Research Spotlights: April 2021

Epigenetic mechanisms in the brain following early life stress increases vulnerability to lifelong stress

One third of individuals with depression are not adequately treated with current therapeutics, leading researchers to seek additional molecular targets for the treatment of depression. In a study funded by the NIMH, researchers used a mouse model to examine the molecular mechanism by which early life stress affects the brain’s reward system to increase susceptibility to depression in adulthood. Through unbiased proteomics approaches, the research team identified a molecular target and found that inhibition of this molecular event could in fact reverse the increased vulnerability to lifelong stress.

The brain’s reward system has been long studied for its role in gating the effects of stress and contributing to either susceptibility or resiliency to depression following early life stress. Using a mouse model, researchers examined the long-lasting changes in a specific cell type within one of the brain regions involved in the reward pathway, the nucleus accumbens, following chronic social defeat stress. The study focused on epigenetic modifications which are chemical changes in the activity of genes that can be triggered not by inherited DNA code, but by environmental exposure. In particular, researchers measured histone modifications, which have the power to change gene expression long after an initial insult, such as stress.

Using an unbiased proteomics approach, researchers scoured hundreds of epigenetic modifications that may mediate the effects of early-life stress in the nucleus accumbens. A previously unknown epigenetic mechanism—H3K79me2 (demethylation of Lysine 79 of Histone H3)—was found to be the epigenetic mechanism that mediated the lasting effect of early-life stress. To determine if modulation of this molecular event could change behavior, researchers examined the role of the epigenetic enzyme DOT1L which catalyzes H3K79me2. When researchers increased DOT1L in a specific cell type within the nucleus accumbens, this increased stress vulnerability for the mice, while decreasing DOT1L decreased stress vulnerability. These findings reveal a potential new molecular target for the treatment of depression which is urgently needed.

Hope K et al. 2021. Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons. Nature Neuroscience. doi: 10.1038/s41593-021-00814-8

Adverse birth outcomes are associated with evictions during pregnancy

More than 2 million families are evicted each year, a number which is likely to increase due to the economic effects of the COVID-19 pandemic once the various moratoriums against evictions are removed. In a recent study supported by the NICHD and other funding agencies, researchers examined the association of being exposed to any eviction action during pregnancy with infant birth outcomes. Previous studies have shown an association between eviction and housing instability with adverse birth and childhood health outcomes across the life span.

In this case-control study, the researchers compared birth outcomes of infants whose mothers were evicted during gestation with those whose mothers were evicted at other times. Infants born to mothers who were evicted in Georgia from January 1, 2000, to December 31, 2016, were examined in the study. The researchers identified 88,862 births to 45,122 mothers who experienced a total of 99,517 evictions during the study period. This included 10,135 births to women who had an eviction during pregnancy. Five metrics of neonatal health were assessed: birth weight, gestational age, outcomes for low birth weight (<2,500 g), premature births (gestational age <37.0 weeks), and infant death.

Compared with mothers who experienced eviction actions at other times, eviction during pregnancy was associated with worse birth outcomes, including lower infant birth weight, premature birth, and a trend of higher infant mortality. The association of eviction with birth weight was strongest in the second and third trimesters of pregnancy. These findings suggest that experiencing an eviction during pregnancy is associated with adverse birth outcomes, which have been previously shown to have lifelong and multigenerational consequences. Therefore, policies that help to ensure housing, social, and medical assistance to pregnant women at risk for eviction may improve infant health. Additionally, interventions that help to reduce maternal stress and increase infant care and bonding may also help to mitigate these negative outcomes. Importantly, the authors note that while the driver of these outcomes is not well understood, blame should not be placed on the mothers. A limitation of this study is that it demonstrates an association between eviction and birth outcomes, which is not necessarily a cause and effect relationship. However, these findings are consistent with previous research findings about the long-term effects of maternal stress on fetuses.

Himmelstein G, Desmond M. 2021. Association of Eviction with Adverse Birth Outcomes Among Women in Georgia, 2000 to 2016. JAMA Pediatr. 1:e206550. doi: 10.1001/jamapediatrics.2020.6550.

Life expectancy is falling for those without a college education

Race/ethnicity and education interact in complex ways—but how do these factors, in America, impact mortality? More specifically, how have returns on education (in terms of life expectancy) changed relative to race/ethnicity? In a study funded by the NIA, scientists examined how receiving a college education provides positive benefits for health and longevity.

The authors calculated life expectancy estimates using data from the National Vital Statistic System, the American Community Survey, and the Current Population Survey. Specifically, they focused on the average years of life left for U.S. Citizens between 25 and 75 using standard life table methods. Researchers found that life expectancy for those without a four-year degree, even prior to COVID-19, has been declining over time. More specifically, the change in period life expectancy between 25 and 75 in the U.S. population is confined to those without a four-year college degree. This decrease was found in both men and women and for both Black and white people.

The main conclusion of this study is that a college education confers advantages to individuals through broad economic processes in which the college degree is increasingly used to differentiate people in society. The authors could not determine whether those who were born outside of the U.S., compared to those who were native-born, had an increased mortality risk because the death certificates do not contain information on place of birth. It should also be noted that the data used by researchers was collected at the end of 2018, before the COVID-19 pandemic. Although the data to estimate COVID-19 nationally will likely not be available until the end of 2021, the authors suggest that the educational divide in mortality is likely to widen—specifically because those without a college education are more likely to be at risk through their occupations compared to those with a college education or above due to their ability to work remotely and safely.

Case A, Deaton A. 2021. Life expectancy in adulthood is falling for those without a BA degree, but as educational gaps have widened, racial gaps have narrowed. PNAS, 118 (11) e2024777118; doi: