Stress-Induced Noradrenergic Dysregulation of Neuroinflammation & HPA Responses

描述（由申请人提供）：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多有关，这两者都与不良健康后果有关（例如代谢综合征，内脏脂肪，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）。虽然大脑细胞因子，特别是IL-1，已知起着至关重要的作用，但尚不清楚是什么导致了压力下大脑IL-1水平的增加，以及大脑中IL-1信号的重要位置。我们的

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.