Dissertation Defense - James Delorme
Linking intracellular events to network reorganization in sleep-dependent memory consolidation
Dr. Sara Aton, Chair
Research in animal models and human subjects has found that sleep loss profoundly disrupts the consolidation of hippocampus-dependent memories. The studies outlined in this dissertation aim to address how sleep deprivation (SD) negatively impacts memory consolidation from both cell- and circuit- level perspectives. These questions are addressed in the context of a well-studied form of sleep-dependent memory consolidation in mice, contextual fear memory (CFM). CFM is disrupted by sleep loss in the first few hours following contextual fear conditioning (CFC). To describe the contributions of sleep and learning on protein translation, we modified existing translating ribosome affinity purification (TRAP) techniques to immunoprecipitate ribosome-bound mRNAs from multiple hippocampal cell populations and isolated transcripts from two subcellular fractions. Our results identified different effects of SD and learning on ‘cytosolic-’ and ‘membrane-‘ (MB) localized ribosomes, respectively. At cytosolic ribosomes, SD increased synaptic plasticity gene expression and occluded the sparse expression of CFC-related genes in excitatory hippocampal neurons. At MB ribosomes, CFC induced diverging bioenergetic mRNAs dependent on an animal’s state. To assay cell populations differently active during sleep and SD we profiled activated neuron mRNAs by phosphorylated ribosome capture (pS6-TRAP). Bioinformatic, qPCR, and IHC analyses identified hippocampal somatostatin-expressing (SST+) interneurons to be activated by SD. Chemogenetic experiments demonstrate that maintaining elevated SST+ interneuron activity during sleep is sufficient to impair memory consolidation following learning. These results suggest that reduced SST activity during sleep is necessary for post-CFC memory consolidation. Together our results provide two new perspectives on sleep-dependent memory consolidation at the level of protein synthesis and shifts in interneuron activity during sleep.