Early life pain and its modulation by socioenvironmental factors: Implications for substance misuse

ABSTRACT
Roughly 10% of births in the United States are premature and typically involve a stay in the Neonatal Intensive
Care Unit (NICU), where infants endure painful procedures and periods of separation from their primary
caregiver. Premature births often occur in low socioeconomic status (SES) families. The NICU experience has
lasting effects on the brain and behavior, including increasing the risk of later developing substance use disorder
(SUD). This R34 will support the design of a better rat model of the NICU to begin to delineate mechanisms by
which this early adverse experience affects motivated behavior and the medial prefrontal cortex (mPFC), a key
node in the reward network that is affected by other early stressors. Manipulations of early pain are typically
used to model the NICU, but here we will include other aspects of the NICU experience by combining early pain
with socioenvironmental factors associated with premature birth: resource scarcity and separation from the
primary caregiver. A feature of the planned activities is a focus on translation: testing developmentally
appropriate motivated behaviors that occur cross-species, leveraging human imaging data to inform rat imaging
studies, and utilizing an external advisory committee to get input from a range of experts, including those who
study prenatal stress and early pain in humans. Aim 1 will first engage our advisory committee to optimize our
proposed design of the NICU model. Then, using a longitudinal design, we will determine the effects of early
pain vs. the NICU model (combined pain, low resources, and separation) vs. control conditions in male and
female rats on social behavior across development: juvenile play and social motivation in adolescents and adults.
Given many people begin experimenting with drugs by first using cannabis in adolescence, we will next develop
an adolescent tetrahydrocannabinol (THC) gummy self-administration procedure and begin to test if early pain
and/or the NICU model increases adolescent cannabis motivation compared to controls. Aim 2 will investigate
how the NICU model affects the cortical structure. We will leverage existing human neuroimaging data sets by
assessing how relevant variables (preterm birth, low SES) affect human cortical structure to guide our rat imaging
study design. Next, rat diffusion tensor imaging and 3D structural MRI will be used to assess changes in cortical
structure in juvenile, adolescent, and adult males and females following early pain, the NICU model, or control
rearing in a longitudinal design. Finally, we will engage in a hypothesis-generating activity by assessing DNA
methylation in the mPFC in adolescent rats following our early manipulations using cutting-edge long-read native
DNA sequencing for simultaneous profiling of 5mC, 5hmC, and 6mA in the same sample. This will reveal putative
mechanisms by which the NICU experience can have lasting consequences on mPFC development to be tested
in a subsequent R01. Together, the studies in this R34 will allow us to develop a more translational model of the
NICU experience and establish foundational data and an expert team to pursue future R01 proposals aimed at
identifying novel mechanisms by which a common form of adversity, a NICU stay, increases vulnerability to SUD.

Grant Number: 5R34DA061483-02
NIH Institute/Center: NIH
Principal Investigator: Debra Bangasser