Controlled Cortical Impact Traumatic Brain Injury Acutely Disrupts Wakefulness and Extracellular Orexin Dynamics as Determined by Intracerebral Microdialysis in Mice

摘要

Among other deficits, traumatic brain injury (TBI) causes impaired arousal and cognitive dysfunction. Hypothalamic orexin neuropeptides (also called hypocretins) regulate levels of arousal, and cerebrospinal fluid orexin levels are reportedly low in TBI patients. We hypothesized that TBI acutely impairs the dynamics of orexin release into brain interstitial fluid, and that these extracellular orexin levels correlate with wakefulness and motor activity. To test this in mice, we combined an electromagnetic controlled cortical impact (CCI) model of experimental TBI with dual intracerebral microdialysis using one catheter in the hypothalamus and one catheter in the hippocampus, plus electroencephalography/electromyography (EEG/EMG), and motor activity monitoring. Baseline data were continuously collected in tethered but relatively freely moving mice for 2 days. Then, ipsilateral CCI or sham surgery was performed, and data collection was continued for 3 additional days. At baseline, extracellular orexin levels in the hypothalamus showed a circadian rhythm, with peak levels during the dark (wake) phase, and a nadir during the light (rest) phase. Following CCI but not sham surgery, orexin levels were depressed in both the hypothalamus and hippocampus, and diurnal fluctuation amplitudes were blunted in the hypothalamus. At baseline, correlations of orexin with wakefulness and motor activity were positive and highly significant. Following CCI but not sham surgery, the mice exhibited reduced wakefulness and motor activity, and correlations between orexin and these measures were diminished. These abnormal orexin dynamics were associated with hypothalamic astrogliosis, but not acute loss of orexin neurons, as assessed by immunohistochemistry 3 days after injury. Future studies involving experimental manipulations of the orexin system will be required to determine its contribution to neurological outcomes following injury.