Abstract

Autism Spectrum Disorder (ASD) is a significant lifelong neurodevelopmental disorder characterized by alterations in social-emotional communication and the presence of restrictive and repetitive behaviours. Circadian rhythm disruption is one of the most common comorbidities in ASD, affecting up to 80% of individuals. However, despite the increasing prevalence of the disorder over the past decade, insights into the nature of circadian rhythm disruption in the disorder remain poorly investigated and understood.

This objective of this thesis was to characterize the circadian system in a valproic acid (VPA)-induced rodent model of ASD. First, we examined wheel-running behaviour – the current gold standard for describing functional changes within the circadian system – in both male and female Wistar rats exposed to either saline or VPA in utero. We demonstrated the existence of a diminished and unstable master clock in VPA-exposed animals in which aberrant behaviour was driven by alterations in photic-entrainment capacity. Secondly, we investigated the daily expression profile of BMAL1, a core clock-gene necessary for circadian behaviour, in neural structures involved in the pathogenesis of ASD behaviours. Here, we showed altered temporal dynamics of BMAL1 in peripheral tissues involved in the regulation of social behaviours, motivation, reward and monoaminergic output and suggested a potential role for the clock in the emergence of maladaptive behaviours seen in ASD. Finally, we showed that the emergence of circadian disturbances post in utero exposure to VPA can be passed onto the second and third generations, opening the possibility that circadian rhythm disruption can be passed onto future generations through the germline. Collectively, this body of research emphasizes the urgent need for novel perspectives in the treatment of ASD-associated comorbidities and highlights the nature of circadian dysregulation in the disorder.