Induction of brain cytokines during times of stress has potent effects on altering behavior, mood, and cognitive functioning. Currently, it is unknown why exposure to some stressors such as tailshock and footshock elevate brain cytokines, while exposure to swim, predator odor, and restraint stress do not. Recent data indicate that brain noradrenergic signaling mediates brain cytokine production suggests magnitude of norepinephrine release during stress may be critical in initiating brain cytokine production. The aim of the current study was to investigate stress-induced brain cytokines between rat strains that differ in their magnitude of stress responsiveness as measured by brain norepinephrine and HPA responses. Sprague-Dawley and Fischer rats were placed in a restraint bag for 1h or 2h and sacrificed immediately following stressor termination. Exposure to restraint significantly elevated hypothalamic IL-1β and IL-1R2 mRNA after 1h and IL-1β protein after 2h in the high stress responsive Fischer rats, but not in Sprague-Dawley rats. IL-6, IL-1R1, Il-1RA and Cox-2 mRNA were not altered and neither was expression of any cytokines in the hippocampus or circulating cytokines in either strain. Administration of desipramine (a norepinephrine reuptake inhibitor) to Sprague-Dawley rats was sufficient either alone or in combination with stress to increase IL-1β mRNA in the hypothalamus and desipramine combined with stress was sufficient to increase IL-1R2 mRNA in the hypothalamus. These data support our hypothesis that there is a critical threshold of brain norepinephrine necessary to stimulate brain cytokines, which may help to explain why severe stressors are more commonly reported to induce brain cytokines. These data also suggest an organisms’ susceptibility to stress-induced brain cytokine production depends on responsiveness and regulation of noradrenergic neurons.

There is growing evidence that metabolic stressors increase an organism’s risk of depression. Chronic mild stress is a popular animal model of depression and several serendipitous findings have suggested that food deprivation prior to sucrose testing in this model is necessary to observe anhedonic behaviors. Here, we directly tested this hypothesis by exposing animals to chronic mild stress and used an overnight two bottle sucrose test (food ad libitum) on day 5 and 10, then food and water deprive animals overnight and tested their sucrose consumption and preference in a 1h sucrose test the following morning. Approximately 65% of stressed animals consumed sucrose and showed a sucrose preference similar to non-stressed controls in an overnight sucrose test, while 35% showed a decrease in sucrose intake and preference. Following overnight food and water deprivation the previously ‘resilient’ animals showed a significant decrease in sucrose preference and greatly reduced sucrose intake. In addition, we evaluated whether the onset of anhedonia following food and water deprivation corresponds to alterations in corticosterone, epinephrine, circulating glucose, or interleukin-1 beta expression in limbic brain areas. While all stressed animals showed adrenal hypertrophy and elevated circulating epinephrine, only stressed animals that were food deprived were hypoglycemic compared to food deprived controls. Additionally, food and water deprivation significantly increased hippocampus IL-1β while food and water deprivation only increased hypothalamus IL-1β in stress susceptible animals. These data demonstrate that metabolic stress of food and water deprivation interacts with chronic stressor exposure to induce physiological and anhedonic responses.

Zimomra ZR, Porterfield VM, Camp RM, Johnson JD. Time-dependent mediators of HPA axis activation following live Escherichia coli . Am J Physiol Regul Integr Comp Physiol 301: R1648-R1657, 2011. First published September 14, 2011 doi:10.1152/ajpregu.00301.2011.-The hypothalamus-pituitary-adrenal (HPA) axis is activated during an immune challenge to liberate energy and modulate immune responses via feedback and regulatory mechanisms. Inflammatory cytokines and prostaglandins are known contributors to HPA activation; however, most previous studies only looked at specific time points following LPS administration. Since whole bacteria have different immune stimulatory properties compared with LPS, the aim of the present studies was to determine whether different immune products contribute to HPA activation at different times following live Escherichia coli challenge. Sprague-Dawley rats were injected intraperitoneally with E. coli (2.5 ϫ 10 7 CFU) and a time course of circulating corticosterone, ACTH, inflammatory cytokines, and PGE2 was developed. Plasma corticosterone peaked 0.5 h after E. coli and steadily returned to baseline by 4 h. Plasma PGE2 correlated with the early rise in plasma corticosterone, whereas inflammatory cytokines were not detected until 2 h. Pretreatment with indomethacin, a nonselective cyclooxygenase inhibitor, completely blocked the early rise in plasma corticosterone, but not at 2 h, whereas pretreatment with IL-6 antibodies had no effect on the early rise in corticosterone but attenuated corticosterone at 2 h. Interestingly, indomethacin pretreatment did not completely block the early rise in corticosterone following a higher concentration of E. coli (2.5 ϫ 10 8 CFU). Further studies revealed that only animals receiving indomethacin prior to E. coli displayed elevated plasma and liver cytokines at early time points (0.5 and 1 h), suggesting prostaglandins suppress early inflammatory cytokine production. Overall, these data indicate prostaglandins largely mediate the early rise in plasma corticosterone, while inflammatory cytokines contribute to maintaining levels of corticosterone at later time points.corticosterone; prostaglandin; IL-6; indomethacin ACTIVATION OF THE hypothalamus-pituitary-adrenal (HPA) axis is one of the critical brain-mediated sickness responses that enhance survival of an organism during an immune challenge. The resulting elevation in circulating glucocorticoids, mainly cortisol in humans and corticosterone in mice and rats, liberate energy necessary to mount a fever and have numerous immunomodulatory effects that reduce the risk of septic shock and increase the chances of survival during infection (52, 53). For example, glucocorticoids suppress proinflammatory cytokines (2, 17, 34) and prostaglandin production (27, 38), stimulate anti-inflammatory cytokine production (16, 20), upregulate Fc receptors and major histocompatibility complex class II molecules on phagocytes (24), increase cell adhesion molecules on endothelial cells (57), enhance acute phase changes in t...

Memory formation is promoted by stress via the release of norepinephrine and stimulation of beta-adrenergic receptors (β-ARs). Previous data demonstrate that repeated stressor exposure increases norepinephrine turnover and β-AR signaling within the amygdala, which led to the hypothesis that some stress-induced behavioral changes are likely due to facilitated associative learning. To test this, Fischer rats were exposed to chronic mild stress for four days. On day 5, subjects (including non-stressed controls) were injected with the beta-blocker propranolol or vehicle prior to conditioning in an operant box (animals receive two mild foot shocks) or passive avoidance apparatus (animals received a foot shock upon entry into the dark chamber). Twenty-four hours later, subjects were returned to the operant box for measurement of freezing or returned to the passive avoidance apparatus for measurement of latency to enter the dark chamber. Subjects were also tested in an open field to assess context-independent anxiety-like behavior. Animals exposed to chronic stress showed significantly more freezing behavior in the operant box than did controls, and this exaggerated freezing was blocked by propranolol during the conditioning trial. There was no effect of stress on behavior in the open field. Unexpectedly, retention latency was significantly reduced in subjects exposed to chronic stress. These results indicate that chronic exposure to stress results in complex behavioral changes. While repeated stress appears to enhance the formation of fearful memories, it also results in behavioral responses that resemble impulsive behaviors that result in poor decision-making.

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