Systems genetics of sensation seeking

Abstract

Sensation seeking is a multifaceted, heritable trait which predicts the development of substance use and abuse in humans; similar phenomena have been observed in rodents. Genetic correlations among sensation seeking and substance use indicate shared biological mechanisms, but the genes and networks underlying these relationships remain elusive. Here, we used a systems genetics approach in the BXD recombinant inbred mouse panel to identify shared genetic mechanisms underlying substance use and preference for sensory stimuli, an intermediate phenotype of sensation seeking. Using the operant sensation seeking (OSS) paradigm, we quantified preference for sensory stimuli in 120 male and 127 female mice from 62 BXD strains and the C57BL/6J and DBA/2J founder strains. We used relative preference for the active and inactive levers to dissociate preference for sensory stimuli from locomotion and exploration phenotypes. We identified genomic regions on chromosome 4 (155.236-155.742 Mb) and chromosome 13 (72.969-89.423 Mb) associated with distinct behavioral components of OSS. Using publicly available behavioral data and mRNA expression data from brain regions involved in reward processing, we identified (a) genes within these behavioral QTL exhibiting genome-wide significant cis-eQTL and (b) genetic correlations among OSS phenotypes, ethanol phenotypes and mRNA expression. From these analyses, we nominated positional candidates for behavioral QTL associated with distinct OSS phenotypes including Gnb1 and Mef2c. Genetic covariation of Gnb1 expression, preference for sensory stimuli and multiple ethanol phenotypes suggest that heritable variation in Gnb1 expression in reward circuitry partially underlies the widely reported relationship between sensation seeking and substance use.

Stimulus Complexity and Mouse Strain Drive Escalation of Operant Sensation Seeking Within and Across Sessions in C57BL/6J and DBA/2J Mice

“…The ability to easily and rapidly induce escalation or reduction in sensation seeking in genetically distinct mouse strains provides a strong model for discovery of the genetic mechanisms that distinguish controlled from uncontrolled reward-seeking which is a core feature of addiction (American Psychiatric Association, 2013). The study of sensation seeking is directly relevant to addiction because human, mouse and rat studies reveal that sensation seeking and drug and alcohol seeking are driven by shared genetic mechanisms (Zuckerman, 1986;Piazza et al, 1990;Olsen and Winder, 2009;Belin and Deroche-Gamonet, 2012;Flagel et al, 2014;Dickson et al, 2015Dickson et al, , 2016Dickson et al, , 2019. Therefore, studying the loss of control over sensation seeking can reveal mechanisms driving the loss of control over drug and alcohol seeking.…”

“…To our knowledge, the effect of genetic background on sensation seeking and within-session escalation of sensation seeking across multiple levels of stimulus complexity has never been studied in a mouse strain other than C57BL/6J. Comparing the performance of C57BL/6J and DBA/2J strains is useful because they are the founders of the BXD recombinant inbred mouse panel which segregates 6 million C57BL/6J and DBA/2J variants (Peirce et al, 2004;Ashbrook et al, 2019) and can be used to discover genes that drive natural phenotypic variation (Dickson et al, 2016(Dickson et al, , 2019Parker et al, 2017). Findings from the current study indicate that the approach used here could be applied to the full BXD recombinant inbred panel to discover genetic mechanisms driving sensation seeking as well as the sensitization and habituation of sensory reinforcer effectiveness.…”

“…Animal behavior is reinforced by sensory stimuli, and the biological mechanisms driving sensation seeking are shared with those driving substance use (Zuckerman, 1986;Piazza et al, 1990;Olsen and Winder, 2009;Belin and Deroche-Gamonet, 2012;Flagel et al, 2014;Dickson et al, 2015Dickson et al, , 2016Dickson et al, , 2019. This phenomenon is theoretically important because it illustrates that abused substances hijack the most fundamental mechanisms motivating animal behavior.…”

“…This phenomenon is theoretically important because it illustrates that abused substances hijack the most fundamental mechanisms motivating animal behavior. The relationship of sensation seeking and substance use also has practical importance: the discovery of genes driving sensation seeking can lead us to genes driving substance use (Dickson et al, 2019). The genetic mechanisms driving substance use and sensation seeking are largely unknown.…”

“…In the present study, we used the operant sensation seeking (OSS) paradigm (Dickson et al, 2019) to quantify sensation seeking in C57BL/6J and DBA/2J mice. The C57BL/6J and DBA/2J strains are the founders of the BXD recombinant inbred panel (Peirce et al, 2004;Ashbrook et al, 2019) which enables the discovery of genetic mechanisms driving phenotypic variation (Dickson et al, 2016(Dickson et al, , 2019Parker et al, 2017). We quantified OSS in C57BL/6J and DBA/2J mice using sensory stimuli of a low, medium, or high complexity.…”