Principal investigator Aleksandra Badura
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Cerebello-cortical networks in Shank2 mouse model of Autism Spectrum Disorder
Pathogenic SHANK2 variants are extraordinarily rare in the general population but estimated to occur in 0.15%-0.3% of all individuals diagnosed with Autism Spectrum Disorder (ASD). SHANK2 is therefore regarded as a high-confidence ASD risk gene. Heterozygous loss-of-function mutations within the SHANK2 gene show very high prevalence in ASD diagnosis, often accompanied by other deficits.
Previous studies showed that human neurons with SHANK2 mutations make more functional excitatory connections relative to controls, and our own studies identified strong behavioral deficits in Shank2 deficient mice including. We also have preliminary data that shows altered functional brain connectivity in Shank2 mice. However, it is not known if the altered connectivity and behavioral deficits are the result of increased excitation in the cerebello-cortical network. Thus, in this project, we will investigate if the activity of the mPFC, primary motor cortex and cerebellar Crus1 is elevated in Shank2 mice while performing cognitive flexibility tasks.
- Shank2 mouse model
- Intracranial surgery
- Viral injections
- In vivo, awake electrophysiology
- Calcium imaging
- Behavior and functional connectivity
- Prediction models
Can damage to the cerebellum lead to structural changes in the neocortex?
Injury to the cerebellum is the only risk factor that is quantitatively comparable to that of having an identical twin with autism, consistent with the fact that deficits have been reported after cerebellar injury. These findings point to a role for cerebellar dysfunction in the etiology of cognitive disorders, but explaining how they fit into models of autism has been difficult. The most parsimonious hypothesis is that during development cerebellum shapes the development of cortical areas involved in cognition and social interaction. Recent studies show that functional changes restricted to the cerebellum indeed cause behavioral change. However, many questions remain on the regionality of these changes, their critical periods and their effect on functional networks.
Here, we will answer these questions by performing lesion studies in mice at critical time points to investigate the causal role of specific cerebellar regions in shaping cortical anatomy and cerebello-cortical resting state networks. We will quantify changes to dendritic and synaptic densities in the neocortex following cerebellar insult. We will also study the impact of cerebellar lesions on cerebello-cortical resting state networks and white matter tracts.
- Viral injections
- Confocal imaging and analysis
- 3D reconstruction
- (UHF-MRI) 7T in vivo imaging
- MRI data analysis