A possible mechanism of neural read-out from a molecular engram

Elsevier

Available online 11 March 2023, 107748

Neurobiology of Learning and MemoryAuthor links open overlay panel, , Abstract

What is the physical basis of declarative memory? The predominant view holds that stored information is embedded in the structure of a neural net, that is, in the signs and weights of its synaptic connections. An alternative possibility is that storage and processing are separated, and that the engram is encoded chemically, most probably in the sequence of a nucleic acid. One deterrent to adoption of the latter hypothesis has been the difficulty of envisaging how neural actively could be converted to and from a molecular code. Our purpose here is limited to suggesting how a molecular sequence could be read out from nucleic acid to neural activity by means of nanopores.

Section snippets1. A molecular engram?

The physical substrate of memory remains unknown. Gold and Glanzman (2021) give a succinct survey of the several theories of the engram that are currently in play. The majority view is that all forms of memory depend on the growth and attenuation of synaptic connections in a neural net, although there is little agreement on whether the unit of memory is a dendritic spine, a cell or a cell assembly (e.g. Abdou et al., 2018, Asok et al., 2019, Choi et al., 2018, Langille and Brown, 2018, Mayford

The problem of conversion between neural and molecular codes.

Two traditional problems that face a molecular account of the engram – problems that might be thought almost insuperable – are those of how information is encoded and how it is rapidly read out. We here confine ourselves to the problem of read out. Richard Semon, who first introduced the term ‘engram’, called the hypothetical read-out process ‘ecphory’ (Schacter et al., 1978, Semon, 1904, Semon, 1921). How can the stored information be rapidly retrieved and converted into the neural activities

A technological analogue.

We propose that nature might have developed an analogue of the nanopore technology that is now widely used to sequence DNA (Deamer et al., 2016, Wang et al., 2021) – not only DNA of biological origin but also synthetic DNA that encodes images or text (Lopez et al., 2019).

The man-made system – as developed by Oxford Nanopore Technologies – uses a nanometer-sized protein aperture, or ‘nanopore’, embedded in a thin, electrically resistant, polymer membrane (Figure 1, left panel). The channel

Biological nanopores for read-out from a molecular engram?

In the course of evolution, nature has developed a rich variety of biological nanopores, and it is indeed such ‘biopores’ that have most often been exploited in man-made sequencing systems. Typically, biotechnologists alter the natural protein structures by replacing, adding or deleting amino acids so as to tune the dimensions, charge, hydrophobicity etc. (Deamer et al., 2016, Howorka, 2017). The biopores most often used in man-made systems are pore-forming toxin proteins secreted by pathogenic

The advantage of single-stranded reading.

The nucleic-acid channels underlying transformation in bacteria, and the channel identified in mammals by Hanss et al, are specific for single-stranded sequences. If memory were stored in DNA, then single-stranded read-out would have an advantage analogous to the advantage of genetic coding by DNA – the advantage immediately apparent to Watson and Crick in 1953: The single-strand that is left behind after read-out, i.e. the strand that does not pass through the pore, can be rebuilt with

DNA or RNA?

Our discussion above has predominantly been in terms of DNA rather than RNA. The greater stability of DNA recommends it as the ultimate seat of the long-term engram, and non-chromosomal DNA is abundantly available, both in cytoplasm and outside the cell (Aucamp et al., 2018). Cytosolic DNA usually serves as a marker of infection, inflammation or aging (Miller et al., 2021), but of interest in the present context is ‘brain metabolic DNA’, which is modulated when animals learn or are exposed to

Uncited references

Allentoft et al., 2012, Giuditta et al., 2023, Hanss et al., 2002, Shi et al., 2007, Watson and Crick, 1953.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

We are grateful to S. E. Bilgiç for the preparation of Figure 1.

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