Autism spectrum disorder (ASD) represents a group of developmental disabilities characterized by the triad of repetitive actions, deficits in communication skills, and decreased interest in social interaction. ASD affects about 1 in 68 children, with the incidence of diagnosis increasing each year. A diagnosis of an ASD places a significant financial burden on the family. The pathophysiology of ASD is not well understood, there is no cure, and only two FDA-approved treatments exist-both of which only treat associated irritability and not the core Cerebellar irregularities and damage have been associated with ASD and other neurodevelopmental disorders. The cerebellum's output to the rest of the brain is exclusively through polysynaptic connections. Cerebellocerebral connections have remained poorly characterized from the lack transsynaptic neural tracers. Previous tracers only labeled one synapse effectively. Recently developed viral tracers are capable of transsynaptic spread, allowing for polysynaptic circuit characterization. One such tracer, the brainbow virus, changes fluorescence color in neurons expressing Cre, allowing for the discernment of pathway intermediaries. This proposal will use viral tracers to characterize the polysynaptic projections and intermediaries of cerebellar lobules VI and VII; lobules associated with nonmotor functions of the cerebellum and hence may have ASD significance. Studying long distance brain connections offers understanding of how distant brain areas influence each other and can provide insight into neurological disorders. After identifying the connections of lobules VI and VII, their influence on behavior will be explored. The new technology, DREADDs, allows for the temporal and spatial inactivation of neurons. DREADDs will be used to explore behavioral changes that result from the disruption of neuronal activity in lobules VI and VII. Behavioral assays commonly used to test autistic model mice: eyeblink conditioning, the three-chambered task, and the T-maze reversal task, will be used to detect qualities associated with autism in the DREADD-expressing mice. Notably, these mice will not be genetic knockouts; therefore, if autism-associated behaviors are observed it will implicate a cerebellar role in autism. This knowledge can provide novel avenues for both ASD diagnosis and therapeutics. symptoms of ASD.
Poorly understood neurological conditions, including autism have been associated with cerebellar abnormalities. Despite this, the cerebellar role in these conditions is poorly established. This project seeks to identify cerebellar polysynaptic connections, their behavioral influence, and their developmental role.
| Badura, Aleksandra; Verpeut, Jessica L; Metzger, Julia W et al. (2018) Normal cognitive and social development require posterior cerebellar activity. Elife 7: |
