Traumatic brain injury in male mice confers altered hypothalamic neuroendocrine responses, microglial morphological remodeling, and augmented avoidance behavior after acute social stress.

A consequence of neuroinflammation after traumatic brain injury (TBI) is microglial priming and increased sensitivity to secondary challenges including stressors and infections. We investigated whether diffuse TBI was associated with hypothalamic microglial morphological remodeling and altered inflammatory and neuroendocrine responses to a stressor, Acute Social Defeat (ASD). Adult male mice were subjected to diffuse TBI (midline fluid percussion injury) and then were exposed to acute stress (ASD for 2 h) 14 days later. Mice that received both TBI and ASD had increased mRNA expression of several cytokines and chemokines (Il1b, Il6 and Ccl2), receptors (Tlr4 and Itgax) and inflammatory pathways (Nfkb1) in periventricular hypothalamus and the pituitary gland. In addition, neurohormones (Avp and Oxt) were increased by ASD in the TBI mice. CRH immunoreactivity in the hypothalamic paraventricular nucleus (PVN) increased 20 h after ASD in mice with TBI. In behavioral testing, ASD provoked aversion to new objects in the TBI mice. PVN microglial morphological analysis revealed decreased cell size and complexity in mice exposed to TBI and ASD, indicating that ASD and TBI converged to increase microglial morphological remodeling in the hypothalamus. Although these results do not demonstrate that TBI induces microglial priming and sensitization of the hypothalamic stress response, they support that diffuse TBI is associated with changes in the hypothalamus that contribute to an altered response to acute stress, including an amplified neuroinflammatory response, microglial morphological remodeling, alterations in hypothalamic neuroendocrine markers and avoidance-like/anxiety-like behavior. Thus, TBI represents a risk factor for disrupted responses to acute stressors.