Summary: A lack of oxygen as a result of preterm birth does not cause hippocampal neurons to die but does impair hippocampal development. Hypoxia causes hippocampal cells to fail to mature normally, causing a reduction in long-term potentiation and impaired learning.
Source: Oregon Health and Science University
Nearly 15 million babies are born prematurely, or before 37 weeks of pregnancy, around the world each year. When born too early, a baby’s immature respiratory center in the brain often fails to signal it to breathe, resulting in low oxygen levels, or hypoxia, in the brain.
Research published in the Journal of Neuroscience shows that even a brief 30-minute period of hypoxia is enough to persistently disrupt the structure and function of the brain region known as the hippocampus, which is vital for learning and memory.
“Our findings raise new concerns about the vulnerability of the preterm brain to hypoxia. They are concerning for the long-term impact that oxygen deprivation can have on the ability of these preterm babies to learn as they grow to school age and adulthood,” said the study’s principal investigator, Stephen Back, M.D., Ph.D., Clyde and Elda Munson Professor of Pediatric Research and Pediatrics, OHSU School of Medicine, OHSU Doernbecher Children’s Hospital.
In the neonatal intensive care unit, preemies can experience up to 600 short, but impactful periods of hypoxia each week. Consequently, more than one-third of babies who survive preterm birth are likely to have smaller brains, presumably due to brain cell loss, compared with the brains of full-term infants. This can increase the risk of significant life-long neurodevelopmental challenges that will affect learning, memory, attention and behavior.
Using a twin preterm fetal sheep model, Back and colleagues studied the impact of both hypoxia alone, as well as in combination with ischemia — or insufficient blood flow — on the developing hippocampus. The results confirm that, similar to human preterm survivors, growth of the hippocampus is impaired. However, brain cells do not die as previously believed. Rather, hippocampal cells fail to mature normally, causing a reduction in long-term potentiation, or the cellular basis of how the brain learns.
Remarkably, the severity of the hypoxia predicted the degree to which cells in the hippocampus failed to mature normally, explains Back. These findings are all the more unexpected because it was not appreciated that the preterm hippocampus was already capable of these learning processes.
“We want to understand next how very brief or prolonged exposure to hypoxia affects the ability for optimal learning and memory, ” says Back. “This will allow us to understand how the hippocampus responds to a lack of oxygen, creating new mechanisms of care and intervention both at the hospital, and at home.”
In addition to Back, OHSU researchers involved in the project include: Ev McClendon, Ph.D.; Kang Wang, Ph.D.; Kiera Degener-O’Brien; Matthew Hagen; Xi Gong, M.D.; Thuan Nguyen, M.D., Ph.D., Wendy Wu, Ph.D., and James Maylie, Ph.D.
Source:
Oregon Health and Science University
Media Contacts:
Tracy Brawley – Oregon Health and Science University
Image Source:
The image is in the public domain.
Original Research: Closed access
“Transient Hypoxemia Disrupts Anatomical and Functional Maturation of Preterm Fetal Ovine CA1 Pyramidal Neurons”. Evelyn McClendon, Kang Wang, Kiera Degener-O’Brien, Matthew W. Hagen, Xi Gong, Thuan Nguyen, Wendy W. Wu, James Maylie and Stephen A. Back.
Journal of Neuroscience. doi:10.1523/JNEUROSCI.1364-19.2019
Abstract
Transient Hypoxemia Disrupts Anatomical and Functional Maturation of Preterm Fetal Ovine CA1 Pyramidal Neurons
Children who survive premature birth often exhibit reductions in hippocampal volumes and deficits in working memory. However, it is unclear whether synaptic plasticity and cellular mechanisms of learning and memory can be elicited or disrupted in the preterm fetal hippocampus. CA1 hippocampal neurons were exposed to two common insults to preterm brain, transient hypoxia-ischemia (HI) and hypoxia (Hx). We employed a preterm fetal sheep model using both sexes in twin 0.65 gestation fetuses that reproduces the spectrum of injury and abnormal growth in preterm infants. Using Cavalieri measurements, hippocampal volumes were reduced in both Hx and HI fetuses compared to controls. This volume loss was not the result of neuronal cell death. Instead, morphometrics revealed alterations in both basal and apical dendritic arborization that were significantly associated with the level of systemic hypoxemia and metabolic stress regardless of etiology. Anatomical alterations of CA1 neurons were accompanied by reductions in probability of presynaptic glutamate release, long-term synaptic plasticity (LTP) and intrinsic excitability (IE). The reduction in IE was in part due to increased activity of the channels underlying the fast (fAHP) and slow (sAHP) component of the after-hyperpolarization in Hx and HI. Our studies suggest that even a single brief episode of hypoxemia can markedly disrupt hippocampal maturation. Hypoxemia may contribute to long-term working memory disturbances in preterm survivors by disrupting neuronal maturation with resultant functional disturbances in hippocampal action potential throughput. Strategies directed at limiting the duration or severity of hypoxemia during brain development may mitigate disturbances in hippocampal maturation.
SIGNIFICANCE STATEMENT
Premature infants commonly sustain hypoxia-ischemia, which results in reduced hippocampal growth and life-long disturbances in learning and memory. We demonstrate that the circuitry related to synaptic plasticity and cellular mechanisms of learning and memory (long term potentiation) are already functional in the fetal hippocampus. Unlike adults, the fetal hippocampus is surprisingly resistant to cell death from hypoxia-ischemia. However, the hippocampus sustains robust structural and functional disturbances in the dendritic maturation of CA1 neurons that are significantly associated with the magnitude of a brief hypoxic stress. Since transient hypoxic episodes occur commonly in preterm survivors, our findings suggest that the learning problems that ensue may be related to the unique susceptibility of the hippocampus to brief episodes of hypoxemia.
