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AbstractWe have reported differential short- and long-term dysregulation of the neuroendocrine stress response after traumatic brain injury (TBI) produced by controlled cortical impact (CCI). We have now investigated three possible mechanisms for this TBI-induced dysregulation: (1) effects on the sensitivity of negative-feedback systems to glucocorticoids; (2) effects on the sensitivity of pituitary corticotrophs to corticotropin-releasing hormone (CRH); and (3) effects on neuronal loss in the hilar region of the dentate gyrus and in the CA3b layer of the dorsal hippocampus. TBI was induced to the left parietal cortex in adult male rats with a pneumatic piston, at two different impact velocities and compression depths, to produce either moderate or mild CCI. At 7 and 35 days after surgery, the rats were injected SC with the synthetic glucocorticoid analog dexamethasone (DEX; 0.01, 0.10, or 1.00 mg/kg) or saline, and 2 h later were subjected to 30 min of restraint stress and tail vein blood collection. Whereas all doses of DEX suppressed corticosterone (CORT) and adrenocorticotropic hormone (ACTH) responses to stress on both days, CORT and ACTH were significantly more suppressed after 0.01 mg/kg DEX in the moderate TBI group than in the mild TBI or sham groups. At both 7 and 35 days post-TBI, CRH (1.0 and 10.0 μg/kg IP) stimulated CORT and ACTH in all rats, regardless of injury condition. Hippocampal cell loss was greatest at 48 days after moderate TBI. Enhanced sensitivity to glucocorticoid negative feedback and greater hippocampal cell loss, but not altered pituitary responses to CRH, contribute to the short- and long-term attenuation of the neuroendocrine stress response following moderate TBI. The role of TBI-induced alterations in glucocorticoid receptors in limbic system sites in enhanced glucocorticoid feedback sensitivity requires further investigation. [ABSTRACT FROM AUTHOR]

ABSTRACTHaving reported that traumatic brain injury (TBI), produced by moderate lateral controlled cortical impact (CCI), causes long-term dysregulation of the neuroendocrine stress response, the aim of this study was to assess short- and long-term effects of both moderate and mild CCI on stress-induced hypothalamic-pituitary-adrenal (HPA) function. TBI was induced to the left parietal cortex in adult male rats with a pneumatic piston, at two different impact velocities and compression depths to produce either a moderate or mild CCI. Controls underwent sham surgery without injury. Commencing at one week after recovery from surgery, rats were exposed to stressors: 30-min restraint (days 7, 34, and 70) or 15-min forced swim (days 21 and 54). Tail vein blood was analyzed for corticosterone (CORT) content by radioimmunoassay. On days 7 and 21, the stress-induced HPA responses were significantly attenuated by both mild and moderate CCI. Significant attenuation of the CORT response to stress persisted through day 70 after moderate CCI. In contrast, stress-induced CORT levels on days 34, 54, and 70 were significantly enhanced after mild CCI. Differential effects of injury severity were also observed on motor function in a forelimb test on post-injury day 12 and on cortical lesion volume and hippocampal cell loss at day 70, but not on working memory in a radial maze on day 15. The differing short- and long-term stress-induced HPA responses may be mediated by differential effects of moderate and mild CCI on the efficiency of glucocorticoid negative feedback or signaling among hypothalamic and extrahypothalamic components of the neuroendocrine stress-response system. [ABSTRACT FROM AUTHOR]