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.
The overall focus of this investigation is to examine the mechanisms involved in the dysregulation of brain cytokines during repeated stressor exposure and their involvement in sensitizing physiological and behavioral responses.