Almost all neuroscientists base their search—for the physical basis of memory (the engram)—on the assumption that temporal-pairing causes learning. They are dedicated to this assumption—even though, as Rescorla pointed out 50 years ago, experimental attempts to define temporal-pairing have always failed. This failure is as striking now as it was 50 years ago. Anything that gets neuroscientists to abandon the idea that temporal-pairing is a useful scientific concept is a step toward discovering the physical basis of memory. Each neuron contains billions of (almost) incomprehensibly-tiny molecular machines. Molecular biologists have developed an astonishing array of techniques for visualizing/manipulating the actions of these little machines. These techniques will allow molecular biologists to follow the machines inside this huge neuron to the engram—to the tiny machine that encodes the experience-gleaned facts so that these learned/remembered facts can inform later behavior.

2021-11-19: This feels like a really big deal:

Biology feels different right now. New broadly enabling technologies and tools are driving forward progress in nearly every specific field at a rapid pace. The large scale adoption and application of a powerful set of common tools has created a virtuous cycle of further technology refinement and engineering. The rate of iteration is increasing, and previously intractable problems are now within reach. While RNA-seq and MPRAs are both valuable approaches, they come with some limitations. Fundamentally, each measurement represents a single static slice of a dynamic process which is only inferred by attempting to piece together the slices. The quality of the reconstruction is limited by sampling density. What if we could measure these systems continually as they occurred in a way that didn’t require destructive sampling? Here, the fundamental idea is that “DNA is the natural medium for biological information storage, and is easily ‘read’ through sequencing.” This forms the basis for this new technology: ENGRAM (ENhancer-driven Genomic Recording of transcriptional Activity in Multiplex). The workflow of this technique is very similar to that of the MPRA introduced above, but with an important twist. Instead of destroying the cell and sequencing a ratio of barcodes, the transcription event is recorded by the insertion of a barcode into a locus of DNA in the cell via prime editing. They went further and showed that they could effectively multiplex this technique by reading out all 3 signals in response to stimulants in a single population of cells. Even more, they showed a proof-of-concept for reading out the order in which events occurred.

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