Sex and age differences in social and cognitive function in offspring exposed to late gestational hypoxia

dc.creatorMabry, Steveen_US
dc.creatorWilson, E. Nicoleen_US
dc.creatorBradshaw, Jessica L.en_US
dc.creatorGardner, Jennifer J.en_US
dc.creatorFadeyibi, Oluwadarasimien_US
dc.creatorVera Jr., Edwarden_US
dc.creatorKaramichos, Dimitriosen_US
dc.creatorGoulopoulou, Stylianien_US
dc.creatorCunningham, Rebecca L.en_US
dc.creator.orcid0000-0003-0719-8059 (Mabry, Steve)
dc.description.abstractBackground: Gestational sleep apnea affects 8-26% of pregnancies and can increase the risk for autism spectrum disorder (ASD) in offspring. ASD is a neurodevelopmental disorder associated with social dysfunction, repetitive behaviors, anxiety, and cognitive impairment. To examine the relationship between gestational sleep apnea and ASD, we used a chronic intermittent hypoxia (CIH) protocol between gestational days (GD) 15-19 in pregnant rats to model gestational sleep apnea during the third trimester of pregnancy. We hypothesized that late gestational CIH would produce sex- and age-specific social, mood, and cognitive impairments in offspring. Methods: Timed pregnant Long-Evans rats were exposed to CIH or room air normoxia from GD 15-19. Behavioral testing of offspring occurred during either puberty or young adulthood. To examine ASD phenotype, we quantified ASD-associated behaviors (social function, repetitive behaviors, anxiety-like behaviors, and spatial memory and learning), hippocampal activity (glutamatergic NMDA receptors, dopamine transporter, monoamine oxidase-A, neuronal activation, and neurogenesis), and circulating hormones in offspring. Results: Late gestational CIH induced sex- and age-specific differences in social, repetitive and memory functions in offspring. These effects were mostly transient and present during puberty. In female pubertal offspring, CIH impaired social function, increased repetitive behaviors, suppressed circulating estradiol but did not impact memory. In contrast, CIH impaired spatial memory and suppressed circulating estradiol in pubertal male offspring but did not impact social or repetitive functions. Long term effects of gestational CIH were only observed in female offspring, wherein CIH induced social disengagement and suppression of circulating estradiol during puberty was maintained in young adulthood. No effects of gestational CIH were observed on anxiety-like behaviors, hippocampal activity, circulating testosterone, or circulating corticosterone, regardless of sex or age of offspring. Conclusions: Our results indicate that hypoxia-associated pregnancy complications during the third trimester can increase the risk for ASD, such as pubertal social dysfunction, neuroendocrine suppression, and memory impairments. Current clinical recommendations support ASD screening for all children up to their 24-month checkup. Based on our findings, children from hypoxia-associated pregnancies should be screened for ASD throughout puberty.en_US
dc.description.sponsorshipThis study was supported by NIH R01 NS0091359 and UNTHSC Seed grant funding to RLC, NIH R01 HL146562-02S1 to SG, AHA 22PRE-900431 to JG, AHA 22POST-903250 to JB, NIH R25HL125447 to EVJ, and NIH T32 AG020494 to SM.en_US
dc.titleSex and age differences in social and cognitive function in offspring exposed to late gestational hypoxiaen_US