Dingwall_2025_Genes.Brain.Behav_24_e70032

Autism affects ~1 in 100 people and arises from the interplay between rare genetic changes and the environment. Diagnosis is based on social and communication difficulties, as well as the presence of restricted and repetitive behaviours. Autism aetiology is complex. However, the social motivation hypothesis proposes that an imbalance in the salience of social over non-social stimuli contributes over time to the autism phenotype. Accordingly, motivational dysfunction in autism is widespread, and human imaging data has identified broad impairments to reward processing. The R451C mutation of the neuroligin-3 gene is one such rare genetic change. Knock-in mice harbouring this mutation (NL3) exhibit a range of autism-related phenotypes, including impaired sociability and social motivation. However, no prior report has directly probed non-social motivation. Here, we explore conflicting results from the progressive ratio (PR) and conditioned place preference tasks of non-social motivation. Initial PR results were inconsistent, suggesting reduced, unaltered, and elevated non-social motivation, respectively. Utilising several experimental designs, we probed a range of confounders likely to influence task performance. Overall, reduced PR responding by NL3s likely arose from a combination of their superior ability to withhold responding during prior training and a short PR training schedule. Meanwhile, increased PR responding by NL3s was attributable to their heightened degree of habitual responding. The NL3 mouse model therefore likely best represents autistic individuals with intact non-social motivation but altered behavioural updating. Finally, we discuss the benefits and limitations of using heterogenous experimental designs to probe behavioural phenotypes and offer some general recommendations for PR.