Epigenetic Restructuring of Human DNA following early-life stress

Nim Tottenham, Ph.D.

University of California, Los Angeles

Funded in October, 2012: $200000 for 3 years
LAY SUMMARY . BIOGRAPHY .

LAY SUMMARY

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Does early life stress create a pathway to brain changes associated with anxiety?

 Investigators will correlate MRI brain imaging with studies of stress-related gene alterations and anxiety behaviors to explore how early life stress may influence brain development and then mental health years later.

Prior animal and human studies have shown that early exposures to stress enlarge and increase activation of the brain’s amygdala andthat these changes are associated with anxiety behaviors. The amygdala isan early developing limbicsystem structure that is involved in emotional learning. Its cells have large numbers of “receptors” that take up stress hormones. Production of the hormone receptors, though, may be diminished bystress. Research indicates

that stress can promote “epigenetic” changes in DNAthat silence the genes that ordinarily produce hormone receptors.   The investigators hypothesize that children with ahistoryofearlylifestress

will have greater epigeneticmodifications; and, that these modifications will be associated with alteredlimbicsystemdevelopment that influences stress-induced anxiety behaviors.

They will test this hypothesis by correlating imaging, genetic, and behavioraldatafroma total of 250 children in two groups: one group consists of children who as infants were in an orphanage (stressful environment) but then adopted; the other group consists of children who have alwayslivedwiththeirbirthparents.Children in both groups range from ages 3-17, enabling the investigators to associate genetic, brain, andbehavioral changes seen during a 14 year timeframe. Building upon an NIH-fundedstudy of these children, investigators now will assess MRI and fMRI imaging that, respectively, views structural and functional development of the amygdala in the children that has occurred over this 14 yeartimeframe. Imaging data will be correlated with gene samples (taken from cheek swabs) to assess patterns of epigenetic changes that occurred over

this 14-year period; these findings will be correlated with behavioral tests measuring current levels of anxiety in the children. Investigators anticipate: 1) that children with an early life stress history will show evidence of genetic modification; and 2)that the genetic modifications will be associated with developmental alterations in the brain’s limbic system that mediate behavioral anxiety. .

Significance: Theresearchmayhelptoelucidate the process by which early life stress influences later mental health, and may identify critical stress-related vulnerable points in brain development that could be amenable to preventive (pharmacologic or behavioral)interventions.

INVESTIGATOR BIOGRAPHIES

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Nim Tottenham, Ph.D.

Nim Tottenham, Ph.D. (Assistant Professor of Psychology, University of California Los Angeles) studies the development of the human amygdala and its connections with cortical regions. She received her training at the University of Minnesota, with Dr. Charles Nelson and Dr. Megan Gunnar, and then at the Sackler Institute for Developmental Psychobiology, Weill Cornell Medical College under the mentorship of Dr. BJ Casey. Her program of research focuses on amygdala development from early childhood through adolescence and young adulthood. To better understand the role of environment influences on the amygdala, her work also examines development following exposure to early-life adversity. Her methods include structural and functional neuroimaging (magnetic resonance imaging), laboratory-based behavior, and physiological measures using both large cross-sectional and longitudinal designs. She is a recipient of the National Institute for Mental Health Biobehavioral Research Awards for Innovative New Scientists (BRAINS), designed to support the research and career development of outstanding early-stage scientists, which has supported much of this work. With funding from the Dana Foundation’s Brain and Immuno-Imaging program, Dr. Tottenham will examine how early-life stress alters human DNA structure as a means of shaping the development of neural structures involved in anxiety and emotion regulation.