There is growing evidence that stress-induced brain cytokines are important in the etiology of depression and anxiety. Here, we review how the neuroendocrine responses to psychological stressors affect the immediate and long-term regulation of inflammatory cytokines within the brain and highlight how the regulation changes across time with repeated stress exposure. In doing so, we report on the percentage of studies in the literature that observed increases in either IL-1 β , TNF- α , or IL-6 within the hypothalamus, hippocampus, or prefrontal cortex after either acute or chronic stress exposure. The key takeaway is that catecholamines and glucocorticoids play critical roles in the regulation of brain cytokines after psychological stress exposure. Central catecholamines stimulate the release of IL-1 β from microglia, which is a key factor in the further activation of microglia and recruitment of monocytes into the brain. Meanwhile, the acute elevation of glucocorticoids inhibits the production of brain cytokines via two mechanisms: the suppression of noradrenergic locus coeruleus neurons and inhibition of the NF κ B signaling pathway. However, glucocorticoids and peripheral catecholamines facilitate inflammatory responses to future stimuli by stimulating monocytes to leave the bone marrow, downregulating inhibitory receptors on microglia, and priming inflammatory responses mediated by peripheral monocytes or macrophages. The activation of microglia and the elevation of peripheral glucocorticoid and catecholamine levels are both necessary during times of stress exposure for the development of psychopathologies.

Elevations in brain interleukin-1 beta (IL-1β) during chronic stress exposure have been implicated in behavioral and cognitive impairments associated with depression and anxiety. Two critical regulators of brain IL-1β 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: β-AR) IL-1 β 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-1β. 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 (β-AR antagonist), metyrapone (a glucocorticoid synthesis inhibitor), vehicle, or both drugs and brain IL-1β mRNA was measured by rtPCR in limbic brain areas. In males, administration of propranolol had no effect on IL-1β expression in non-stressed controls but significantly reduced IL-1β in the hippocampus and amygdala of chronically stressed animals. In females, propranolol significantly reduced IL-1β in the amygdala and hypothalamus of both control and stressed rats. In male rats, metyrapone treatment significantly increased IL-1β mRNA regardless of stress treatment in all brain areas, while in female rats metyrapone only increased IL-1β in the hypothalamus. Interestingly, propranolol treatment blocked the metyrapone-induced increase in brain IL-1β indicating the increase in brain IL-1β following metyrapone treatment was due to increase β-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-1β. Overall, data reveal that stress exposure in male rats affects the regulation of brain IL-1β by the norepinephrineβ-AR pathway, while stress had no effect in the regulation of brain IL-1β in female rats.

HighlightsSynapsin I was localized in the human sperm equatorial segment.Presence of synapsin I was confirmed by dot and Western blotting techniques.Treatment of sperm with anti-synapsin antibodies significantly decreased motility.

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