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One of the central predictions of the Hebbian theory of learning is that memories are stored by the same neurons that were engaged during learning. Although Hebb published his famous postulate, “neurons that fire together, wire together” (paraphrasing, of course) over 50 years ago, actual evidence that both learning and memory activate the same population of neurons has largely been absent. However, new research out of the Hausser lab lends experimental support to this long-standing assumption, and also indicates that reactivation of just a fraction of these “memory neurons” is enough to conjure up full blown recall.
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Just a few years ago, Reijmers et al genetically manipulated mice to enable tagging of neurons active at two distinct timepoints: during encoding and during retrieval of a specific memory. Their results showed that a significant number of neurons were active at both time points when compared to chance, suggesting the same neurons that are active during learning are also active during recall. Now, Rizzi et al have taken another leap forward by showing that if neurons engaged during learning are reactivated at a later time point, the memory of the learned content is triggered. How they accomplished this is actually quite simple, though wonderfully elegant. I briefly discussed channelrhodopsin-2 (ChR2) in an earlier post, which is probably the most popular technique in the burgeoning field of optogenics. Briefly, channelrhodopsin is a light-activated cation channel that causes rapid depolarization of cells whenever light of a particular wavelength is encountered. Linking the channelrhodopsin gene to specific gene promoters enables researchers to express ChR2 in a particular cell population, or, in the case of an immediate-early gene promoter, exclusively in active cells. Hausser and colleagues used the latter approach, linking ChR2 to the c-fos promoter. The next step was to administer a task where the brain structure mediating learning is well known. They accomplished this using contextual fear conditioning, which is hippocampal dependent. So, theoretically, hippocampal neurons active when animals are learning the association between foot shock and environment will express ChR2, and thus can be activated by shining light into the hippocampus at a later point in time. And when light was delivered to this region in behaving animals, they froze, an indicator of fear – presumably stemming from recall of the fearful memory. What’s also remarkable is that the researchers were able to elicit a fear response by activating a very small (~100) number of neurons, corresponding to just a fraction of the neuronal population activated during learning. Does stimulation of a few neurons enable activation of the complete network of neurons encoding the memory (similar to a pattern completion function)? Does incomplete reactivation cause incomplete recall? Are memories stored in redundant networks, where stimulation of just one of these is enough to activate recall? Or is it simply that within a single network there exist several backups of a memory, expressed as multiple neurons encoding the same information? Previous work from Han et al has shown that memory for a fearful event remains intact following inactivation of up to 20% of the neurons engaged during learning, suggesting that multiple memory traces exist. However, other interpretations certainly can’t be ruled out just yet. A few caveats, of course. Anytime you are using immediate-early gene expression as a metric of neuronal activation, you must be careful. Several of these genes exist, and all seem to be expressed under specialized conditions and time points. But, expression of genes like c-fos in the hippocampus does show reliable correlation to things like contextual fear learning. Also, I wonder how long the c-fos–ChR2 gene was “expressible” during the experiment. Obviously, the hippocampus is a pretty active structure, and background activity or exposure to extraneous learning opportunities could increase expression of ChR2 and dilute specific expression due to contextual fear conditioning. Nevertheless, freakin’ cool study.
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