PMID- 36175941 OWN - NLM STAT- MEDLINE DCOM- 20221003 LR - 20221118 IS - 2042-6410 (Electronic) IS - 2042-6410 (Linking) VI - 13 IP - 1 DP - 2022 Sep 30 TI - Gestational hypoxia in late pregnancy differentially programs subcortical brain maturation in male and female rat offspring. PG - 54 LID - 10.1186/s13293-022-00463-x [doi] LID - 54 AB - 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). CI - (c) 2022. The Author(s). FAU - Wilson, E Nicole AU - Wilson EN AD - Department of Pharmaceutical Sciences, UNT System College of Pharmacy, School of Pharmacy, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX, 76107, USA. FAU - Mabry, Steve AU - Mabry S AD - Department of Pharmaceutical Sciences, UNT System College of Pharmacy, School of Pharmacy, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX, 76107, USA. FAU - Bradshaw, Jessica L AU - Bradshaw JL AD - Department of Pharmaceutical Sciences, UNT System College of Pharmacy, School of Pharmacy, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX, 76107, USA. FAU - Gardner, Jennifer J AU - Gardner JJ AD - Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA. AD - Department of Pharmaceutical Sciences, UNT System College of Pharmacy, School of Pharmacy, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX, 76107, USA. FAU - Rybalchenko, Nataliya AU - Rybalchenko N AD - Department of Pharmaceutical Sciences, UNT System College of Pharmacy, School of Pharmacy, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX, 76107, USA. FAU - Engelland, Rachel AU - Engelland R AD - Department of Pharmaceutical Sciences, UNT System College of Pharmacy, School of Pharmacy, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX, 76107, USA. FAU - Fadeyibi, Oluwadarasimi AU - Fadeyibi O AD - Department of Pharmaceutical Sciences, UNT System College of Pharmacy, School of Pharmacy, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX, 76107, USA. FAU - Osikoya, Oluwatobiloba AU - Osikoya O AD - Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA. FAU - Cushen, Spencer C AU - Cushen SC AD - Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA. AD - Texas College of Osteopathic Medicine, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA. FAU - Goulopoulou, Styliani AU - Goulopoulou S AD - Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA. AD - Department of Basic Sciences, Lawrence D. Longo, MD Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA, 92350, USA. FAU - Cunningham, Rebecca L AU - Cunningham RL AUID- ORCID: 0000-0001-5984-5516 AD - Department of Pharmaceutical Sciences, UNT System College of Pharmacy, School of Pharmacy, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX, 76107, USA. rebecca.cunningham@unthsc.edu. LA - eng GR - T32 AG020494/AG/NIA NIH HHS/United States GR - NS0091359/NS/NINDS NIH HHS/United States GR - R01 HL146562/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20220930 PL - England TA - Biol Sex Differ JT - Biology of sex differences JID - 101548963 SB - IM MH - Animals MH - Brain/metabolism MH - Female MH - Humans MH - Hypoxia/complications/metabolism MH - Male MH - Placenta/metabolism MH - Pregnancy MH - *Prenatal Exposure Delayed Effects MH - Rats MH - Rats, Long-Evans MH - Rats, Sprague-Dawley PMC - PMC9524087 OTO - NOTNLM OT - Chronic intermittent hypoxia OT - Oxidative stress OT - Prenatal programming OT - Sex differences OT - Substantia nigra OT - Ultrasonic vocalizations COIS- The authors declare that they have no competing interests. EDAT- 2022/09/30 06:00 MHDA- 2022/10/04 06:00 PMCR- 2022/09/30 CRDT- 2022/09/29 23:51 PHST- 2022/07/20 00:00 [received] PHST- 2022/09/22 00:00 [accepted] PHST- 2022/09/29 23:51 [entrez] PHST- 2022/09/30 06:00 [pubmed] PHST- 2022/10/04 06:00 [medline] PHST- 2022/09/30 00:00 [pmc-release] AID - 10.1186/s13293-022-00463-x [pii] AID - 463 [pii] AID - 10.1186/s13293-022-00463-x [doi] PST - epublish SO - Biol Sex Differ. 2022 Sep 30;13(1):54. doi: 10.1186/s13293-022-00463-x.