Objective Hypoxic ischemia (HI) is a secondary insult that can cause fatal neurologic outcomes after traumatic brain injury (TBI), ranging from mild cognitive deficits to persistent vegetative states. We here aimed to unravel the underlying pathological mechanisms of HI injury in a TBI mouse model.Methods Neurobehavior, neuroinflammation, and oxidative stress were assessed in a mouse model of controlled cortical impact (CCI) injury followed by HI. Mice underwent CCI alone, CCI followed by HI, HI alone, or sham operation. HI was induced by one-vessel carotid ligation with 1 hour of 8% oxygen in nitrogen. Learning and memory were assessed using the novel object recognition test, contextual and cued fear conditioning, and Barnes maze test. Brain cytokine production and oxidative stress-related components were measured.Results Compared to TBI-only animals, TBI followed by HI mice exhibited significantly poorer survival and health scores, spatial learning and memory in the Barnes maze test, discrimination memory in the novel object recognition test, and fear memory following contextual and cued fear conditioning. Malondialdehyde levels were significantly lower, whereas glutathione peroxidase activity was significantly higher in TBI followed by HI mice compared to TBI-only and sham counterparts, respectively. Interleukin-6 levels were significantly higher in TBI followed by HI mice compared to both TBI-only and sham animals.Conclusion Post-traumatic HI aggravated deficits in spatial, fear, and discrimination memory in an experimental TBI mouse model. Our results suggest that increased neuroinflammation and oxidative stress contribute to HI-induced neurobehavioral impairments after TBI.

Objective Chronic stress in adolescence may affect brain maturation and predispose individuals to psychiatric disorders in adulthood. However, whether chronic juvenile stress influences vulnerability to nonpsychiatric brain injuries, such as traumatic brain injury (TBI), remains unclear. Therefore, we hypothesized that juvenile stress-related neuronal circuit disturbances could aggravate brain damage following TBI in adulthood.Methods For chronic stress, we used an unpredictable chronic mild stress (UCMS) procedure for 5 weeks in adolescent mice. This was followed by a controlled cortical impact (CCI) injury to evaluate the influence of chronic juvenile stress on brain damage progression following TBI in adult mice. Mice underwent UCMS alone, UCMS followed by CCI, CCI alone, or sham operation. We characterized neurobehavioral deficits (Barnes maze, open field, and light-dark tests), neuroinflammation (ionized calcium-binding adapter molecule 1 [Iba-1], glial fibrillary acidic protein [GFAP], and neuron-specific nuclear protein [NeuN] immunoreactivity), and apoptosis (B-cell lymp [Bcl-2], Bcl-2-associated X protein [Bax], and procaspase-3 immunoreactivity). ResultsFollowing CCI, mice exposed to UCMS showed decreased spatial learning and memory in the Barnes maze test compared with unstressed mice. A significant increase in Iba-1, GFAP, and Bax/Bcl-2 immunostaining levels was observed in the mice exposed to UCMS followed by CCI compared with the CCI-only mice. In contrast, a significant decrease in NeuN immunostaining levels was observed in the UCMS with CCI group compared with the CCI alone group.Conclusions Chronic stress in adolescence aggravates neurobehavioral impairments and potentiates glial reactivity, neuronal injury, and apoptosis following moderate-to-severe TBI that occurs in adulthood. The present study suggests that juvenile chronic stress may influence poor outcomes following TBI in later adulthood.