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Imaging cortical codes for learning and memory in models of autism spectrum disorders


About This PhD Project

Project Description

Project Code: 2020-SIDB-09

How do cortical codes for associative learning and memory change in rodent models of autism spectrum disorders? Experiments will test the overarching hypothesis that memory deficits in ASD is a result of disruptions in hippocampus mediated encoding of neocortical memory. The primary experimental approach will be to use miniscopes1 as animals carry out hippocampus-dependent behavioural tasks to image activity of populations of cortical neurons that are identified to be receiving hippocampal input. This will enable evaluation of task-specific population codes and their evolution during hippocampus-dependent learning 2 and how these are disrupted in ASD animal models3.

Experiments will focus on rodents with deletion of the gene encoding FMRP, which are well studied models for autism-like disorders. These animals are substantially impaired in some hippocampal-dependent behaviours, for example associative recognition memory and pattern separation, whereas others are largely normal, for example watermaze learning. The behavioural roles for the hippocampus are mediated through its connections to diverse cortical targets. While much attention has focused on roles of the hippocampus in behavioural deficits associated with autism spectrum disorders, it is not known how neural codes and computations in cortical targets of the hippocampus contribute to the specific behavioural profile of FMRP mutant animals or to ASDs more generally3.

The PhD will explore hypotheses for how aberrant hippocampal function leads to deficits in behaviour through altered representation of information in the neocortex. We will employ head mounted miniature microscopes to image activity in populations of cortical neurons in freely moving rodents performing hippocampus dependent visio-spatial tasks4. Results will help to achieve a mechanistic understanding of behavioural deficits in fragile X models in particular, and for validating approaches that could be applied more generally to other autism models. Learning objectives include gaining skills to perform miniscope recordings in behaving mice and analysis of large ensemble neuronal activity recordings.

References

1. Ghosh, K. K. et al. Miniaturized integration of a fluorescence microscope. Nat. Methods 8, 871–878 (2011).

2. Driscoll, L. N., Pettit, N. L., Minderer, M., Chettih, S. N. & Harvey, C. D. Dynamic Reorganization of Neuronal Activity Patterns in Parietal Cortex. Cell 170, 986–999.e16 (2017).

3. Talbot, Z. N. et al. Normal CA1 Place Fields but Discoordinated Network Discharge in a Fmr1-Null Mouse Model of Fragile X Syndrome. Neuron 97, 684–697.e4 (2018).

4. Yoo, S.-W. & Lee, I. Functional double dissociation within the entorhinal cortex for visual scene-dependent choice behavior. eLife Sciences 6, e21543 (2017).

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