No 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.

The propensity to attribute incentive salience to reward cues, measured by Pavlovian sign-tracking, is strongly associated with addiction-related traits including cocaine self-administration, impulsivity, novelty reactivity, and novelty preference. Despite its critical role in addiction, the genetic underpinnings of incentive salience attribution and its relationship to drug addiction are unknown. Mouse genetics can be a powerful means to discover genetic mechanisms underlying this relationship. However, feasibility of genetic dissection of sign-tracking in mice is unknown as only a single study limited to male C57BL/6J mice has rigorously examined this behavior, and limited sign-tracking was observed. Highly diverse mouse populations such as the Collaborative Cross (CC) and Diversity Outbred population (DO) possess a greater range of behavioral and genetic variation than conventional laboratory strains. In the present study, we evaluated sign-tracking and the related phenotype goal-tracking in mice of both sexes from five inbred CC and DO founder strains. Male CAST/EiJ mice exhibited robust sign-tracking; male NOD, male C57BL/6J, and female A/J mice also exhibited significant sign-tracking. Male and female mice from all strains exhibited significant goal-tracking, and significant strain and sex differences were observed. Sign-tracking in males was genetically correlated with exploration of a novel environment, and heritability of sign-tracking and goal-tracking ranged from .32 to .41. These data highlight the importance of considering genetic diversity when evaluating the occurrence of specific behavioral traits in the laboratory mouse and demonstrate that the CC and DO mouse populations can be used to discover mechanisms underlying genetic relationships among sign-tracking and addiction-related behaviors.

Successful social interactions are assumed to depend on theory of mind—the ability to represent others’ mental states—yet most studies of the relation between theory of mind and social-interactive success rely on non-interactive tasks that do not adequately capture the spontaneous engagement of theory of mind, a crucial component of everyday social interactions. We addressed this gap by establishing a novel observational rating scale to measure the spontaneous use of theory of mind (or lack thereof) within naturalistic conversations ( conversational ToM; cToM). In 50 age- and gender-matched dyads of autistic and typically developing youth aged 8–16 years (three dyad types: autistic–typically developing, typically developing–typically developing, autistic–autistic), we assessed cToM during 5-min unstructured conversations. We found that ratings on the cToM Negative scale, reflecting theory-of-mind-related violations of neurotypical conversational norms, were negatively associated with two forms of non-interactive theory of mind: visual-affective and spontaneous. In contrast, the cToM Positive scale, reflecting explicit mental state language and perspective-taking, was not associated with non-interactive theory of mind. Furthermore, autistic youth were rated higher than typically developing youth on cToM Negative, but the groups were rated similarly on cToM Positive. Together, these findings provide insight into multiple aspects of theory of mind in conversation and reveal a nuanced picture of the relative strengths and difficulties among autistic youth. Lay abstract Conversation is a key part of everyday social interactions. Previous studies have suggested that conversational skills are related to theory of mind, the ability to think about other people’s mental states, such as beliefs, knowledge, and emotions. Both theory of mind and conversation are common areas of difficulty for autistic people, yet few studies have investigated how people, including autistic people, use theory of mind during conversation. We developed a new way of measuring cToM using two rating scales: cToM Positive captures behaviors that show consideration of a conversation partner’s mental states, such as referring to their thoughts or feelings, whereas cToM Negative captures behaviors that show a lack of theory of mind through violations of neurotypical conversational norms, such as providing too much, too little, or irrelevant information. We measured cToM in 50 pairs of autistic and typically developing children (ages 8–16 years) during 5-min “getting to know you” conversations. Compared to typically developing children, autistic children displayed more frequent cToM Negative behaviors but very similar rates of cToM Positive behaviors. Across both groups, cToM Negative (but not Positive) ratings were related to difficulties in recognizing emotions from facial expressions and a lower tendency to talk about others’ mental states spontaneously (i.e., without being instructed to do so), which suggests that both abilities are important for theory of mind in conversation. Altogether, this study highlights both strengths and difficulties among autistic individuals, and it suggests possible avenues for further research and for improving conversational skills.

In adults with autism spectrum disorder, co-occurring psychiatric conditions are prevalent, and depression is one of the most common co-occurring disorders. This study examined the relationship between depression and cognitive ability, autism symptom severity, and self-reported social impairments in autism spectrum disorder. A total of 33 adults with autism spectrum disorder and 28 adults with typical development completed a standardized psychiatric interview, cognitive test, measure of clinician-rated autism symptom severity, and self-report of social impairments. Nine participants with autism spectrum disorder (27%) met the criteria for a depressive disorder (autism spectrum disorder + depressive disorder). Relatively more females with autism spectrum disorder had a co-occurring depressive disorder. The typical development group had a higher intelligence quotient than the autism spectrum disorder group, but the autism spectrum disorder + depressive disorder group did not differ from the typical development or autism spectrum disorder group. While the autism spectrum disorder + depressive disorder group had lower clinician-rated autism symptom severity than the autism spectrum disorder group, the autism spectrum disorder + depressive disorder group reported more social impairments than the autism spectrum disorder group. Self-reported social impairments predicted depression in adults with autism spectrum disorder when accounting for symptom severity and cognitive ability. These findings suggest that more self-perceived social impairments are related to depressive disorders in autism spectrum disorder, and may help clinicians identify individuals who are vulnerable in developing a co-occurring depressive disorder. Future directions include follow-up studies with larger cohorts and longitudinal designs to support inferences regarding directionality of these relationships.