Sex differences in the regulation of brain IL-1β in response to chronic stress

Elevations in brain interleukin-1 beta (IL-1 beta) during chronic stress exposure have been implicated in behavioral and cognitive impairments associated with depression and anxiety. Two critical regulators of brain IL-1 beta production during times of stress are glucocorticoids and catecholamines. These hormones work in opposition to one another to inhibit (via glucocorticoid receptors) or stimulate (via beta-adrenergic receptors: beta-AR) IL-1 beta production. While chronic stress often heightens both corticosterone and catecholamine levels, it remains unknown as to how chronic stress may affect the yin-yang balance between adrenergic stimulation and glucocorticoid suppression of brain IL-1 beta. To investigate this further, male and female rats underwent 4 days of stress exposure or served as non-stressed controls. On day 5, animals were administered propranolol (beta-AR antagonist), metyrapone (a glucocorticoid synthesis inhibitor), vehicle, or both drugs and brain IL-1 beta mRNA was measured by rtPCR in limbic brain areas. In males, administration of propranolol had no effect on IL-1 beta expression in non stressed controls but significantly reduced IL-1 beta in the hippocampus and amygdala of chronically stressed animals. In females, propranolol significantly reduced IL-1 beta in the amygdala and hypothalamus of both control and stressed rats. In male rats, metyrapone treatment significantly increased IL-1 beta mRNA regardless of stress treatment in all brain areas, while in female rats metyrapone only increased IL-1 beta in the hypothalamus. Interestingly, propranolol treatment blocked the metyrapone-induced increase in brain IL-1 beta indicating the increase in brain IL-1 beta following metyrapone treatment was due to increase beta-AR activation. Additional studies revealed that metyrapone significantly increases norepinephrine turnover in the hypothalamus and medial prefrontal cortex in male rats and that microglia appear to be the cell type contributing to the production of IL 1 beta. Overall, data reveal that stress exposure in male rats affects the regulation of brain IL-1 beta by the nor epinephrine -beta-AR pathway, while stress had no effect in the regulation of brain IL-1 beta in female rats.