Chronic juvenile stress exacerbates neurobehavioral dysfunction and neuroinflammation following traumatic brain injury in adult mice

Abstract

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). Results Following 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. Conclusion Chronic stress in a juvenile mouse model 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.

Keywords

• unpredictable chronic mild stress
• controlled cortical impact
• neuroinflammation
• neurobehavior