Annefleur Langedijk, hoofdredacteur
Hedwig Ens (eindredactie)
Will van Houten (eindredactie)
dr. M. Dekker
dr. M. Keestra
drs. S. Sitalsing
prof. dr. F. van Vree
drs. L. Wenting
What is the best present you have ever received? Thanks to the activation of a certain combination of brain cells, you will now vividly remember the best gift you once got. In my case, it is my first bike: bright yellow with an orange flag, for my fifth birthday. Even though this memory was formed over twenty years ago, I can still clearly remember the anticipation when I saw the flag peeking through the wrapping paper. And the wonderful first ride through the living room is imprinted in my brain.
The remarkable processes of memory formation, consolidation, and retrieval have intrigued great thinkers over many centuries, like Plato and John Locke. And indeed, memories are very special conceptions. They allow you to sing along to all those torturous Christmas songs, remember your all-time favourite pet, and permit a squirrel to relocate his buried nuts after hibernation. Besides, memories were a source of inspiration for numerous movies like ‘Eternal sunshine of the spotless mind’, ‘Fifty first dates’, and Leonardo DiCaprio’s ‘Inception’. While in these movies memories can be erased or implanted in the blink of an eye, neuroscientists are actually taking baby steps in unravelling the elusive physiological substrates of memories, the so-called memory engrams.
Already in 1921, the German zoologist and biologist Richard Wolfgang Semon postulated his theory on memory engrams: “The enduring though primarily latent modification in the irritable substance, produced by a stimulus”.1 In other words: memories are formed by lasting biophysical changes in brain cells. Furthermore, memories could subsequently be reactivated, leading to retrieval of the memory. In his famous book in 1949, psychologist Donald Hebb proposed a neurobiological mechanism based on plasticity of synapses, as a substrate of memory.2 He hypothesised that when the activation of one cell leads to the activation of another cell, the connection between these two cells is reinforced. In other words: “cells that fire together, wire together”. His theory was confirmed in numerous studies a few years later and it remains to date one of the most influential theories in neuroscience. However, in a brain containing over 80 billion neurons, how do you find the cells that are connected and contain a memory?
For decades, memory research focussed on damaging parts of the brain to find out their role in memory formation and retrieval. This approach is courteously illustrated by the remarkable case of epileptic patient H.M. Back in the fifties of the previous century, H.M. underwent surgery with the aim of alleviating his epileptic seizures. In both hemispheres of his brain, considerable parts of the medial temporal cortex were removed. The surgery appeared to be successful in mitigating the epileptic seizures, but H.M. was unable to form new memories. Like the main character of romantic comedy ‘Fifty first dates’, he suffered from anterograde amnesia. This important case study highlighted the crucial role of the hippocampus, part of the removed medial temporal lobe, in the formation of new memories. The next decades of research confirmed the vital importance of the hippocampus in several memory processes and indicated that memory loss in psychopathologies, like Alzheimer’s disease, can often be traced back to damage in the hippocampus. However, if you want to study memory formation or retrieval on a cellular level, a more detailed and precise analysis is required.
Recently, researchers have been able to zoom in on the networks of neurons that contain memories. By using markers of neuronal activity, researchers estimated that only about ~10% of neurons in certain brain areas are active upon memory retrieval. This indicates that only a small subset of neurons constitutes a memory engram. By using modern molecular methods, combined with for example optogenetics, researchers can nowadays find and manipulate activated, memory-harbouring neurons.3 In case of optogenetics, a technique awarded prestigious titles like Science’s ‘Breakthrough of the Decade’ 4 and Nature’s ‘Method of the Year’,3 genes for light-sensitive proteins are inserted in selected neurons. Neurons can be selected based for example on their cell-type or activation. In these cells, light-sensitive proteins will be inserted in the cell membrane and can subsequently be activated by (laser) light of a certain wavelength. Depending on whether you opted for an exciting or inhibiting protein, this will lead to activation or suppression of the cell, respectively. That way, you can determine the contribution of these cells to a certain action or behaviour, even in living animals. If you insert these light-sensitive genes into memory-harbouring cells, you can investigate how these cells contribute to memory expression or reconsolidation.
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1. Semon, R. W. The Mneme. George Allen & Unwin Ltd. (1921).
2. Hebb, D. The organization of behavior; a neuropsychological theory. Wiley & Sons (1949).
3. Deisseroth, K. Optogenetics. Nat. Methods 8, 26–29 (2011).
4. Staff, T. new. Insights of the decade. Stepping away from the trees for a look at the forest. Introduction. Science 330, 1612–1613 (2010).
5. Liu, X. et al. Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature 484, 381–5 (2012).
6. Hsiang, H.-L. et al. Manipulating a ‘Cocaine Engram’ in Mice. J. Neurosci. 34, 14115–14127 (2014).
7. Roy, D. S. et al. Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease. Nature 531, 508–12 (2016).
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