Project Summary/Abstract
Early environmental and genetic influences exert significant effects on risk for Substance Use Disorders
(SUDs). Understanding precursors to SUDs, such as externalizing behavior, that come online prior to the
initiation of substances allows for earlier identification and potentially, ability to intervene on those phenotypes
before behaviors become disorders. This R34 application proposes to establish a bidirectional translational team
and generate preliminary data for an R01 application designed to identify both behavioral and genetic risk factors
for neurocognitive phenotypes that precede SUDs. Aim 1 will determine the extent to which early life environment
influences neurocognitive development and the relationship between neurocognitive development and adult
delay-discounting behavior. Aim 2 will identify genomic network signatures of early life resource scarcity from
publicly available datasets and determine the extent to which expression of identified hub genes is associated
with neurocognitive behavioral outcomes related to substance use disorder. Aim 3 will allow for generation of
polygenic risk scores for externalizing-related phenotypes in GWAS datasets and assess the extent to which
these polygenic risk scores predict precursors to SUD behaviors such as impulsivity in the ABCD Study. This
aim will also determine whether these aggregate genetic risk scores are moderated by aspects of environment
within the ABCD Study. Ultimately, the cross-species approach used here will provide support for an innovative
R01 that will leverage preliminary data generated by this study to assess the most influential early life moderators
of risk behavior development (identified in Aim 3) which can be systematically assessed in a preclinical
developmental behavioral framework (established in Aim 1) and mechanistically assessed through cutting-edge
neuroscience techniques focused on critical gene targets (identified in Aim 2). This project is strengthened by
the translational team with expertise in early life environmental factors impacting neurocognitive development
(Dr. Neigh), polygenic risk for externalizing phenotypes and substance use phenotypes in humans, structural
and longitudinal modeling (Dr. Bountress), neuroepigenetics of stress and addiction (Dr. Hamilton), and
translational rat models of drug addiction and neurocognitive behaviors (Dr. Banks). The research described
herein pairs sophisticated modeling via latent profile analyses (LPA) with animal data, proposes to aggregate
existing RNAseq datasets to identify candidate hub genes, and integrates approaches that encompass early life
resource manipulations, linking these conditions with measures of impulsivity using delay discounting in
adulthood.
