ESR12

Host institution: University of Edinburgh, UK

ESR12 – Using functional magnetic imaging (fMRI) to characterise cerebellar interactions with large-scale fear networks related to fear behaviour in a transgenic rat model of autism spectrum disorder (ASD)

This project will use 9.4T fMRI in a rat model of ASD to understand the contribution of the cerebellum to disordered emotional control.

Given prediction errors are encoded in cerebellar circuits are thought to be essential to the fear extinction process and are thought to underlie many core ASD symptoms, such deficits may thus reflect aberrant activity within distributed cerebellar-fear circuits. However, despite the extensive behavioural and pathological changes in ASD that can be associated with the cerebellum, surprisingly little is known about the processing of predication errors within this structure during, for example, associative learning in pre-clinical models of the disorder.

MRI has the potential to provide translatable and non-invasive system-wide and repeatable measures of brain structure (volume measurement) and function (fMRI). Moreover, this approach enables findings from basic neuroscience in rodent models to be translated into clinical studies. fMRI of rodents is established within the Simons Initiative for the Developing Brain (making this project highly feasible) and enables assessment of temporal and spatial changes in network activation patterns in response to specific tasks (e.g. associative memory learning tasks).

Aim 1 of this project will combine targeted silencing of cerebellar Purkinje cells and fMRI in male and female rats that model ASD and wild-type controls to chart functional connections between the cerebellum and fear circuitry at rest. Aim 2 will use fMRI to correlate cerebellar activation with components of the fear circuitry (e.g. PAG, prefrontal cortex, amygdala) related to recall and extinction of conditioned fear. This set of experiments will provide the first insights into distributed cerebellar activity in rodent models of ASD linked to associative learning. This project will be conducted in close collaboration with Uppsala and Essen. This will allow us to standardise our behavioural protocols, data acquisition and analysis. The findings will be compared with electrophysiological data in rodents (ESRs 1, 6, 9), and 7T fMRI data in patients with cerebellar (ESR13) and anxiety disorders (ESR15). Collaboration with Essen and Uppsala on 7T fMRI.

These experiments will determine how distributed cerebellar-fear circuits contribute to emotional processing in a rat model of ASD.

Planned secondments: Uppsala, month 7: experimental design standardisation; Essen: month 14: training in cerebellar signal analysis; AtaxiaUK, month 25, purpose: training in NGO work.