Investigating the impact of adolescent social experiences on neurodevelopmental regulators of addiction susceptibility

The National Institute on Drug Abuse awarded The University of Chicago a $1.010 million cooperative agreement on April 15, 2026, under the Drug Use and Addiction Research Programs (CFDA 93.279) to investigate how social experiences during adolescence affect neurodevelopmental mechanisms regulating addiction susceptibility.

The research integrates behavioral assays, computational tools, drug self-administration studies, and single-cell genomic analyses in rats across adolescence and adulthood. Aim 1 identifies the developmental window in which decision-making functions are most sensitive to social experiences by assessing decision-making trajectories in socially isolated rats versus those housed at different adolescent ages. Aim 2 characterizes cocaine-taking behaviors to identify mechanisms responsible for elevated cocaine use in adult rats isolated during adolescence. Aim 3 identifies gene regulatory mechanisms within orbitofrontal circuits that are altered by adolescent social isolation and associated with greater addiction risk. The research tests the hypothesis that adolescent social isolation disrupts neurodevelopmental processes regulating orbitofrontal circuit development and decision-making functions central to addiction vulnerability.

Performance occurs in Illinois. The period of performance runs from the award date through January 31, 2031. The cooperative agreement obligated $1,010,328.

Abstract

Adolescence - the developmental stage between childhood and adulthood - is associated with robust neural and behavioral changes, including greater connectivity between brain regions that are involved in decision-making functions and increased sensitivity to social rewards. Social experiences that occur during adolescence can have a lasting effect on the individual, as adolescent social isolation is associated with impaired decision-making functions and greater drug use in adulthood. We, and others, hypothesize that isolation during adolescence disrupts the neurodevelopmental processes that regulate addiction susceptibility. The identity of these mechanisms, however, is not known. This proposal will determine how social isolation during key developmental periods disrupts gene regulatory mechanisms crucial for the development of orbitofrontal circuits that regulate decision-making and addiction susceptibility. To accomplish this goal, this proposal will integrate sophisticated behavioral assays with computational tools, drug self-administration, and single-cell genomic analyses across adolescence and adulthood in the RAT to identify the neurodevelopmental mechanisms that are altered by adolescent social isolation and associated with greater risk for drug use and addiction-like behaviors. In aim 1 we will identify the developmental window in which decision-making functions are most sensitive to social experiences by assessing decision-making trajectories in rats that are socially isolated or housed at different adolescent ages. We will then conduct the first in-depth characterization of cocaine-taking behaviors in aim 2 to identify the behavioral mechanism(s) responsible for the elevations in cocaine use observed in adult rats who were isolated during adolescence. Finally, in aim 3 we will identify the gene regulatory mechanisms within the amygdala-orbitofrontal circuit that are responsible for social isolation induced decision-making impairments using circuit-specific single-nucleus RNA-sequencing and single-nucleus DNA methylation sequencing. These innovative and integrative series of studies will generate a novel framework linking circuity-specific gene regulation with complex behaviors to understand how adolescent social experiences impacts the precise neurodevelopmental mechanisms that mediate addiction susceptibility.