Russell, Lloyd. E; (2020) All-optical interrogation of mouse visual cortex during behaviour. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis addresses the fundamental question of the relationship between cortical activity and perception, which remains one of the most challenging problems in neuroscience. Optogenetic and microstimulation experiments have provided evidence for a causal role of bulk activity in specific brain areas in biasing perception and have elicited detectable artificial percepts in the absence of sensory stimuli. Nevertheless, the number and functional identity of the stimulated neurons which were responsible for modulating behaviour are almost completely unknown. To make causal links between activity in neural circuits and behaviour necessitates more sophisticated methodology that allows the experimenter precise control over the spatial and temporal patterns of neural activity in the intact brain. In this thesis I describe the development of an ‘all-optical’ strategy for simultaneously manipulating and recording the activity of hundreds to thousands of neurons with unprecedented resolution in vivo. I combined two-photon optogenetic activation and two-photon calcium imaging of neuronal populations by coexpressing a red-shifted opsin with a genetically encoded calcium indicator in the same neurons. A spatial light modulator (SLM) allows groups of functionally characterised neurons to be holographically targeted for spatiotemporally precise optogenetic activation, while simultaneous calcium imaging provides network-wide readout of the manipulation. I further refined this approach by implementing online fast calcium imaging analysis directly linked to SLM programming in a feedback loop, allowing closed-loop manipulation of activity patterns in neural circuits. Finally, I harnessed this ‘all-optical’ approach in the visual cortex of mice performing a visual detection task. Only activation of groups of cells with similar tuning to the relevant visual stimulus led to a measurable bias of detection behaviour. Moreover, the behavioural effects depended on overall performance: when the task was challenging for the mouse, V1 activity was more closely linked to performance, and cortical stimulation boosted perception. In contrast, when the task was easy, V1 activity was less informative about performance and cortical stimulation suppressed stimulus detection. These results thus help to reconcile contradictory findings about the involvement of primary sensory cortex in behavioural tasks, suggesting that the influence of cortical activity on behaviour is dynamically reassigned depending on the demands of the task.

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