Abstract
We aimed to delineate sex-based differences in neuroplasticity that may be associated with previously reported sex-based differences in physiological alterations caused by repetitive succession of hypoxemia-reoxygenation encountered during obstructive sleep apnea (OSA). We examined long-term changes in the activity of brainstem and diencephalic cardiorespiratory neuronal populations induced by chronic intermittent hypoxia (CIH) in male and female mice by analyzing Fosb expression. Whereas the overall baseline and CIH-induced Fosb expression in females was higher than in males, possibly reflecting different neuroplastic dynamics, in contrast, structures responded to CIH by Fosb upregulation in males only. There was a sex-based difference at the level of the rostral ventrolateral reticular nucleus of the medulla, with an increase in the number of FOSB/ΔFOSB-positive cells induced by CIH in males but not females. This structure contains neurons that generate the sympathetic tone and which are involved in CIH-induced sustained hypertension during waking hours. We suggest that the sex-based difference in neuroplasticity of this structure contributes to the reported sex-based difference in CIH-induced hypertension. Moreover, we highlighted a sex-based dimorphic phenomenon in serotoninergic systems induced by CIH, with increased serotoninergic immunoreactivity in the hypoglossal nucleus and a decreased number of serotoninergic cells in the dorsal raphe nucleus in male but not female mice. We suggest that this dimorphism in the neuroplasticity of serotoninergic systems predisposes males to a greater alteration of neuronal control of the upper respiratory tract associated with the greater collapsibility of upper airways described in male OSA subjects.
Highlights
Obstructive sleep apnea (OSA) is a breathing dysfunction characterized by collapse of the upper airways from atonia of upper airway and tongue muscles in the presence of continued diaphragmatic efforts during sleep (Dempsey et al, 2010)
The proportion of FOSB/ FOSB-positive cells co-labeled for tyrosine hydroxylase (TH) in these catecholaminergic structures was relatively small, but was significantly higher than under sham conditions in the rostral part of the VLM (rVLM) (12.2 ± 6.4% vs. 1.0 ± 0.5%; p < 0.0001; Figures 5E–H) and caudal part of the VLM (cVLM) (6.5 ± 6.9 vs. 0.8 ± 1.2; p < 0.05), but unchanged in the SolC (≈5.2 vs. ≈0.4%) and SolM (≈0.6 vs. ≈0.7%)
This study significantly contributes to the knowledge of similarities and differences in the chronic intermittent hypoxia (CIH)-induced neuroplasticity between males and females, making it possible to highlight potential mechanisms behind the functional differences observed between women and men with OSA (O’Donnell et al, 2000; Jordan et al, 2004; Huang et al, 2008; Chin et al, 2012; Yu et al, 2014) and male and female rodents subjected to CIH (Hinojosa-Laborde and Mifflin, 2005; Skelly et al, 2012)
Summary
Obstructive sleep apnea (OSA) is a breathing dysfunction characterized by collapse of the upper airways from atonia of upper airway and tongue muscles in the presence of continued diaphragmatic efforts during sleep (Dempsey et al, 2010). The origin of this collapse is multifactorial, with an anatomical predisposition to airway closure, such as adipose soft tissue deposition or compromised craniofacial structures and/or non-anatomical features, such as upper. CIH has been reported to alter the density of serotonin (5-HT) and noradrenaline terminals in the hypoglossal nucleus (12N), which contains motoneurons that innervate upper airway and tongue muscles (Rukhadze et al, 2010), suggesting that CIH per se contributes to upper airway
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