Sleep fragmentation engages stress-responsive circuitry, enhances inflammation and compromises hippocampal function following traumatic brain injury.
HPA-axis
Neuroinflammation
Schaffer collateral
Sleep fragmentation
Stress
Traumatic brain injury
fear conditioning
glucocorticoid receptor
hippocampus
Journal
Experimental neurology
ISSN: 1090-2430
Titre abrégé: Exp Neurol
Pays: United States
ID NLM: 0370712
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
received:
31
08
2021
revised:
04
03
2022
accepted:
24
03
2022
pubmed:
1
4
2022
medline:
4
5
2022
entrez:
31
3
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35358498
pii: S0014-4886(22)00083-8
doi: 10.1016/j.expneurol.2022.114058
pmc: PMC9068267
mid: NIHMS1795384
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
114058Subventions
Organisme : NINDS NIH HHS
ID : R01 NS118037
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS112805
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG051902
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS109585
Pays : United States
Organisme : NINDS NIH HHS
ID : T32 NS105864
Pays : United States
Organisme : NIDCR NIH HHS
ID : T32 DE014320
Pays : United States
Organisme : NINDS NIH HHS
ID : F31 NS122471
Pays : United States
Organisme : NINDS NIH HHS
ID : P30 NS045758
Pays : United States
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
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