The Detrimental Effects of Neonatal Hypoxic Ischemic Brain Injury: An Investigation of Behavioral Impairments and Anatomic Anomalies as Modulated by Sex and Intra-insult Hypothermia

Hypoxic ischemic (HI) brain injury is common among preterm infants and term infants with birth complications. HI reflects neuropathological sequelae that can include hemorrhage, reperfusion failure, birth trauma, prolonged labor, or placental abnormalities. Despite varied causes, a common array of cognitive and behavioral disorders follow HI (e.g., motor, memory, attention and language impairments). Males are also more likely to experience HI, and are more prone to negative outcomes. Yet research on sex differences in neonatal brain injury (i.e., employing and comparing both sexes) is scant in both clinical and animal work. Hypothermia is now routinely used for neuroprotection in term infants, but relative benefits by sex have not been investigated. The current studies focus on sex differences in response to experimentally induced HI (rat model), and the benefits of hypothermia for both sexes. Results confirm behavioral/neuropathological deficits in male HI rats, replicating prior findings. We also report that learning/memory deficits can be attenuated by gradual training, thus avoiding impulsive responses/increased errors when task demands are too high. We show that multiple co-occurring behavioral deficits do not correlate, and subjects with severe impairments in one domain may not be severely affected in another. This has clinical relevance in suggesting that “degree of initial injury” is a poor predictor of specific behavioral outcomes, and variability following seemingly comparable injury demands individualized prognosis. Finally, results confirm sex differences in response to an HI injury (males worse than females), although nosex differences were seen in gross neuropathology -- again undermining “degree of injury” as a sole basis for outcome prognosis. A similar pattern of sex differences were seen with hypothermia during HI, again confirming the importance of evaluating outcomes by sex. Finally, to explore the female advantage in HI outcomes in the memory domain, we assessed measures of hippocampal cellular layer thickness in the “uninjured” contralateral hemisphere of male and female HI rats. Results again showed sex differences, with different patterns of compensatory reorganization in the hippocampus for HI males and females. Cumulative results stress the importance of employing both sexes in neonatal HI research, and examining more multi-faceted predictors for long-term outcomes. In turn, clinicians may continue to optimize protective strategies, and enhance quality of life for infants affected by HI injury