Quantitative and morphological analyses reveal microglia-specific neuroinflammation in brain regions linked to cognitive function in ovariectomized and chronic intermittent hypoxia-exposed female rats

Women affected by obstructive sleep apnea (OSA) face an increased risk of cognitive impairment and mood disorders, with emerging evidence suggesting that neuroinflammation plays a significant role in the pathophysiology. OSA causes intermittent hypoxia and activates the immune response in the brain. Additionally, menopause is a separate risk factor that can put women with OSA at an even higher risk of cognitive decline. Although neuroinflammation occurs in OSA, the underlying mechanisms of the neuroinflammatory response are not well understood, and it remains unknown whether ovarian hormones modify these mechanisms. To examine the impact of OSA and hormone status on neuroinflammation, we used a 7-day chronic intermittent hypoxia (CIH) and ovariectomy (OVX) to model OSA and hormone status in female rats, respectively. To examine neuroinflammation, we investigated changes in brain microglia and astrocyte morphology and the number of reactive cells. We used a comprehensive three-dimensional reconstruction and analysis of microglia and astrocytes to study the changes in the morphology of these cells. We focused on brain regions associated with cognitive function (CA1 of the dorsal hippocampus, medial prefrontal cortex - mPFC, caudate and putamen - CP). Specifically, immunofluorescence of Iba1 (microglia marker) and GFAP (astrocyte marker) was conducted, along with measuring indicators of glial reactivity (branching, complexity, cell size, and number of reactive cells). Our results found that there were CIH and hormone effects on neuroinflammation in these brain regions. Microglia activation was impacted by an interaction between CIH and hormone status in all regions examined. In contrast, astrocytes showed no reactivity in all regions examined, regardless of CIH or hormone status. These findings suggest that menopause and OSA may impact microglia remodeling in brain areas associated with cognitive function. Microglia-specific neuroinflammation may be part of early mechanisms that lead to the cognitive impairments observed in CIH and hormone loss in females.