Dynamics of information processing and spontaneous activity during sleep

Brain oscillations are critical for inter-regional communication and the orchestration of higher order cognitive processes such as attention and memory consolidation. Oscillations underlying these phenomena are typically mediated via underlying neural population activity, but the exact mechanisms that determine how the oscillations are generated remain open questions in the field. In this work, I examined two classes of oscillations that are crucial for memory consolidation: the cortical slow wave and hippocampal sharp wave-ripples, in pursuit of elucidating the contributions of single neurons to these processes. Critically, these oscillations occur during sleep, which also enables us to understand the intrinsic mechanisms underlying their spontaneous initiation, devoid of sensory inputs. I used the spatial navigation system as a model to study memory consolidation, as spatially tuned activity is a relatively simple readout compared to other brain systems. Specifically, I examined the organization of sequences in the cortical head-direction system and uncovered a dorsoventral activation pattern. Using the head-direction cell activity as a readout, I was able to elucidate the content of these sequences and showed that population activity rapidly converges towards a stable orientation, and this direction is chosen at random during each oscillatory period. Finally, using a combination of computational modeling, and ex vivo patch clamp experiments I, in collaboration with colleagues from the University of Edinburgh, uncovered a hitherto ignored key player in the dynamics of the slow oscillation in the cortex – hyperpolarization-activated currents. I showed that these currents might play brain-wide roles in the organization of cortical sequences. This finding has important implications for the organization of activity along the dorsoventral axis, a common feature observed throughout the navigation system, and the organization of sequences in the cortex, more generally. I then turned to a downstream structure, the hippocampus, to examine the other key oscillation in memory consolidation – sharp wave-ripples. In collaboration with colleagues from the department of Pharmacology and Therapeutics at McGill University, I worked on a mouse model of Christianson Syndrome, a recently discovered neurodevelopmental and neurodegenerative disorder, and led the first investigation, to our knowledge, into understanding the mechanisms underlying the cognitive deficits in this disorder, focusing on oscillatory activity in the hippocampus. We tested these animals on a hippocampal-dependent spatial memory task and found deficits in their performance. To further investigate the neural mechanisms underlying these cognitive deficits, we examined their hippocampal place cell activity. Interestingly, these animals had intact place fields. Instead, I found differences in the frequency composition of sharp wave-ripples in the disease model, suggesting that alterations in the composition of these oscillations might be crucial for deficits in cognitive processes. Broadly, by characterizing hippocampal activity in these animals, I provide insights into how a single gene mutation can affect network activity in the hippocampus, which leads to debilitating cognitive deficits. Taken together, my findings reveal novel aspects of single neuron activity that shape oscillations during sleep. These findings have important implications for gaining mechanistic insights into the organization of spontaneous activity patterns during sleep, but also into their functional roles within the spatial navigation system. Critically, my work lies at the interface of health and disease, laying the foundation for further discovery and characterization of neural biomarkers in preclinical models of Christianson Syndrome to inform future clinical studies and precision medicine therapies

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