Divergent risky decision-making and impulsivity behaviors in Lewis rat substrains with low genetic difference.

Abstract

Substance use disorder (SUD) is associated with a cluster of cognitive disturbances that engender vulnerability to ongoing drug seeking and relapse. Two of these endophenotypes—risky decision-making and impulsivity—are amplified in individuals with SUD and are augmented by repeated exposure to illicit drugs. Identifying genetic factors underlying variability in these behavioral patterns is critical for early identification, prevention, and treatment of SUD-vulnerable individuals. Here, we compared risky decision-making and different facets of impulsivity between two fully inbred substrains of Lewis rats—LEW/NCrl and LEW/NHsd. We performed whole genome sequencing of both substrains to identify almost all relevant variants. We observed substantial differences in risky decision-making and impulsive behaviors. Relative to LEW/NHsd, the LEW/NCrl substrain accepts higher risk options in a decision-making task and higher rates of premature responses in the differential reinforcement of low rates of responding task. These phenotypic differences were more pronounced in females than males. We defined a total of ∼9,000 polymorphisms between these substrains at 40× whole genome short-read coverage. Roughly half of variants are located within a single 1.5 Mb region of Chromosome 8, but none impact protein-coding regions. In contrast, other variants are widely distributed, and of these, 38 are predicted to cause protein-coding variants. In conclusion, Lewis rat substrains differ significantly in risk-taking and impulsivity and only a small number of easily mapped variants are likely to be causal. Sequencing combined with a reduced complexity cross should enable identification of one or more variants underlying multiple complex addiction-relevant behaviors.

Lateral Orbitofrontal Cortex Encodes Presence of Risk and Subjective Risk Preference During Decision-Making

“…The abridged version of RDT used here produced robust individual differences in risk preference, replicating previous observations with standard RDT 3,4,17–19,22,23,25,26,100 . Differences in subjective risk preference were accompanied by differences in risk and reward magnitude signaling in lOFC, and Random Forest choice classification using trial X trial neuronal data was sufficient to predict subjective risk preference.…”

“…Critically, the RDT consistently yields a wide range of individual risk-preferences similar to that observed in human populations 4,[15][16][17][18] , including a subpopulation of "risk-preferring" rats that demonstrate preference for risky rewards regardless of high probabilities of punishment 2,[19][20][21] . Despite showing no distinctions from the rest of the population in pain tolerance, weight, anxiety-like behavior, or gross measures of motivation 22 , risk-preferring rats exhibit several behavioral traits associated with vulnerability to SUD, including elevated cocaine self-administration 21,23 , nicotine sensitivity and resilience to nicotine-evoked anxiety 17 , sensitivity to reward-predictive cues 24 , and increased impulsive action 17,24,25 . Furthermore, risk-taking is associated with several neurobiological patterns including altered dopamine receptor expression in striatum and prefrontal cortex 21,22 and greater mesolimbic phasic dopamine release and autoreceptor function 17,21,23,26 .…”