REM sleep suppression after penetrating traumatic brain injury is associated with alterations in the supramammillary-hippocampal circuit.

Sleep-wake disturbances are among the most prevalent and persistent consequences of traumatic brain injury (TBI), yet the circuit mechanisms underlying post-traumatic alterations in rapid eye movement sleep (REM) and associated cortical oscillations remain incompletely understood. Previous work has shown that REM-associated theta oscillations are determined by a Supramammillary (SuM) - hippocampal vesicular glutamate transporter 2 (Vglut2) circuit. First, we examined whether severe focal penetrating TBI (pTBI) suppresses REM and REM-associated theta power. Secondly, we examined whether these changes are associated with alterations in hypothalamic neuropeptide systems and SuM-hippocampal glutamatergic signaling. Adult male Sprague-Dawley rats (pTBI, n = 7; Sham, n = 6) were exposed to pTBI or sham procedures. After sham/TBI surgeries, EEG/EMG data was continuously sampled for 14 days by using telemetric implants, enabling analyses of sleep-wake states and cortical oscillations. At 14 days post injury, animals were sacrificed and brain tissue was sampled for immunohistochemical and in situ hybridization analyses. We analyzed orexin A (OXA) and melanin-concentrating hormone (MCH) in the lateral hypothalamus (LHA), Vglut2 in the SuM and hippocampus (CA2 and dentate gyrus), and nitric oxide synthase 1 (NOS1) in the SuM. pTBI resulted in reduced wakefulness during the light phase, increased non-REM sleep (NREM), and reduced REM. Power spectral density analyses of EEG data showed reduced theta (4-8 Hz) power during wake, REM, and NREM. Also, alpha (8-12 Hz) and sigma (12-16 Hz) reduced, in contrast to delta (1-4 Hz) power which increased across all vigilance states. Histological analyses showed reduced OXA and MCH in the LHA in pTBI animals. Similarly, Vglut2 transcript levels were reduced in the lateral SuM, and Vglut2 immunoreactivity was decreased in hippocampal CA2 and dentate gyrus. NOS1 expression in the SuM was not altered. Correlation analyses showed an association between the Vglut2 reduction in SuM hippocampal circuit and REM-theta oscillations. For the first time, we show that severe focal pTBI produces a sustained suppression of REM and REM associated theta oscillations, associated with decreased Vglut2 within the SuM-hippocampal circuit. These findings provide a framework linking SuM-hippocampal circuit dysfunction to post-traumatic REM sleep disturbances. Further research is needed to study potential causal effects of TBI on suppression of the SuM-hippocampal circuit and effects on hippocampal dependent cognitive functions.