Intermittent Hypoxia Damages Tyrosine Hydroxylase-Containing Neurons in the Substantia Nigra and Locus Coeruleus but Not Hippocampal Neurons in Male Mouse Models of Early-Stage Sleep Apnea

Abstract

In sleep apnea, repeated hypovolemic ventilation or apnea in sleep leads to intermittent hypoxia (IH) of the brain. Thus, the impacts of sleep apnea on the brain need to be investigated. In this study, a mouse model with sleep-associated chronic IH and behavior tests was used to evaluate how IH impacts brain function and the expression of tyrosine hydroxylase (TH)-containing neurons in the substantia nigra, ventral tegmental area (VTA), and locus coeruleus. In an open-field test, mice subjected to chronic IH (5%–21% oxygen) for 10 and 20 days exhibited a significant decrease in spontaneous locomotor activity compared to the room air (RA, 21% oxygen) control mice. In the Y-maze test, the ability to recognize novel and familiar arms was similar between groups. In immunostaining of the brains of IH mice, TH-positive neurons in the substantia nigra, VTA, and locus coeruleus were significantly reduced compared to RA mice. Furthermore, in the brains of mice with decreased TH-positive neurons induced by IH, the expression of hippocampal neurons has not been affected. In the analysis of glial cells, in IH group mice, a significant increase of microglia was found in the substantia nigra, VTA, locus coeruleus, and hippocampus compared to the RA mice. These findings suggest that there is a loss of TH-containing neurons and neuronal inflammation in the substantia nigra, VTA, and locus coeruleus under chronic IH. Our findings provide precise evidence for the loss of TH-containing neurons in the setting of chronic IH mouse models, which can provide relevant empirical observations for clinicians.