Bäumler, Edgar Jacob; (2024) All-optical approaches for investigating downstream readout of hippocampal activity patterns. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Understanding how downstream circuits read out specific features of neural activity patterns is a fundamental problem in neuroscience. Recent advances in 2-photon holographic optogenetics and simultaneous 2-photon calcium imaging – known as “all-optical interrogation” – allow us to manipulate ensembles of functionally defined cell types but cannot assess the impact of these perturbations on distant downstream networks. To tackle this problem, I have developed a novel approach which combines simultaneous all-optical interrogation with electrophysiological recordings from downstream brain regions using novel high-density silicon probes (“Neuropixels”). I developed a range of optimisations which allow me to successfully mitigate optical crosstalk, drive downstream responses, and implement this approach chronically. This allows the functional impact of specific neural activity patterns to be measured simultaneously across multiple brain regions with single spike resolution. I subsequently apply this approach in the hippocampus of mice performing a virtual reality spatial learning paradigm to study how the temporal order of rapid place cell reactivation sequences influences downstream activity in the lateral septum, the consolidation of the place cell map and spatial learning. While mouse behaviour was not affected by manipulation, photoactivated place cells were significantly more likely to remap their place fields upon subsequent re-exposure to the same virtual environment. Most notably, population activity in the lateral septum, but not the frontal cortex, was selectively increased when the reactivation sequence occurred in forward order of the behavioural experience. Finally, I extend this approach by introducing 2-photon voltage imaging as an alternative readout modality to study functional connectivity across hippocampal subfields at subthreshold resolution. These experimental strategies represent a powerful new approach for mapping long-range functional connectivity in awake, behaving animals. By applying this approach in the hippocampus, I provide the first causal evidence that the temporal order of behavioural firing field sequences affects information processing in the brain.

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