Biology subjects

Cristancho, A. G.

Publications and source records attributed to Cristancho, A. G..

3 recordsLinked to original sources

bioRxiv2025

Chromatin Disruption After Prenatal Hypoxia Predicts Lasting Neuron Deficits

Prenatal exposure to transient hypoxia can result in various developmental disabilities presumably by disrupting normal neurodevelopmental processes, even in milder injuries without detectable cell death or structural damage1,2. Emerging evidence suggests that disruption of the epigenome may be one of the most critical consequences of prenatal brain exposure to hypoxia3-8. However, the cell-type-selective effects of hypoxia on the developing brains transcriptome and epigenome remain unknown. Here, we demonstrate that immediately after hypoxia, transcriptional and chromatin disruptions occur in all cell types, consistent with the energy deficit dynamics caused by prenatal hypoxia. Unexpectedly, we identify a selective dissociation of transcriptional and chromatin regulation in glutamatergic neurons after hypoxia. Genes neighboring sites of differential chromatin accessibility, but not differential gene expression, correlate with structural and functional deficits in glutamatergic neurons one month after the injury. Our approach reveals novel, shared, and cell-type-specific changes that reflect potential short- and long-term consequences of the hypoxic response. Together, these data provide insight into the mechanisms that lead to lasting changes in the epigenome following an injury to the developing brain, resulting in long-term functional deficits.

neuroscience↗

bioRxiv2022

Intrauterine inflammation leads to some sex and age-specific behavior and molecular differences in mice

BackgroundPrenatal inflammation is associated with long-term adverse neurobehavioral outcomes in exposed children. Sex-specific differences in behavior have been observed in anxiety and learning; however, whether these differences manifest differently by age is unknown. This study assesses possible behavioral changes from in utero inflammation as a function of age in neonatal, juvenile, and adult animals. We also tested if the observed behavioral differences correlated to neonatal sex-specific neurogenesis gene expression changes in the hippocampus to suggest a mechanism for observed behavioral differences. MethodsCD-1 timed pregnant dams were injected in utero with lipopolysaccharide (LPS, 50g/animal) or saline at embryonic day 15 (E15). Neonatal behavioral testing was performed on postnatal day (P) 5 on male and female pups born at term using the Ultrasonic Vocalization test (USV). Juvenile and mature animals of each sex were tested in Open Field (OF) and Barnes Maze (BM) on P28 and P67 (OF), and 32-36 and 70-75 (BM). A commercially available array designed to assess the expression of genes involved in mammalian neurogenesis was utilized for profiling gene expression in the hippocampal tissue isolated from LPS and saline-exposed P7 pups. ResultsThere were no differences in stress responses measured by neonatal USV between LPS- and saline-exposed groups of either sex. In contrast, exposure to prenatal inflammation caused a male-specific increase in anxiety in mature but not juvenile animals. Juvenile LPS-exposed females had decreased movement in OF that was not present in adult animals. In addition, we observed improved memory retrieval in response to in utero LPS in the juvenile animals of both sexes. However, there was an impairment of long-term memory in adult LPS-exposed females. Finally, gene expression analyses revealed that LPS induced sex-specific changes in genes involved in hippocampal neurogenesis. ConclusionsIntrauterine exposure to inflammation has age and sex-specific effects on anxiety and learning. These differences are not apparent in the neonatal period but begin to be evident in juvenile animals and evolve in adult animals. These sex-specific differences in learning may be correlated to sex-specific disruption of the expression of genes associated with neurogenesis in the hippocampus.

developmental biology↗

bioRxiv2021

Transient late gestation prenatal hypoxic insult results in functional deficits but not gross neuroanatomic deficits in mice

Intrauterine hypoxia is a common cause of brain injury in children resulting in a broad spectrum of long-term neurodevelopmental sequela, including life-long disabilities that can occur even in the absence of severe neuroanatomic damage. Postnatal hypoxia-ischemia rodent models are commonly used to understand the effects of ischemia and transient hypoxia on the developing brain. Postnatal models, however, have some limitations. First, they do not test the impact of placental pathologies on outcomes from hypoxia. Second, they primarily recapitulate severe injury because they provoke substantial cell death, which is not seen in children with mild hypoxic injury. Lastly, they do not model preterm hypoxic injury. Prenatal models of hypoxia in mice may allow us to address some of these limitations to expand our understanding of developmental brain injury. The published rodent models of prenatal hypoxia employ multiple days of hypoxic exposure or complicated surgical procedures, making these models challenging to perform consistently in mice. Furthermore, large animal models suggest that transient prenatal hypoxia without ischemia is sufficient to lead to significant functional impairment to the developing brain. However, these large animal studies are resource-intensive and not readily amenable to mechanistic molecular studies. Therefore, here we characterized the effect of late gestation (embryonic day 17.5) transient prenatal hypoxia (5% inspired oxygen) on long-term anatomical and neurodevelopmental outcomes in mice. Late gestation transient prenatal hypoxia increased hypoxia-inducible factor 1 alpha protein levels (a marker of hypoxic exposure) in the fetal brain. Hypoxia exposure predisposed animals to decreased weight at postnatal day 2, which normalized by day 8. However, hypoxia did not affect gestational age at birth, litter size at birth, or pup survival. No differences in fetal brain cell death or long-term gray or white matter changes resulted from hypoxia. Animals exposed to prenatal hypoxia did have several long-term functional consequences, including sex-dichotomous changes. Hypoxia exposure was associated with a decreased seizure threshold and abnormalities in hindlimb strength and repetitive behaviors in males and females. Males exposed to hypoxia had increased anxiety-related deficits, whereas females had deficits in social interaction. Neither sex developed any motor or visual learning deficits. This study demonstrates that late gestation transient prenatal hypoxia in mice is a simple, clinically relevant paradigm for studying putative environmental and genetic modulators of the long-term effects of hypoxia on the developing brain.

animal behavior and cognition↗