UNCERTHAIN · Unraveling the consequences of early cerebellothalamic dysfunction and its role in autism spectrum disorder symptoms

Cerebellar abnormalities are consistently reported in autism spectrum disorder patients, however the cerebellar contribution in the etiology of this pathophysiology remains poorly understood.It has been proposed that the cerebellum may drive the maturation and functionality of cortical high-order structures involved in the core symptoms of autism. However, the mechanisms by which the cerebellum could control these processes remain to be determined. The neural circuits linking cerebellum with the cerebral cortex via thalamic relay stations are the anatomical scaffolds underlying the cerebellar cognition. Recent data have shown that the thalamus plays a key role in the reorganization of cortical areas after early sensory deprivation. Therefore, during early development, abnormal cerebellar inputs to the thalamus may contribute to cortical dysfunctions that could lead in high-order deficits. However, despite being autism a neurodevelopmental disorder, any study has addressed the analysis of cerebello-thalamo-cortical circuits from a developmental perspective.The present project (UNCERTHAIN) offers an exceptional opportunity to shed light onto this issue as a result of the unique combination of approaches. Accordingly, we will use an experimental model that offers the possibility to embryonically alter the cerebellothalamic connectivity and thus, study the mechanisms underlying the events that influence the normal development and functioning of cortical circuits. Hence, we will adopt both multidisciplinary and innovative approaches to characterize the thalamocortical network in presence of a disrupted cerebellar input, the functional consequences and its relationship with autistic-like behaviors.The successful execution of this high-risk, high-impact research will provide insights on how the cerebellum governs the development of cortical areas essential for social and cognitive behaviors and its involvement in high-order neurodevelopmental disorders such as autism.