On the molecular basis of enduring memory in neurons, and cell fate in fibroblasts.

Memories can last a lifetime, and how this is achieved remains an unanswered challenge. Most current thinking sees molecular traces of memories (engrams) as sets of synaptic proteins facilitating neuronal co-firing and co-wiring. However, most proteins turn over in months or less. Another challenge is how fibroblasts remember their cell fate for decades, and an emerging model sees functionally related genes co-firing in clusters (called transcription factories and condensates) that make RNAs specifying cell fate. As clustering is driven by entropic forces acting throughout time, the first cells may have possessed this memory system, and Nature could have exploited it to store engrams when nervous systems evolved. Then, transcription creates the naïve neuronal substrate and defines which cells are included in co-wiring and co-firing circuits, before progressive cell differentiation consolidates long-term memories. I speculate that transcription plays another central role. For every nucleotide added to a nascent RNA, transcription generates a pyrophosphate-a chelating agent that sequesters the calcium ions that can modify action-potential spike-trains. In other words, the same nano-wired DNA computer that specifies cell fate could store and manipulate our memories.