TY - JOUR
T1 - Gestational hypoxia in late pregnancy differentially programs subcortical brain maturation in male and female rat offspring
AU - Wilson, E. Nicole
AU - Mabry, Steve
AU - Bradshaw, Jessica L.
AU - Gardner, Jennifer J.
AU - Rybalchenko, Nataliya
AU - Engelland, Rachel
AU - Fadeyibi, Oluwadarasimi
AU - Osikoya, Oluwatobiloba
AU - Cushen, Spencer C.
AU - Goulopoulou, Styliani
AU - Cunningham, Rebecca L.
N1 - Funding Information:
We would like to acknowledge UNTHSC Office of Vice President of Research for funding these studies.
Funding Information:
This 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, and NIH T32 AG020494 to SM.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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).
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).
KW - Chronic intermittent hypoxia
KW - Oxidative stress
KW - Prenatal programming
KW - Sex differences
KW - Substantia nigra
KW - Ultrasonic vocalizations
UR - http://www.scopus.com/inward/record.url?scp=85138979054&partnerID=8YFLogxK
U2 - 10.1186/s13293-022-00463-x
DO - 10.1186/s13293-022-00463-x
M3 - Article
C2 - 36175941
AN - SCOPUS:85138979054
SN - 2042-6410
VL - 13
JO - Biology of Sex Differences
JF - Biology of Sex Differences
IS - 1
M1 - 54
ER -