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.
Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA.
Biol Sex Differ. 2022 Sep 30;13(1):54. doi: 10.1186/s13293-022-00463-x.
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.
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).
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.
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).
缺氧与妊娠并发症有关，如子痫前期、胎盘早剥和妊娠期睡眠呼吸暂停。妊娠期缺氧损伤会影响皮质和皮质下通路（如黑质纹状体通路）的大脑成熟。然而，宫内缺氧应激暴露对后代大脑成熟的长期影响尚不清楚，特别是在妊娠晚期暴露的影响。本研究的目的是通过关注黑质纹状体通路，确定妊娠晚期宫内缺氧对皮质下脑成熟发育编程的影响。
将处于妊娠期的长耳大白鼠从妊娠第 15-19 天（妊娠期 22-23 天）暴露于慢性间歇性缺氧或房间空气正常氧中。在两个关键时期评估雄性和雌性后代：青春期（出生后第 40-45 天）或成年早期（出生后第 60-65 天）。通过分析运动行为和黑质多巴胺能神经元细胞体，以及通过量化超声发声（USV）来检查（1）黑质纹状体通路的结构发育，来定量脑成熟。
本研究的主要发现是，宫内缺氧对后代皮质下脑成熟具有年龄和性别依赖性影响，通过对黑质纹状体通路的精细度产生不利影响，而对通路的结构发育没有任何影响。在青春期，雌性后代受到的影响比雄性后代更大，表现为 USV 叫声频率、啁啾 USV 叫声持续时间和简单 USV 叫声频率降低。相反，在成年早期，雄性后代受到的影响比雌性后代更大，表现为首次 USV 潜伏期延长、简单 USV 叫声强度降低和谐波 USV 叫声带宽增加。没有观察到宫内缺氧对黑质纹状体通路结构发育的影响。
这些新发现表明，妊娠期缺氧损伤会介导皮质和皮质下通路的发育编程，其中雄性后代比雌性后代表现出长期的不利影响。黑质纹状体通路等皮质和皮质下通路的成熟受损可能会增加神经精神障碍（如情绪障碍、认知功能障碍、大脑连接功能障碍）的风险。
