated by noradrenergic neurons located in the locus coeruleus (LC). These data support previously published work demonstrating that following immune stimuli, NTS neurons are rapidly and robustly activated, while only a subpopulation of LC neurons become activated. Furthermore, we propose that activation of LC neurons during an immune response function to inhibit NTS activity. This hypothesis is supported by observations that demonstrate stimulation of LC neurons suppresses NTS activity, and our preliminary data that lesions of LC projections results in exaggerated cytokine production following E. coli challenge in NTS projection sites. These data lead to our current hypothesis to be tested in this proposal that during an immune challenge activation of noradrenergic neurons in the NTS induce cytokine production in discrete brain areas via activation of ¿-adrenoceptors, while activation of LC neurons during an immune response serve to inhibit NTS activity.