The central importance of nuclear mechanisms in the storage of memory

The neurobiological nature of the memory trace (engram) remains controversial. The most widely accepted hypothesis at present is that long-term memory is stored as stable, learning-induced changes in synaptic connections. This hypothesis, the synaptic plasticity hypothesis of memory, is supported by extensive experimental data gathered from over 50 years of research. Nonetheless, there are important mnemonic phenomena that the synaptic plasticity hypothesis cannot, or cannot readily, account for. Furthermore, recent work indicates that epigenetic and genomic mechanisms play heretofore underappreciated roles in memory. Here, we critically assess the evidence that supports the synaptic plasticity hypothesis and discuss alternative non-synaptic, nuclear mechanisms of memory storage, including DNA methylation and retrotransposition. We argue that long-term encoding of memory is mediated by nuclear processes; synaptic plasticity, by contrast, represents a means of relatively temporary memory storage. In addition, we propose that memories are evaluated for their mnemonic significance during an initial period of synaptic storage; if assessed as sufficiently important, the memories then undergo nuclear encoding.