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Reversing effects of mistreatment

Animation by Jeffrey Chase and photo by Evan Krape

New UD study focuses on genetic impact and potential therapies

Life at any level leaves scars in its wake – the remnants of struggle, conflict and assorted mishaps. That's life as we all know it.

Research has shown that adversity can produce damage long after the bleeding has stopped or the traumatic event has ended. Mistreatment by a caregiver early in life, for example, is related to greater risk for cognitive impairment and psychiatric disorders later in life.

Now scientists are exploring the idea that changes in gene regulation and activity triggered by such mistreatment may be the cause of those later problems.

University of Delaware neuroscientist Tania Roth, a pioneer in the growing field known as behavioral epigenetics, already has shown that these changes occur in the brain with exposure to mistreatment.

Now she has received a $1.5 million, five-year grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development to study whether those molecular changes are a cause of the behavioral changes.

The study will focus on female rats and their young, but such a connection could have far-reaching implications for treatment of children who have suffered early-life adversity and for adults whose childhood suffering was never addressed.

The term "epigenetics" refers to changes in genetic activity caused by something outside the genetic code such as viruses, bacteria, exposure to toxic substances, dietary practices and other external factors including psychosocial stress.

Roth, who joined the University faculty in 2010, likens the epigenome to a computer's software and the genome to its hardware. They work together and interact, but they have different characteristics and objectives.

If you buy Apple products, for example, you are buying into a system that has many implications for the software available to you. The hardware is wired in a systemic way, as is the human genome. The software and applications work within that system to perform separate functions.

Just as virus software on a computer looks for aberrant coding sequences to identify security threats, scientists can look for unusual patterns in cellular development and genetic behavior to study how and why things go wrong.

Roth studies such development and behavior in rodent models to learn how adversity meddles with genetic function.

Specifically, she looks at how methyl groups – clusters of hydrocarbons – attach to strands of DNA, the genetic code that regulates cell life. Some genes have many methyl groups attached, some have few.

"It's very gene-specific," Roth said, "and context-specific."

Methyl groups act as signals along the genetic circuitry, turning genetic activity off and occasionally on in much the same way trail markers steer hikers down one path or another.

When that methylation goes wrong and methyl groups attach in unusual quantity or unexpected places – as they do in cancerous tumors, for example – it can scramble the genetic signals, deprive cells of necessary proteins and cause disorders.

Roth and her lab use a process called direct bisulfite sequencing to identify methyl clusters and track changes over time.

"There are a lot of changes at the epigenetic and behavioral levels that we don't see until adulthood," Roth said. In the rodent population, the cycle from embryo to adult is about 90 days, which allows researchers to track developmental changes relatively quickly.

In this study, Roth's lab focuses on how stress changes maternal behavior, the epigenome of offspring, and the way these offspring then raise their young.

Bedding material is a critical resource for these mothers, and insufficient supply is one of the stressors Roth's lab is studying.

In addition to studying those changes, she and her team will study the effect of pharmacological treatments designed to manipulate methyl groups. Can treatments prevent or rescue aberrant methylation? In turn, do these approaches change behavior?

Roth's lab is looking specifically at the BDNF gene, which provides the code for production of the BDNF (brain-derived neurotrophic factor) protein, critical to brain function. If the gene is prevented from that job and the cell is deficient in BNDF protein, neurons and cell-to-cell communication suffers.

Many drugs and behavioral therapies can target the epigenome, Roth said. If DNA methylation is causing these behavioral changes, treatments that can reprogram the epigenome may be critical to prevention and intervention efforts.

"There are no data that show you reach a point where you can't change anything," she said.

And that offers hope for many.

About the researcher

Tania Roth is an associate professor of psychological and brain sciences at the University of Delaware. She earned her bachelor of science degree at Roanoke College in 1998 and her doctoral degree at the University of Oklahoma, in the laboratory of Regina Sullivan. She did postdoctoral work in the laboratory of David Sweatt at the University of Alabama at Birmingham.

Roth has received a Young Investigator Award from the Brain and Behavior Research Foundation, the 2010 Ziskind-Somerfeld award from the Society of Biological Psychiatry, a 2015 Early Career Impact Award from the Federation of Associations in Behavioral and Brain Sciences, and the 2015 Gerard J. Mangone Young Scholars Award from the Francis Allison Society. She was elected a Kavli Fellow of the National Academy of Sciences in 2012.

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