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198626 https://hdl.handle.net/2286/R.2.N.198626 http://rightsstatements.org/vocab/InC/1.0/ http://creativecommons.org/licenses/by-nc-sa/4.0 2024-12 2026-05-22T05:00:00 67 pages Truong, Vincent Verpeut, Jessica Bimonte-Nelson, Heather Opendak, Maya Barrett, The Honors College School of Humanities, Arts, and Cultural Studies Department of Psychology School of Molecular Sciences Text Autism Spectrum Disorder (ASD) is a heterogeneous condition dynamic to the aging process, yet little research focuses on the relationship between aging and ASD in regards to health outcomes. Social deficits, a hallmark symptom of ASD, limit essential healthcare engagement, which can vary between neurotypical and neurodivergent individuals as they age. However, it is unknown whether social deficits intensify or reduce with age in individuals with autism. To assess rates of social decline, we analyzed male mice with non-ASD (n=33) and ASD phenotypes (n=13) at juvenile and aged life. This study proposed to evaluate changes in social behavior across the lifespan by perturbing the cerebellar nuclei (CN) to ventral tegmental area (VTA) pathway using chemogenetics during developmental critical periods. Projections from the CN to the VTA have long-distance influence on reward-based social circuits implicated in ASD. Neural pathways were inhibited with the chemogenetic ligand, clozapine-N-oxide (CNO), during postnatal days 21-35 (juveniles) or at 9 months (aged), followed by a 5-day washout period before behavioral testing. Behavioral tests, including the open field, 3-chamber social preference, olfactory habituation and dishabituation, and the water Y-maze test, were used to evaluate changes in behavior, which will be correlated with biological markers obtained from in-situ hybridization assays in the future. Results showed that perturbations in the CN-VTA pathway impaired social memory across all ages but had distinct effects on sociability and cognitive flexibility. Perturbed juveniles demonstrated enhanced learning during the Y-maze acquisition phase, likely due to compensatory plasticity in younger neural circuits. In contrast, aged animals experienced exacerbated deficits in social behaviors and cognitive flexibility. CNO-treated aged animals exhibited atypical behaviors, including increased preference for non-social stimuli, highlighting potential off-target effects of CNO on aging dopaminergic pathways. Autism Autism Spectrum Disorder ASD Aging Cerebellum Neuroscience Social Behavior Mice Aging and Autism: Modulation of the cerebellar nuclei during critical periods of development to assess social changes with age in mice