Ortibus, Wyatt2025-09-022025-09-022025-08-30https://hdl.handle.net/10222/85421Autism spectrum disorder (ASD) is characterized by deficits in social communication, social interaction, repetitive behaviours, and poor responses to social cues. ASD is most likely caused by multiple interactions between environmental and genetic factors, including the Neurexin (NRXN) family of membrane protein synaptic organizers. These proteins are implicated in neurodevelopmental disorders, such as ASD and schizophrenia, due to their unique functions at the synapse. Neurexins are encoded by three genes (Nrxn1, Nrxn2, and Nrxn3) and classified into three isoforms (α, β, and γ), all of which are thought to have specific functions at the synapse by binding to postsynaptic neuroligins. These cell adhesion proteins modulate synaptic transmission and downstream gene regulatory networks (e.g., DAT) that control neural function. Nrxn1 gene disruption leads to synaptic destabilization and cognitive impairment, suggesting that Nrxn1 may play an important role in learning and memory. Using an operant olfactometer, we tested cognitive flexibility in wild-type (C57BL/6J) and Nrxn1+/- mice, which were developed as a model for human autism. We used rodent translational studies to examine the cognitive and behavioral consequences of alterations (e.g., knockdowns) in the Nrxn1 genes. Our novel Nrxn1+/- mice have a 140 bp deletion knocking down the α, β, and γ isoforms and have no learning and memory comparisons to wild-type controls. Mice were trained at 2-4 months of age to discriminate an initial odour pair (A vs. B) to a criterion of 85% accuracy, then to a criterion of 85% accuracy on a second odour pair (C vs. D), and then to a criterion of 85% accuracy on reversal learning of the second odour pair, where the rewarded outcomes are switched (S+ becomes S- and vice versa). Secondly, we tested for overtraining effects by overtraining mice on the second odour pair for an extra 180 trials after 85% accuracy criterion before a reversal to study its effects on total errors in reversal. Our results found no significant memory performance differences between Nrxn1+/- and wildtype (C57BL/6J) littermates in the initial odour pair discrimination, second odour pair discrimination or reversal learning discrimination. We also observed no sex differences or interactions on total errors in these discriminations, as well as no effect of overtraining on any of the genotypes compared to mice that were not overtrained. Our investigations into individual learning differences using our models determined common response phases in learning styles during tasks. We used signal detection theory to examine these learning style patterns in the olfactometer based on four possible outcomes: hits, misses, false alarms (FA), and correct rejections (CR). Using these responses, we coded discrimination and reversal learning styles into four different learning phases, which we defined as Perseverance (Misses & FA), Responds None (Misses & CR), Responds All (FA & Hits), and Respond S+ (Hits & CR). These phases of reversal learning allow us to analyze individual differences and explain how mice perform operant reversal tasks within an olfactometer. Our reversal learning theory also showed that “Learning to Learn” performance increases in reversal learning tasks is the reduction of Perseveration and Responds None responses. Future studies should consider the effects of age on reversal learning to determine whether age affects cognitive flexibility in the Nrxn1+/− mouse model.enNeurexins (NRXN)Odour DiscriminationReversal LearningAutismOlfactometerMouse studyOlfactionCognitive Flexibility