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

Abstract

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. The 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 patients 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 the normalization of sleep patterns, BBB functional recovery is a protracted process that merits further investigation.

The Interplay between Ferroptosis and Neuroinflammation in Central Neurological Disorders

“…Destruction of the endothelial cells of the blood-brain barrier leads to the invasion of peripheral immune cells into the brain at different stages of the disease [51]. These infiltrating peripheral cells further disrupt the integrity of the brain structure, harm neurons, and worsen the organic brain damage caused by neuroinflammation [52].…”

“…Most central nervous system diseases are associated with neuroinflammatory cascades, and the relationship between cerebral neuroinflammation and the blood-brain barrier is bidirectional. Neuroinflammation contributes to an increase in blood-brain barrier permeability due to various factors, while dysfunction of the blood-brain barrier leads to an amplification of the neuroinflammatory response [52]. At the core of this positive feedback loop is microglia, which can initiate inflammatory pathways following brain damage from diverse causes, impact the structure of BMECs, and disrupt the tight junctions of the blood-brain barrier through the release of inflammatory cytokines.…”

“…At the core of this positive feedback loop is microglia, which can initiate inflammatory pathways following brain damage from diverse causes, impact the structure of BMECs, and disrupt the tight junctions of the blood-brain barrier through the release of inflammatory cytokines. Once the cell-cell connections of the blood-brain barrier are compromised, the infiltration of peripheral immune cells and exogenous neurotoxic substances further stimulate microglia [52,197]. This sequence of events encompasses several classic inflammatory manifestations, including the release of TNF-α, IL-6, and IL-1β, as well as the transition of microglia from the M2 to M1 phenotype [198,199].…”

“…First, the chemokines and cytokines released by peripheral cells can directly breach the blood-brain barrier and activate the inflammatory response in the brain parenchyma [200]. Secondly, the infiltration of the peripheral immune cell barrier into the brain can lead to damage of the original neurovascular unit (NVU) [52]. Finally, the proinflammatory phenotypic changes in microglia are also directly or indirectly associated with the infiltration of peripheral cells [197].…”

“…In addition, the inflammatory effect of microglia is reflected in its role in mediating the death of other nerve cells within the central nervous system. Microglia can disrupt the blood-brain barrier by releasing pro-inflammatory factors that damage brain microvascular endothelial cells and tight junction proteins [52]. Microglia activated prior to astrocytes can influence astrocyte A1/A2 phenotypes through pro-inflammatory/anti-inflammatory factors, thereby influencing astrocyte outcomes [207].…”