2005 : WHAT DO YOU BELIEVE IS TRUE EVEN THOUGH YOU CANNOT PROVE IT?

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Computational Neuroscientist; Francis Crick Professor, the Salk Institute; Coauthor, The Computational Brain
Computational Neuroscientist, Howard Hughes Medical Institute; Coauthor, The Computational Brain

How do we remember the past? There are many answers to this question, depending on whether you are an historian, artist or scientist. As a scientist I have wanted to know where in the brain memories are stored and how they are stored¦the genetic and neural mechanisms. Although neuroscientists have made tremendous progress in uncovering neural mechanisms for learning, I believe, but cannot prove, that we are all looking in the wrong place for long-term memory.

I have been puzzled by my ability to remember my childhood, despite the fact that most of the molecules in my body today are not the same ones I had as a child¦in particular, the molecules that make up my brain are constantly turning over, being replaced with newly minted molecules. Perhaps memories only seem to be stable. Rehearsal strengthens memories, and can even alter them. However, I have detailed memories of specific places where I lived 50 years ago that I doubt I ever rehearsed but can be easily verified, so the stability of long-term memories is a real problem.

Textbooks in neuroscience, including one that I coauthored, say that memories are stored at synapses between neurons in the brain, of which there are many. In neural network models of memory, information can be stored by selectively altering the strengths of the synapses, and "spike-time dependent plasticity" at synapses in the cerebral cortex has been found with these properties. This is a hot area of research, but all we need to know here is that patterns of neural activity can indeed modify a lot of molecular machinery inside a neuron.

If memories are stored as changes to molecules inside cells, which are constantly being replaced, how can a memory remain stable over 50 years? My hunch is that everyone is looking in the wrong place: that the substrate of really old memories is located not inside cells, but outside cells, in the extracellular space. The space between cells is not empty, but filled with a matrix of tough material that is difficult to dissolve and turns over very slowly if at all. The extracellular matrix connects cells and maintains the shape of the cell mass. This is why scars on your body haven't changed much after decades of sloughing off skin cells.

My intuition is based on a set of classic experiments on the neuromuscular junction between a motor neuron and a muscle cell, a giant synapse that activates the muscle. The specialized extracellular matrix at the neuromuscular junction, called the basal lamina, consists of proteoglycans, glycoproteins, including collagen, and adhesion molecules such as laminin and fibronectin. If the nerve that activates a muscle is crushed, the nerve fiber grows back to the junction and forms a specialized nerve terminal ending. This occurs even if the muscle cell is also killed. The memory of the contact is preserved by the basal lamina at the junction. Similar material exists at synapses in the brain, which could permanently maintain overall connectivity despite the coming and going of molecules inside neurons.

How could we prove that the extracellular matrix really is responsible for long-term memories? One way to disprove it would be to disrupt the extracellular matrix and see if the memories remain. This can be done with enzymes or by knocking out one or more key molecules with techniques from molecular genetics. If I am right, then all of your memories¦what makes you a unique individual¦are contained in the endoskeleton that connects cells to each other. The intracellular machinery holds memories temporarily and decides what to permanently store in the matrix, perhaps while you are sleeping. It might be possible someday to stain this memory endoskeleton and see what memories look like.