Molecular Mechanisms of Memory Consolidation in the Amygdala-Hippocampal Circuit

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Project Summary Sleep and memory dysfunction are key features across many psychiatric disorders. Patients with schizophrenia commonly display both decreased sleep spindles and memory consolidation deficits. In comparison, people suffering from post-traumatic stress disorder have sleep disruption and nightmares associated with heightened fear memories. A growing number of studies support the theory that infrequently used dendritic spines are pruned during sleep, thus improving memories by enhancing the signal to noise ratio of frequently reinforced synaptic connections. Our published and preliminary data demonstrates that dendritic spines in neurons that encoded a recent contextual fear memory trace are upscaled during sleep in the presence of broad downscaling. Furthermore, our data pointing to broad upscaling of dendritic spines in the amygdala during sleep compared to broad downscaling in the hippocampus indicates that synapses in two key areas of the emotional memory circuit are differentially regulated. There is a critical knowledge gap regarding the molecular pathways involved in dendritic spine upscaling and downscaling during sleep. The proposed studies will use a combination of state-of-the-art single nucleus RNA sequencing, spatial transcriptomics and targeted mass spectrometry along with a novel transgenic mouse model, and complementary human brain postmortem studies, to create a much-needed foundation of molecular signaling pathways involved in upscaling and downscaling of synapses in the fear memory circuit during sleep and identify new molecules involved in this process. Thus, the aims of this proposal will significantly leverage the expertise and technological capabilities uniquely offered through the Molecular Center of Health and Disease- COBRE. The expected data will serve as a foundation for future studies examining disruption of these pathways in psychiatric disorders, and studies designed to identify novel targets for therapeutic strategies.