A comprehensive assay of social motivation reveals sex-differential roles of ASC-associated genes and oxytocin

Abstract

Social motivation is critical to the development of healthy social functioning. Autism spectrum condition (ASC) is characterized in part by challenges with social communication and social interaction. The root of these challenges is hypothesized to be a deficit in social motivation, specifically in one or more subcomponents (e.g. social reward reward seeking or social orienting). Current social behavior assays lack the ability to quantitatively measure both social reward seeking and social orienting simultaneously. We have developed an automated socially-rewarded operant conditioning task coupled with video tracking, to quantify effort to achieve access to a social partner and concurrent social orienting behavior in mice. We established that adult wildtype mice will work for access to a social partner, that male mice exhibit greater social motivation compared to females, and there is high test-retest reliability in the task across multiple days. We then benchmarked the method with two test-case manipulations. We first tested a mouse model of Phelan-McDermid syndrome, a neurodevelopmental disorder associated with ASC. These Shank3B mutants failed to show social reward seeking and exhibited reduced social orienting. Next, we demonstrated that oxytocin receptor antagonism decreased social motivation in wildtype mice, consistent with its role in social reward circuitry. Intriguingly, only male mice were vulnerable to Shank3B mutation, while females were more vulnerable to oxytocin blockade, a double dissociation suggesting separate circuits for social motivation in male and female brain. Overall, we believe this method provides a valuable addition to the assessment of social phenotypes in rodent models of ASC and the mapping of potentially sex-specific social motivation circuits in the brain.

Extensive characterization of a Williams Syndrome murine model showsGtf2ird1-mediated rescue of select sensorimotor tasks, but no effect on enhanced social behavior

“…2004), and finally a 14-day Social Operant task we recently designed to be a direct measure of social motivation in rodents in cohort 1 (Chen et al . 2021; Maloney et al . 2022).…”

“…Our 16-day paradigm allows for assessment of both social reward seeking and social orienting, two components of social motivation (Chevallier et al 2012). We followed the procedure outlined in our previous work (Chen et al 2021;Maloney et al 2022). Briefly, an operant conditioning chamber was modified to include a door that raised in response to a nosepoke in the active hole to provide 12 seconds of access to a novel sex-and age-matched partner stimulus mouse.…”

“…Previous work in our lab failed to identify differences in the 3-Chamber task alone, though on a C57BL/6J x FVB hybrid background that showed lower social approach in general (Kopp et al 2019;Nygaard et al 2019). Thus, our comprehensive battery here included a deliberate precise replication of the Open Field Social Approach conditions as a baseline control in cohort 1 (Sakurai et al 2011;Segura-Puimedon et al 2014), the standard 3-Chamber Social Approach assay in cohort 2 (Crawley 2004;Moy et al 2004), and finally a 14-day Social Operant task we recently designed to be a direct measure of social motivation in rodents in cohort 1 (Chen et al 2021;Maloney et al 2022).…”

Extensive characterization of a Williams syndrome murine model shows Gtf2ird1‐mediated rescue of select sensorimotor tasks, but no effect on enhanced social behavior

“…Previous work in our lab failed to identify differences in the 3‐chamber task alone, although on a C57BL/6J × FVB hybrid background that showed lower social approach in general 11,24 . Thus, our comprehensive battery here included a deliberate precise replication of the OFSA conditions as a baseline control in cohort 1, 27,29 the standard 3‐chamber social approach assay in cohort 2 5,21 and finally a 14‐day social operant task we recently designed to be a direct measure of social motivation in rodents in cohort 1 3,18 …”

“…Our 16‐day paradigm allows for assessment of both social reward seeking and social orienting, two components of social motivation 4 . We followed the procedure outlined in our previous work 3,18 . Briefly, an operant conditioning chamber was modified to include a door that raised in response to a nosepoke in the active hole to provide 12 s of access to a novel sex‐ and age‐matched partner stimulus mouse.…”