Sleep fragmentation engages stress-responsive circuitry, enhances inflammation and compromises hippocampal function following traumatic brain injury.

Traumatic brain injury (TBI) impairs the ability to restore homeostasis in response to stress, indicating hypothalamic-pituitary-adrenal (HPA)-axis dysfunction. Many stressors result in sleep disturbances, thus mechanical sleep fragmentation (SF) provides a physiologically relevant approach to study the effects of stress after injury. We hypothesize SF stress engages the dysregulated HPA-axis after TBI to exacerbate post-injury neuroinflammation and compromise recovery. To test this, male and female mice were given moderate lateral fluid percussion TBI or sham-injury and left undisturbed or exposed to daily, transient SF for 7- or 30-days post-injury (DPI). Post-TBI SF increases cortical expression of interferon- and stress-associated genes characterized by inhibition of the upstream regulator NR3C1 that encodes glucocorticoid receptor (GR). Moreover, post-TBI SF increases neuronal activity in the hippocampus, a key intersection of the stress-immune axes. By 30 DPI, TBI SF enhances cortical microgliosis and increases expression of pro-inflammatory glial signaling genes characterized by persistent inhibition of the NR3C1 upstream regulator. Within the hippocampus, post-TBI SF exaggerates microgliosis and decreases CA1 neuronal activity. Downstream of the hippocampus, post-injury SF suppresses neuronal activity in the hypothalamic paraventricular nucleus indicating decreased HPA-axis reactivity. Direct application of GR agonist, dexamethasone, to the CA1 at 30 DPI increases GR activity in TBI animals, but not sham animals, indicating differential GR-mediated hippocampal action. Electrophysiological assessment revealed TBI and SF induces deficits in Schaffer collateral long-term potentiation associated with impaired acquisition of trace fear conditioning, reflecting dorsal hippocampal-dependent cognitive deficits. Together these data demonstrate that post-injury SF engages the dysfunctional post-injury HPA-axis, enhances inflammation, and compromises hippocampal function. Therefore, external stressors that disrupt sleep have an integral role in mediating outcome after brain injury. • Traumatic brain injury (TBI) compromises stress responses to mechanical sleep fragmentation. • Post-TBI sleep fragmentation enhances inflammation associated with inhibition of NR3C1. • TBI alters agonist-induced glucocorticoid receptor activity in the hippocampus. • Sleep fragmentation impairs long-term potentiation after brain injury. • Post-TBI sleep fragmentation compromises hippocampal-dependent cognition. [ABSTRACT FROM AUTHOR]