TY  - JOUR
PY  - 2022//
TI  - Sleep fragmentation engages stress-responsive circuitry, enhances inflammation and compromises hippocampal function following traumatic brain injury
JO  - Experimental neurology
A1  - Tapp, Zoe M.
A1  - Cornelius, Sydney
A1  - Oberster, Alexa
A1  - Kumar, Julia E.
A1  - Atluri, Ravitej
A1  - Witcher, Kristina G.
A1  - Oliver, Braedan
A1  - Bray, Chelsea
A1  - Velasquez, John
A1  - Zhao, Fangli
A1  - Peng, Juan
A1  - Sheridan, John
A1  - Askwith, Candice
A1  - Godbout, Jonathan P.
A1  - Kokiko-Cochran, Olga N.
SP  - ePub
EP  - ePub
VL  - ePub
IS  - ePub
N2  - 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.<p />  <p>Language: en</p>
LA  - en
SN  - 0014-4886
UR  - http://dx.doi.org/10.1016/j.expneurol.2022.114058
ID  - ref1
ER  -