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Sleep. 2015 Oct 1;38(10):1537-46. doi: 10.5665/sleep.5042.

Chronic Intermittent Hypoxia Induces Chronic Low-Grade Neuroinflammation in the Dorsal Hippocampus of Mice.

Sapin E1,2, Peyron C3,4, Roche F5,6, Gay N3,4, Carcenac C1,7, Savasta M1,7, Levy P1,2,8, Dematteis M1,2,9.

Author information

1
Université Grenoble Alpes, Grenoble, F-38042, France.
2
INSERM U1042, Laboratoire HP2, Grenoble, F-38042, France.
3
INSERM U1028, CNRS UMR 5292, Lyon Neuroscience Research Center, Team SLEEP, F-69372, France.
4
Université Claude Bernard Lyon 1, Lyon, F-69372, France.
5
CHU, Hôpital Nord, Service de Physiologie Clinique et de l'Exercice, Saint-Etienne, F-42270, France.
6
Université Jean Monnet, Saint-Etienne, F-42023, France.
7
INSERM U836, Grenoble Institut des Neurosciences, équipe 10, Grenoble, F-38042, France.
8
CHU, Hôpital Michallon, Laboratoires du Sommeil et EFCR, Grenoble F-38043, France.
9
CHU, Hôpital Michallon, Addictologie, Pôle Pluridisciplinaire de Médecine, Grenoble F-38043, France.

Abstract

STUDY OBJECTIVES:

Obstructive sleep apnea (OSA) induces cognitive impairment that involves intermittent hypoxia (IH). Because OSA is recognized as a low-grade systemic inflammatory disease and only some patients develop cognitive deficits, we investigated whether IH-related brain consequences shared similar pathophysiology and required additional factors such as systemic inflammation to develop.

DESIGN:

Nine-week-old male C57BL/6J mice were exposed to 1 day, 6 or 24 w of IH (alternating 21-5% FiO2 every 30 sec, 8 h/day) or normoxia. Microglial changes were assessed in the functionally distinct dorsal (dH) and ventral (vH) regions of the hippocampus using Iba1 immunolabeling. Then the study concerned dH, as vH only tended to be lately affected. Seven proinflammatory and anti-inflammatory cytokine messenger RNA (mRNA) were assessed at all time points using semiquantitative real-time reverse transcription polymerase chain reaction (RT-PCR). Similar mRNA analysis was performed after 6 w IH or normoxia associated for the past 3 w with repeated intraperitoneal low-dose lipopolysaccharide or saline.

MEASUREMENTS AND RESULTS:

Chronic (6, 24 w) but not acute IH induced significant microglial changes in dH only, including increased density and morphological features of microglia priming. In dH, acute but not chronic IH increased IL-1β and RANTES/CCL5 mRNA, whereas the other cytokines remained unchanged. In contrast, chronic IH plus lipopolysaccharide increased interleukin (IL)-6 and IL10 mRNA whereas lipopolysaccharide alone did not affect these cytokines.

CONCLUSION:

The obstructive sleep apnea component intermittent hypoxia (IH) causes low-grade neuroinflammation in the dorsal hippocampus of mice, including early but transient cytokine elevations, delayed but long-term microglial changes, and cytokine response alterations to lipopolysaccharide inflammatory challenge. These changes may contribute to IH-induced cognitive impairment and pathological brain aging.

KEYWORDS:

hippocampus; inflammation; intermittent hypoxia; mice; microglia

PMID:
26085297
PMCID:
PMC4576327
DOI:
10.5665/sleep.5042
[Indexed for MEDLINE]
Free PMC Article

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