Effect of Gender on Chronic Intermittent Hypoxic Fosb Expression in Cardiorespiratory-Related Brain Structures in Mice

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.

Sex-specific vagal and spinal modulation of swallow and its coordination with breathing

“…Due to the strong evidence that PSR and other vagal feedback influences respiratory phase regulation, we hypothesized that loss of these important sensory feedback components would shift swallow occurrence more toward the inspiratory phase of the breathing cycle. Various studies have reported breathing-related sex differences such as respiratory rate [49], ventilatory responses to hypoxia and hypercapnia [49][50][51], prevalence of sleep apnea [52], cardiorespiratory homeostasis and neuroplasticity [53], and hormones (including progesterone, a respiratory stimulant) [54]. These differences lead us to suspect there may also be important sex-specific differences in swallow-breathing coordination.…”

Sex Differences of the Brain Structural Adaptation to Hypoxic Environment

“…In our previous study on sea-level residents after 4-week exposure on the Qinghai-Tibet Plateau, both males and females showed significant increases in cerebral iron deposition in the deep nuclei of brains, while the increased proportion of females (4%) was greater than males (2%) [17]. Baum et al [42] found that chronic intermittent hypoxia induced a higher Fosb gene expression in females than in males, reflecting stronger neuroplastic dynamics. (2) Secondly, these results suggest that females may have a better capacity to adapt to hypoxia.…”

Progesterone decreases apnoea and reduces oxidative stress induced by chronic intermittent hypoxia in ovariectomized female rats

“…Likewise, Prog or Prog's metabolite have also been identified as allosteric modulators of brain nicotinic (Bullock et al., 1997), 5‐HT (Wetzel et al., 1998), or glycine (Yevenes & Zeilhofer, 2011) receptors. Prog might also modulate the central respiratory output by altering neurochemical regulation in brainstem or hypothalamic nuclei that are involved in respiratory control, including orexinergic neurons (Loiseau, Casciato, Barka, Cayetanot, & Bodineau, 2019), or other brainstem nuclei that are activated in a sex‐specific pattern following exposure to CIH (Baum et al., 2018).…”