Single‐neuron analysis of aging‐associated changes in learning reveals impairments in transcriptional plasticity

The molecular mechanisms underlying age‐related declines in learning and long‐term memory are still not fully understood. To address this gap, our study focused on investigating the transcriptional landscape of a singularly identified motor neuron L7 in Aplysia, which is pivotal in a specific type of nonassociative learning known as sensitization of the siphon‐withdraw reflex. Employing total RNAseq analysis on a single isolated L7 motor neuron after short‐term or long‐term sensitization (LTS) training of Aplysia at 8, 10, and 12 months (representing mature, late mature, and senescent stages), we uncovered aberrant changes in transcriptional plasticity during the aging process. Our findings specifically highlight changes in the expression of messenger RNAs (mRNAs) that encode transcription factors, translation regulators, RNA methylation participants, and contributors to cytoskeletal rearrangements during learning and long noncoding RNAs (lncRNAs). Furthermore, our comparative gene expression analysis identified distinct transcriptional alterations in two other neurons, namely the motor neuron L11 and the giant cholinergic neuron R2, whose roles in LTS are not yet fully elucidated. Taken together, our analyses underscore cell type‐specific impairments in the expression of key components related to learning and memory within the transcriptome as organisms age, shedding light on the complex molecular mechanisms driving cognitive decline during aging. The image illustrates a single‐neuron total RNA sequencing approach designed to uncover molecular insights into age‐related learning impairments. We studied short‐term and long‐term sensitization, a type of nonassociative learning, in the sea slug Aplysia californica at three distinct ages. Our molecular analyses identified mRNAs and lncRNAs that were differentially expressed during sensitization. These results indicate that transcriptional plasticity associated with learning is compromised with aging.