Learning is a protracted process, which allows for modification of the memory trace during the consolidation period. Three prominent oscillatory brain patterns have been linked to consolidation: hippocampal sharp wave ripples (SPW-Rs), slow oscillations of the neocortex, and thalamocortical sleep spindles. Of these, the causal role of SPW-Rs in memory is best understood, as selective elimination of SPW-Rs severely impairs memory performance in rodents. However, while both spindles and slow oscillations are temporally correlated with hippocampal SPW-Rs, it is unclear whether these neocortical patterns entrain SPW-Rs or exert their beneficial effects independently. Irrespective of their relationships, we hypothesize that selective enhancement (or elimination) of these patterns can improve (or deteriorate) memory performance in rodents and humans. Accordingly, we propose to experimentally manipulate these distinct brain rhythms in both rodents and human subjects and examine how such interventions affect memory performance. In rodents, a series of large-scale recordings in both hippocampus and selected neocortical areas, combined with optogenetics and transcranial electrical stimulation (TES) experiments, will be performed. The behavioral impact of these circuit perturbations will be assessed in a memory task, known to be dependent on SPW-Rs. Specifically, SPW-Rs and spindles will be artificially generated through optogenetic experiments, or these spontaneously occurring oscillations will be enhanced or interrupted in closed-loop TES experiments. In another set of experiments, coupling between hippocampal SPW-Rs and thalamocortical spindles will be strengthened (or weakened) by optogenetics or TES and correlated with memory performance. The human studies include both non-invasive and invasive intervention strategies. Non-invasive experiments will involve the application of open- and closed-loop TES (combined with scalp EEG recordings) to determine how the timing to the phase of slow oscillations affects sleep physiology and memory consolidation in healthy subjects. The invasive experiments will involve both open- and closed-loop direct cortical stimulation (DCS) of the entorhinal cortex during slow wave sleep in patients undergoing intracranial EEG monitoring for epilepsy surgery. Changes in neocortical slow/spindle oscillations and hippocampal-neocortical network connectivity after DCS will be correlated with memory performance. Taken together, the findings will provide a clearer understanding of the causal role of these oscillatory brain patterns in memory consolidation and offer potential treatments for memory disorders.
Using correlational and intervention strategies in rodents and humans, we examine the hypothesis that enhancement of brain rhythms associated with memory consolidation will improve memory performance. Our studies will not only advance our basic understanding of the mechanisms by which memories are consolidated in the normal brain, but will also have important therapeutic implications for patients with neuropsychiatric disorders that are associated with cognitive and memory impairments, such as depression and schizophrenia.
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