Stress-Induced Noradrenergic Dysregulation of Neuroinflammation & HPA Responses

描述（由申请方提供）：慢性或反复应激源暴露与脑细胞因子升高和循环糖皮质激素过量相关，两者均与不良健康后果（例如代谢综合征、内脏肥胖、骨质疏松症、心脏病、神经退行性疾病、认知能力下降和抑郁症）相关。虽然脑细胞因子，特别是IL-1，已知发挥关键作用，但尚不清楚是什么原因导致应激期间脑IL-1水平的增加以及脑中IL-1信号传导的重要性。我们 实验室和其他实验室已经证明脑IL-1产生主要来自于刺激小胶质细胞上的β-肾上腺素能受体（β-AR），且初步研究表明暴露于慢性应激的动物在中枢给予异丙肾上腺素（β-AR激动剂）后与对照动物相比具有显著更高的IL-1产生。有趣的是，仅在下丘脑和杏仁核中观察到更大的IL-1产生，而在其他大脑区域中没有观察到，这表明这些区域在尼古丁介导的健康损害中起关键作用。虽然先前已在应激动物中观察到引发的细胞因子应答，但它们仅在免疫攻击后进行了研究，并被认为是由于小胶质细胞上toll样受体的上调。我们的工作表明，增强的细胞因子反应也发生在β-AR刺激后，但这些反应是脑区特异性的。这表明引发的细胞因子反应可能在改变去甲肾上腺素释放后的“正常”/常规行为反应中发挥作用，而不仅仅是免疫挑战期间的疾病反应。此外，我们证明，去甲肾上腺素本身可以启动小胶质细胞的细胞因子反应，并提出了新的假设，即内源性水平的去甲肾上腺素释放慢性应激暴露过程中足以启动小胶质细胞。总体目标是：1）确定增强的β-AR信号传导的生理和行为意义; 2）确定β-AR信号传导如何导致应激动物中过度的细胞因子产生以及它们对生理和行为反应的影响;以及3）检查在应激物暴露期间重复的去甲肾上腺素释放是否是必要的和/或足以以区域特异性方式引发小胶质细胞。

DESCRIPTION (provided by applicant): Chronic or repeated stressor exposure is associated with elevated brain cytokines and excessive circulating glucocorticoids, which are both linked to poor health consequences (e.g. metabolic syndrome, visceral adiposity, osteoporosis, heart disease, neurodegenerative conditions, cognitive decline, and depression). While brain cytokines, particularly IL-1, are known to play a critical role it is unclear what causes the increase in brain IL-1 levels during stress and where in the brain IL-1 signaling is important. Our laboratory and those of others have demonstrated that production of brain IL-1 largely comes from stimulation of beta- adrenergic receptors (beta-ARs) on microglia and preliminary studies demonstrate that animals exposed to chronic stress have significantly greater IL-1 production following central administration of isoproterenol (a beta-AR agonist) compared to control animals. Interestingly, the greater IL-1 production is only observed in the hypothalamus and amygdala and not in other brain areas suggesting these areas play a pivotal role in cytokine-mediated health impairments. While primed cytokine responses have previously been observed in stressed animals, they have only been investigated following an immune challenge and are thought to be due to an upregulation of toll-like receptors on microglia. Our work indicates enhanced cytokine responses also occur following beta-AR stimulation, but these responses are brain area specific. This suggests primed cytokine responses may play a role in altering 'normal'/routine behavioral responses following norepinephrine release not just sickness responses during an immune challenge. Additionally, we demonstrate that norepinephrine itself can prime microglia cytokine responses and propose the novel hypothesis that endogenous levels of norepinephrine released during chronic stressor exposure are sufficient to prime microglia. The overall goals are to: 1) determine the physiological and behavioral significance of enhanced beta-AR signaling; 2) determine how beta-AR-signaling results in exaggerated cytokine production in stressed animals and their impact on physiological and behavioral responses; and 3) examine whether repeated norepinephrine release during stressor exposure is necessary and/or sufficient to prime microglia in a regionally specific manner.