Elucidation of RNA-Based Mechanisms of Long-Term Memory Storage

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How our memories persist more-or-less unchanged for years, decades, and, in some cases, for lifetime remains poorly understood. The project investigates the mechanisms that underlie long-term memory. A guiding hypothesis of the project is that memories are not stored in the brain as changes in the connections between neurons but, rather, as modifications in the nuclei of neurons. A major goal of the project is to identify the processes that mediate the nuclear modifications that encode long-term memory. Data from the proposed project could facilitate the development of novel treatments for disorders of memory, including Alzheimer’s disease and posttraumatic stress disorder. In addition, the project enhances the scientific literacy of high school and undergraduate students from underrepresented or economically disadvantaged backgrounds. This goal is accomplished through formal lectures on the neurobiology of memory to be offered in UC Santa Barbara’s Summer Research Academy (SRA), as well as giving high school students in the SRA and undergraduates associated with UCLA’s Brain Research Institute Brain Research Institute Summer Undergraduate Research Experience (BRI SURE) the opportunity to participate in guided research in the Principal Investigator’s laboratory during the summer.Recently, the principal investigator has discovered that long-term memory (LTM) in the marine snail Aplysia appears to be stored in neurons by nuclear changes. One type of nuclear change that has been implicated in LTM storage in Aplysia is epigenetic changes; however, genomic changes may also play a critical role in encoding LTM. A type of genomic change that may mediate LTM is retrotransposition. The proposed project investigates the potential involvement of retrotransposons in LTM in Aplysia. Specifically, the investigators test whether retrotransposition is required for a type of synaptic memory, long-term facilitation (LTF) of Aplysia sensorimotor synapses in dissociated cell culture. To accomplish this objective, the investigators test whether inhibitors of reverse transcriptase and of DNA double-strand breaks disrupt LTF. The project also identifies species of non-coding RNAs (ncRNAs) that trigger nuclear changes that encode a form of non-associative memory in Aplysia, long-term sensitization (LTS) of the siphon-withdrawal reflex. Both RNA-seq and small RNA-seq will be performed on RNA extracted from the identified sensory and motor neurons dissociated from the central nervous system of LTS-trained and untrained animals. Differential expression analyses on the RNA-seq data is carried out to identify potential memory-inducing ncRNAs; the mnemonic potency of the candidate ncRNAs then is assessed through bioassays performed using sensory and motor neurons in dissociated cell culture. Data from the proposed project can, potentially, significantly alter thinking about how the brain encodes memory. This, in turn, could lead to new approaches to artificial intelligence (AI). At present, models of machine learning in AI are heavily influenced by synaptic models of memory that are based on neuroscientific findings. Finally, results from the proposed project may facilitate the development of novel treatments for disorders of memory, including Alzheimer’s disease and posttraumatic stress disorder.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.