6/8 NADIA U01 Adolescent Alcohol and Prefrontal Cortical Function in the Adult

PROJECT SUMMARY
The consumption and abuse of alcohol during adolescence is a serious public health problem. In this age
group, alcohol is often consumed in large quantities within repeated binge-like episodes that result in high levels
of intoxication. In addition to legal ramifications and concerns with physical safety, these patterns of alcohol
consumption appear to adversely impact continued brain and behavioral maturation during the transition from
adolescence to adulthood. The prefrontal cortex (PFC) controls higher-order cognitive functions such as
working-memory and behavioral flexibility. Adolescence represents a critical period of refinement of PFC
neurocircuitry that supports maturation of executive cognitive functioning. This research component of the
NADIA consortium will test the overarching hypothesis that AIE-induced deficits in cognitive control in adulthood
are associated with alterations in DA neurotransmission in the PFC. This hypothesis is based upon previous
studies demonstrating AIE-induced deficits in PFC-mediated behaviors and alterations in expression and
function of prefrontal DA. The proposed studies are designed to establish a direct link between AIE-induced
altered DA signaling and behavioral impairments, and further test the hypothesis that epigenetic alterations in
gene expression are a primary mechanism underlying AIE-induced cognitive deficits. The proposed studies
involve the following four specific aims: Aim 1 will test the hypothesis that alterations in activity of DA D1
receptor-expressing neurons in the mPFC contribute to AIE-induced deficits in behavioral flexibility. Aim 2 will
test the hypothesis that DNA hypermethylation in the mPFC underlies AIE-induced cognitive deficits. Aim 3
will test the hypothesis that normalization of DNA hypermethylation will reverse AIE-induced alterations in
structural plasticity in the mPFC. Aim 4 will test the hypothesis that AIE disrupts the in-growth of VTA-DA axons
from the nucleus accumbens to the mPFC. These studies involve an innovative and multidisciplinary set of
experiments that utilize state-of-the-art methodologies and procedures. Together, these studies will yield novel
and exciting new findings and will significantly advance our understanding of the effect of adolescent alcohol
exposure on cognitive function and behavioral control in the adult, and identify novel therapeutic approaches
for treatment.

Grant Number: 5U01AA019967-15
NIH Institute/Center: NIH
Principal Investigator: L Chandler