Gestational hypoxia in late pregnancy differentially programs subcortical brain maturation in male and female rat offspring

Abstract

Background Hypoxia is associated with pregnancy complications, such as preeclampsia, placental abruption, and gestational sleep apnea. Hypoxic insults during gestation can impact the brain maturation of cortical and subcortical pathways, such as the nigrostriatal pathway. However, the long-term effects of in utero hypoxic stress exposure on brain maturation in offspring are unclear, especially exposure during late gestation. The purpose of this study was to determine the impact of gestational hypoxia in late pregnancy on developmental programming of subcortical brain maturation by focusing on the nigrostriatal pathway. Methods Timed pregnant Long–Evans rats were exposed to chronic intermittent hypoxia or room air normoxia from gestational day (GD) 15–19 (term 22–23 days). Male and female offspring were assessed during two critical periods: puberty from postnatal day (PND) 40–45 or young adulthood (PND 60–65). Brain maturation was quantified by examining (1) the structural development of the nigrostriatal pathway via analysis of locomotor behaviors and the substantia nigra dopaminergic neuronal cell bodies and (2) the refinement of the nigrostriatal pathway by quantifying ultrasonic vocalizations (USVs). Results The major findings of this study are gestational hypoxia has age- and sex-dependent effects on subcortical brain maturation in offspring by adversely impacting the refinement of the nigrostriatal pathway in the absence of any effects on the structural development of the pathway. During puberty, female offspring were impacted more than male offspring, as evidenced by decreased USV call frequency, chirp USV call duration, and simple call frequency. In contrast, male offspring were impacted more than female offspring during young adulthood, as evidenced by increased latency to first USV, decreased simple USV call intensity, and increased harmonic USV call bandwidth. No effects of gestational hypoxia on the structural development of the nigrostriatal pathway were observed. Conclusions These novel findings demonstrate hypoxic insults during pregnancy mediate developmental programming of the cortical and subcortical pathways, in which male offspring exhibit long-term adverse effects compared to female offspring. Impairment of cortical and subcortical pathways maturation, such as the nigrostriatal pathway, may increase risk for neuropsychiatric disorders (e.g., mood disorders, cognitive dysfunction, brain connectivity dysfunction).

Sex-dependent effects of chronic intermittent hypoxia: implication for obstructive sleep apnea

“…To examine the impact of sex on OSA-associated symptoms (inflammation, OS, memory, motor, anxiety, compulsivity), we utilized an experimental rat model of OSA called chronic intermittent hypoxia (CIH). CIH exposure replicates the fragmented episodes of hypoxia observed in OSA [ 52 ]. Further, to examine the mechanisms of mtOS on sex differences in CIH, we implanted osmotic pumps subcutaneously in a subgroup of rats to continuously administer a mitochondria-targeting superoxide dismutase mimetic, MitoTEMPOL (MT), to block mtOS.…”

“…During their sleep phase of the circadian cycle, CIH was performed for 8 h starting at 21:00. The CIH protocol consisted of intermittent oxygen reduction from 21% (room air) to 10% in 6-min cycles per hour (i.e., 10 cycles/h) over 8 h/day for a period of 14 days, as previously described [ 6 , 52 , 78 , 79 ]. 10 CIH cycles per hour results in an apnea–hypopnea index (AHI) of 10, which is consistent with mild sleep apnea in humans [ 31 , 79 ].…”

“…Fine motor function was assessed using a small novel open field arena (40.64 × 40.64 × 38.1 cm) with a bi-directional main field bar (San Diego Instruments Photobeam Activity System; Open Field Arena), as previously published [ 52 , 56 , 78 ]. To increase the difficulty of locomotion, a wire mesh platform elevated 2 cm above the floor was placed in the arena.…”

“…Individual rears were classified as either assisted or unassisted. These were defined by whether the animal reared with (assisted) or without (unassisted) its forelimbs braced against the wall [ 52 ].…”

Intermittent hypoxia-induced enhancement of sociability and working memory associates with CNTNAP2 upregulation

“…The impact of hypoxia on the brain’s development and function is also manifested in an age-dependent manner. Abundant evidence has shown that hypoxia exposure causes neurodevelopmental deficits in rats ( Moromisato et al, 1996 ; Wilson et al, 2022 ) and infants ( Wang et al, 2018 ; Dassios et al, 2022 ; Plomgaard et al, 2022 ) at prenatal and perinatal stages, contributes to brain myelin injury in adult mice ( Chen et al, 2021 ) and brain white matter injury in adult human ( Muttikkal and Wintermark, 2013 ), and exacerbates memory impairment in aging mice ( Sun et al, 2006 ) and human ( Park et al, 2013 ). However, few studies have addressed the impact of hypoxia on adolescents, especially brain functions during this developmental stage.…”