UCLA

Learning and memory have long been hot topics in the field of neuroscience, not only because they play fundamental roles in human experience, but also because there are multiple diseases that are associated with deficits in learning and memory. At the cellular level, memory results from changes in the strength of the synaptic connections between neurons, and alterations in gene expression underly the persistence of many of these changes.

Translation of synaptically localized mRNAs is important for long-term synaptic plasticity. Extracellular vesicles (EVs) contain RNAs and neuronal EV secretion has been reported to be regulated by synaptic activity, which leads to the hypothesis that EVs are transferred between cells in the nervous system and that mRNAs and microRNAs transferred through this pathway are important for local translation during neuronal plasticity. To test this hypothesis, we purified EVs from primary neuronal culture media and performed small RNA sequencing on neuronal evRNAs and their respective donor cells. We found an enrichment of small RNAs in EVs, and the composition of the small RNAs, including the miRNA profile, was distinct from that in donor cells. Our findings reveal a comprehensive map of RNAs inside neuronal EVs and identify multiple miRNAs as promising candidates for future investigation.

Normal aging often involves some level of memory impairment and as such represents a physiologically relevant manipulation of plasticity and memory, with the comparison between young and aged mice providing insights into differences in gene regulation that may be central to plasticity and memory. We performed ATAC-seq and RNA-seq on the hippocampus of young and aged mice and found that aging resulted in significant changes in the expression of genes involved in neurogenesis, immune response, and cell adhesion, and in the alternative splicing of select myelin sheath genes. We found that aged female mice had higher levels of expression of several myelin sheath genes compared to aged male mice. Chromatin accessibility analysis revealed a more open chromatin structure in the hippocampus of aged animals compared to young animals, and many of these changes occurred at repetitive elements. However, changes in chromatin accessibility were not well-correlated with changes in gene expression. Our results provide insights into the changes in gene expression that occur with aging, highlighting changes in genes important for myelin sheath maintenance, and suggest that age-related chromatin accessibility changes may play an indirect role in age-related transcriptional changes.