Effects of Sleep Loss on Memory Consolidation Within a Corticothalamic Circuit

About This Grant

PROJECT SUMMARY/ABSTRACT This proposal outlines a five-year career development program to investigate neural circuit mechanisms that lead to impaired memory consolidation after sleep loss in a corticothalamic circuit. The candidate, Dr. Jessica Jimenez, is currently a Clinical Fellow in Neurology at UCSF in the division of Sleep Medicine. This proposal builds on Dr. Jimenez’s previous research experience in neural circuits mediating learned and innate fear behaviors, by allowing her to obtain new expertise in sleep dependent memory consolidation under the guidance of her primary mentor, Dr. Karunesh Ganguly. The proposed experiments, advisory team, and didactics will provide Dr. Jimenez with the skillset needed to transition to independence as a physician scientist and leader in the field of sleep neurology. Sleep disturbances have detrimental effects on learning and cognitive function, and are a cardinal feature of many chronic diseases, including stroke, neurodegenerative diseases, and depression. Despite these observations, the mechanisms by which sleep loss impairs learning and memory are not well understood. The goal of this proposal is to understand how sleep loss impairs sleep microarchitecture after learning. This will ultimately enable the development of targeted therapies that restore the features of sleep that are critical for memory consolidation. To accomplish this, this proposal aims to investigate how dynamics during non-rapid eye movement (NREM) sleep between the medial prefrontal cortex (mPFC) and thalamus become altered after learning and sleep loss. Specifically, this proposal will assess how slow oscillations (SOs) and delta waves, which are generated by the cortex, become temporally coupled to spindles, which are generated by the thalamic reticular nucleus (TRN). A large body of work has causally shown that the temporal coupling between SOs and spindles during NREM sleep is necessary for memory consolidation, while the coupling of delta waves to spindles weakens memory strength. Still, how corticothalamic inputs modulate the generation of spindles to facilitate spindle coupling to SOs and delta waves after learning and sleep loss is unknown. This proposal hypothesizes that after learning, the mPFC drives SO-spindle coupling and memory consolidation during NREM sleep. Moreover, this proposal predicts that sleep loss impairs this process by altering the balance of SOs and delta waves, thereby desynchronizing mPFC inputs to the TRN and resulting in forgetting. To test this hypothesis, Aim 1 will assess mPFC-TRN circuit dynamics during NREM sleep after learning via chronic in vivo Neuropixels electrophysiological recordings. Aim 2 will employ closed-loop optogenetic silencing of mPFC axon terminals within the TRN to determine if mPFC-TRN input is necessary for SO-spindle coupling after learning. Aim 3 will then assess how mPFC-TRN dynamics become altered after sleep deprivation. The work outlined in this proposal will increase our understanding of how NREM corticothalamic circuit dynamics facilitate memory consolidation after learning and reveal potential therapeutic targets to restore aberrant activity after sleep loss.