Development of repetitive behavior in a mouse model: roles of indirect and striosomal basal ganglia pathways

Abstract

Restricted repetitive behaviors (stereotypy, compulsions, rituals) are diagnostic for autism spectrum disorder and common in related neurodevelopmental disorders. Despite their prevalence in clinical populations, underlying mechanisms associated with the development of these behaviors remain poorly understood. We examined the role of the indirect basal ganglia pathway in the development of stereotypy using deer mice. We measured neuronal metabolic activity in the subthalamic nucleus (STN) and other relevant brain regions using cytochrome oxidase (CO) histochemistry at three developmental time-points. Although no differences were observed in STN across development, significant differences were found when mice were grouped by developmental trajectory. At 6 weeks post-weaning, significantly lower CO activity in STN was found in those trajectory groups that developed high levels of repetitive behavior versus the trajectory group that did not, suggesting the development of stereotypy is associated with decreased indirect basal ganglia pathway activity. In addition, we tested the hypothesis that preferential activation of striatal striosomes relative to surrounding matrix would be associated with the development of stereotypy. No differences in the relative activation of these striatal compartments were observed across development or among trajectory groups. Our results point to dynamic changes in the indirect pathway associated with the development of repetitive behavior and extends our prior work linking reduced indirect pathway activation to stereotypy in adult deer mice.