Heritable variation in locomotion, reward sensitivity and impulsive behaviors in a genetically diverse inbred mouse panel

Abstract

Drugs of abuse, including alcohol and stimulants like cocaine, produce effects that are subject to individual variability, and genetic variation accounts for at least a portion of those differences. Notably, research in both animal models and human subjects point toward reward sensitivity and impulsivity as being trait characteristics that predict relatively greater positive subjective responses to stimulant drugs. Here we describe use of the eight collaborative cross (CC) founder strains and 38 (reversal learning) or 10 (all other tests) CC strains to examine the heritability of reward sensitivity and impulsivity traits, as well as genetic correlations between these measures and existing addiction‐related phenotypes. Strains were all tested for activity in an open field and reward sensitivity (intake of chocolate BOOST®). Mice were then divided into two counterbalanced groups and underwent reversal learning (impulsive action and waiting impulsivity) or delay discounting (impulsive choice). CC and founder mice show significant heritability for impulsive action, impulsive choice, waiting impulsivity, locomotor activity, and reward sensitivity, with each impulsive phenotype determined to be non‐correlating, independent traits. This research was conducted within the broader, inter‐laboratory effort of the Center for Systems Neurogenetics of Addiction (CSNA) to characterize CC and DO mice for multiple, cocaine abuse related traits. These data will facilitate the discovery of genetic correlations between predictive traits, which will then guide discovery of genes and genetic variants that contribute to addictive behaviors.

What Have We Learned (or Expect to) From Analysis of Murine Genetic Models Related to Substance Use Disorders?

“…Inbred strains also exhibit substantial and heritable differences in their cocaine responses, which include the extent of cocaine-induced locomotor activation (28,29), cocaine selfadministration (CSA) (30)(31)(32)(33); and SUD risk-related behaviors that include impulsivity, and sensitivity to drug reward (33). Of the various addiction-related phenotypes studied in mice, the gold standard is operant self-administration (34,35), where the subjects voluntarily and actively seek and consume drugs with rewarding properties.…”

“…The rate of CSA reflects the reinforcing potential of cocaine (36). The substantial differences in CSA among the inbred strains (30)(31)(32)(33) reflects their different propensities to abuse cocaine (37)(38)(39). There are obvious benefits from using a contingent model like CSA, since it more accurately recapitulates the drug-taking and drug-seeking behaviors of humans.…”

A Role for Serotonin in Modulating Opposing Drive and Brake Circuits of Impulsivity

“…However, impulsive behavior has many diverse presentations and complex neurobiological underpinnings ( Dalley and Robbins, 2017 ; Strickland and Johnson, 2021 ). Many lines of work have fractionated impulsivity into a number of different subtypes and components, with dissociable biological bases ( Winstanley et al, 2004 ; Robbins et al, 2012 ; Bari and Robbins, 2013 ; MacKillop et al, 2016 ; Dalley and Robbins, 2017 ; Nautiyal et al, 2017 ; Bailey et al, 2021 ). Impulsive choice is described as risky decision making, including discounting of delayed rewards.…”

Reversal Learning Phenotypes are Linked with Novel Genetic Loci in Diversity Outbred Mice

“…One procedure, called reversal learning, measures a subject's ability to suppress the response to a previously reinforced behavior when response-outcome contingencies unexpectedly change (Izquierdo & Jentsch, 2012). Reversal learning deficits are associated with drug use and SUDs, both in laboratory animals and human subjects, and therefore may be informative of biological factors that drive impulsivity and subsequent risk for SUDs (Calu et al, 2007;Camchong et al, 2011;Cervantes et al, 2013a;Gullo et al, 2010;Izquierdo & Jentsch, Reversal learning is influenced by genetic variation in rodent populations that can be utilized to map associated genetic loci (Bailey et al, 2021;Laughlin et al, 2011). Laboratory rodent populations offer some distinct advantages in forward genetic approaches.…”

“…High genetic diversity can expand phenotypic distributions and provide unique opportunities for discovery of variants that drive extreme phenotypes (Chesler, 2014). Reversal learning is heritable in CC strains and their founders (Bailey et al, 2021), indicating these populations may be suitable for genetic dissection of this trait. The DO mice may thus be utilized for relatively high-resolution QTL mapping studies.…”