Buchholz, Moritz Oliver; (2023) All-optical interrogation of memory in the hippocampus. Doctoral thesis (Ph.D), UCL (University College London).

Text MoritzBuchholz_PhD_2023.pdf - Accepted Version Access restricted to UCL open access staff until 1 December 2024. Download (19MB)

Abstract

Understanding the neural basis of episodic memory is a fundamental goal in neuroscience. Episodic memory is the ability to remember experiences in their spatial and temporal context. The hippocampus is thought to support this ability by generating neural activity sequences of place cells and time cells that associate events across space and time. However, experimental evidence linking such hippocampal representations to memory and behaviour is largely correlational and the causal role of these activity patterns remains to be established. In this thesis, I leverage all-optical technology combining two- photon imaging with holographic two-photon optogenetics to read out and manipulate hippocampal activity in mice solving both spatial and non-spatial cognitive tasks. First, I contribute to providing the first direct evidence for a causal role of place cells in memory-guided spatial behaviour. Targeted activation of place cells outside their natural firing field during a virtual reality navigation task drove specific behaviours that were associated with the stimulated cells’ spatial tuning. Second, I develop an olfactory task to study the formation of new associations between events across a mnemonic delay. Reorganisation of hippocampal time cell sequences facilitated the formation of new temporal associations. Third, I drive such hippocampal sequences across the mnemonic delay during the formation of new associations. Sequential photostimulation led to context-specific and timing-specific imprinting – photoactivated neurons began to encode the new experience. Finally, I extend the olfactory temporal association task for investigating generalisation and inference in the hippocampus. Together, these experiments are amongst the first to pioneer all-optical technology in the hippocampus. The results shed light on decades-old ideas of hippocampal function and bring us closer to cracking the neural code of memory.

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