Explicit memory, anxiety and depressive like behavior in mice exposed to chronic intermittent hypoxia, sleep fragmentation, or both during the daylight period

Puech, Clémentine; Badran, Mohammad; Runion, Alexandra R.; Barrow, Max B.; Qiao, Zhuanhong; Gozal, David

doi:10.1016/j.nbscr.2022.100084

Cited by 16 publications

(19 citation statements)

References 95 publications

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“…Sleep is a fundamental physiological function involved in the restoration of cellular and organ homeostasis and is essential for optimal daytime functioning [28,29]. Voluntary or imposed sleep deprivation or restriction has been extensively associated with neurobehavioral and cognitive deficits [22,50,58,[65][66][67], and several studies have suggested that such sleep deficits lead to BBB dysfunction and activation of inflammatory processes within the CNS, as illustrated by increased levels of proinflammatory cytokines and microglial activation [38,41,[68][69][70][71].…”

Section: Discussionmentioning

confidence: 99%

“…These processes can persist and even be amplified in a positive feedback loop, whereby microglia activation leading to increased inflammation and BBB disruption in turn leads to propagation and expansion of microglia activation [73,74]. Once the BBB is compromised, immune cells and potentially harmful substances such as toxins and pathogens can enter the brain, leading to incremental inflammation and brain cellular damage and apoptosis, a phenomenon that pertains to many neurodegenerative disorders such as Alzheimer disease and Parkinson disease [21,24,45,[75][76][77] We have previously shown that chronic SF mimicking the sleep disruption that characterizes moderate to severe patients with OSA induces increased oxidative stress in the brain that culminates in cognitive and behavioral deficits in mice [41,50,55,78]. Furthermore, subsequent studies further indicated that SF exposures induced increases in TNF-α levels in CNS which were critically involved in the increased sleep propensity that accompanies SF despite the absence of sleep deprivation in this experimental paradigm [41].…”

Section: Discussionmentioning

confidence: 99%

“…The SF device used to induce sleep disruption has been extensively described in previous studies [41,50,52,55,57,58]. Briefly, mice were housed in custom-designed cages containing an automatic horizontal bar sweeping immediately above the cage floor from one side to the other side of the cage.…”

Section: Sleep Fragmentation (Sf)mentioning

confidence: 99%

“…The total exploration time for both objects was recorded. Results were reported as preference score using the following formula [50,[58][59][60]:…”

Section: Novel Object Recognition (Nor) Testmentioning

confidence: 99%

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Cognitive Impairments, Neuroinflammation and Blood Brain Barrier Permeability in Mice Exposed to Chronic Sleep Fragmentation During the Daylight Period.

Puech¹,

Badran²,

Runion³

et al. 2023

Preprint

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Obstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH) and sleep fragmentation (SF). In murine models, chronic SF can impair endothelial function and induce cognitive declines. These deficits are likely mediated, at least in part, by alterations in Blood-Brain Barrier (BBB) integrity. Male C57Bl/6J mice were randomly assigned to SF or sleep control (SC) conditions for 4 or 9 weeks, and in a subset 2 or 6 weeks of normal sleep recovery. Presence of inflammation and microglia activation were evaluated. Explicit memory function was assessed with the novel object recognition (NOR) test, while BBB permeability was determined by systemic dextran-4kDA-FITC injection and Claudin 5 expression. SF exposures resulted in decreased NOR performance and in increased inflammatory markers and microglial activation as well as enhanced BBB permeability. Explicit memory and BBB permeability were significantly associated. BBB permeability remained elevated after 2 weeks of sleep recovery (p<0.01) and returned to baseline values only after 6 weeks. Chronic SF exposures mimicking the fragmentation of sleep that characterizes patient with OSA elicits evidence of inflammation in brain regions and explicit memory impairments in mice. Similarly, SF is also associated with increased BBB permeability, the magnitude of which is closely associated with cognitive functional losses. Despite normalization of sleep patterns, BBB functional recovery is a protracted process that merits further investigation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Sleep Fragmentation (Sf)mentioning

confidence: 99%

“…The total exploration time for both objects was recorded. Results were reported as preference score using the following formula [50,[58][59][60]:…”

Section: Novel Object Recognition (Nor) Testmentioning

confidence: 99%

See 2 more Smart Citations

Cognitive Impairments, Neuroinflammation and Blood Brain Barrier Permeability in Mice Exposed to Chronic Sleep Fragmentation During the Daylight Period.

Puech¹,

Badran²,

Runion³

et al. 2023

Preprint

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show abstract

“…The in ammatory, OS, and behavioral phenotypes of CIH in males are clearly de ned. CIH increases in ammation [6, 47, 48], increases OS [6, 49,50], impairs recollective memory [51][52][53], impairs spatial learning and memory [47,[54][55][56], and increases anxiety-like behavior [51,52,57,58]. Studies examining sex as a biological variable in CIH are scarce.…”

Section: Introductionmentioning

confidence: 99%

Sex-dependent effects of chronic intermittent hypoxia: Implication for obstructive sleep apnea

Mabry,

Bradshaw,

Gardner

et al. 2024

Preprint

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Background Obstructive sleep apnea (OSA) affects 10–26% of adults in the United States with known sex differences in prevalence and severity. OSA is characterized by elevated inflammation, oxidative stress (OS), and cognitive dysfunction. However, there is a paucity of data regarding the role of sex in the OSA phenotype. Prior findings suggest women exhibit different OSA phenotypes than men, which could result in under-reported OSA prevalence in women. To examine the relationship between OSA and sex, we used chronic intermittent hypoxia (CIH) to model OSA in rats. We hypothesized that CIH would produce sex-dependent phenotypes of inflammation, OS, and cognitive dysfunction, and these sex differences would be dependent on mitochondrial oxidative stress (mtOS). Methods Adult male and female Sprague Dawley rats were exposed to CIH or normoxia for 14 days to examine the impact of sex on CIH-associated circulating inflammation (IL-1β, IL-4, IL-6, IL-10, TNF-α), circulating OS, and behavior (recollective and spatial memory; gross and fine motor function; anxiety-like behaviors; and compulsive behaviors). A subset of rats was implanted with osmotic minipumps containing either a mitochondria-targeting antioxidant (MitoTEMPOL) or saline vehicle 1 week prior to CIH initiation to examine how inhibiting mtOS would affect the CIH phenotype. Results Sex-specific differences in CIH-induced inflammation, OS, motor function, and compulsive behavior were observed. In female rats, CIH increased inflammation (plasma IL-6 and IL-6/IL-10 ratio) and impaired fine motor function. Conversely, CIH elevated circulating OS and compulsivity in males. These sex-dependent effects of CIH were blocked by inhibiting mtOS. Interestingly, CIH impaired recollective memory in both sexes but these effects were not mediated by mtOS. No effects of CIH were observed on spatial memory, gross motor function, or anxiety-like behavior, regardless of sex. Conclusions Our results indicate that the impact of CIH is dependent on sex, such as an inflammatory response and OS response in females and males, respectively, that are mediated by mtOS. Interestingly, there was no effect of sex or mtOS in CIH-induced impairment of recollective memory. These results indicate that mtOS is involved in the sex differences observed in CIH, but a different mechanism underlies CIH-induced memory impairments.

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Long-term intermittent hypoxia induces anxiety-like behavior and affects expression of orexin and its receptors differently in the mouse brain

Tang

Shen

et al. 2023

Sleep Biol. Rhythms

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Explicit memory, anxiety and depressive like behavior in mice exposed to chronic intermittent hypoxia, sleep fragmentation, or both during the daylight period

Cited by 16 publications

References 95 publications

Cognitive Impairments, Neuroinflammation and Blood Brain Barrier Permeability in Mice Exposed to Chronic Sleep Fragmentation During the Daylight Period.

Cognitive Impairments, Neuroinflammation and Blood Brain Barrier Permeability in Mice Exposed to Chronic Sleep Fragmentation During the Daylight Period.

Sex-dependent effects of chronic intermittent hypoxia: Implication for obstructive sleep apnea

Long-term intermittent hypoxia induces anxiety-like behavior and affects expression of orexin and its receptors differently in the mouse brain

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