Sex differences in Hippocampal Memory and Learning following Neonatal Brain Injury: Is There a Role for Estrogen Receptor-α?

Abstract

Neonatal encephalopathy due to hypoxia-ischemia (HI) leads to severe, life-long morbidities in thousands of neonates born in the USA and worldwide each year. Varying capacities of long-term episodic memory, verbal working memory, and learning can present without cerebral palsy and have been associated with the severity of neonatal encephalopathy sustained at birth. Among children who sustain a moderate degree of HI at birth, girls have larger hippocampal volumes compared to boys. Clinical studies indicate that female neonatal brains are more resistant to the effects of neonatal HI, resulting in better long-term cognitive outcomes compared to males with comparable brain injury. Our most recent mechanistic studies have addressed the origins and cellular basis of sex differences in hippocampal neuroprotection following neonatal HI-related brain injury and implicate estrogen receptor-α (ERα) in the neurotrophin receptor-mediated hippocampal neuroprotection in female mice. This review summarizes the recent findings on ERα-dependent, neurotrophin-mediated hippocampal neuroprotection and weighs the evidence that this mechanism plays an important role in preservation of long-term memory and learning following HI in females.

Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences

“…Sex differences in the distribution of ERs (Bourque et al, 2011), together with a different role of ER subtypes in brain plasticity, neuroprotection and repair in male and female neurons (Bryant and Dorsa, 2010; may participate in the generation of sex differences in the neuroprotective actions of estradiol. In addition, there are differences in ER signaling in the brain of males and females (Tabatadze et al, 2015;Oberlander and Woolley, 2016;Koss et al, 2018;Jain et al, 2019;Meitzen et al, 2019;Zafer et al, 2019), which are in part mediated by epigenetic modifications in ER encoding genes (Schwarz et al, 2010;Giatti et al, 2018) and micro RNAs (Giatti et al, 2018) and are also dependent on sexually differentiated interactions with the signaling mechanisms of other neuroprotective factors, such as BDNF (Scharfman and MacLusky, 2014), IGF-1 (Munive et al, 2016) or the endocannabinoid system (Tabatadze et al, 2015), which in turn also present sex differences in the brain. All these sexually differentiated molecular mechanisms cause different responses to estradiol in the brain of male and female animals (Tabatadze et al, 2015;Munive et al, 2016;Koss et al, 2018) and may determine sex differences in the neuroprotective actions of the hormone.…”

Long-Term Effects of Prenatal Severe Hypoxia on Central and Peripheral Components of the Glucocorticoid System in Rats

“…In particular, this leads to dysregulation of the systemic glucose metabolism, weakened immunity, and decreased regenerative potential [39, 40]. Epidemiological data suggest a link between the effects of stress hormones during prenatal or early postnatal development and a subsequent prevalence of cardiac, metabolic, autoimmune, neurological, and psychiatric disorders in humans [38, 41, 42]. It is important to note that symptoms of these diseases can also occur directly when one is exposed to high levels of glucocorticoids, which indicates their crucial role in the etiology of these diseases [22, 43].…”

White matter injury in the neonatal hypoxic‐ischemic brain and potential therapies targeting microglia

“…However, the mechanisms underlying the sex‐specific differences in ischemic damage are unknown. Some evidence indicates a protective effect of estrogen receptor α on long‐term memory and learning following H‐I in female mice (Zafer et al., 2019). Cell death in males is predominantly mediated by a poly(ADP‐ribose) polymerase pathway, resulting in apoptosis‐inducing factor release and translocation, as well as DNA breakage.…”