Amnesia is a deficit of memory function that can result from trauma, stress, disease, drug use, or ageing. Though efforts are being made to prevent and treat the various causes of amnesia, there remains no treatment for the symptom of memory loss itself. Because the defining feature of amnesia is an inability to recall memory, any given case may be due to the possibility that the memory is gone, or the alternative that it is present but irretrievable (Squire, 1982). Discriminating between these two scenarios would be of scientific value, because the neurobiology of memory formation is anchored in experimental amnesia. From a clinical perspective, pathological cases of amnesia that are due to retrieval deficits may in principle be treatable rather than merely preventable. Amnesia could be attributed to a retrieval deficit if the ostensible ‘lost’ memory could be evoked through brain stimulation. The challenge here is to identify exactly where in the brain a particular memory is stored.

Our strategy to meet this challenge was based on Richard Semon’s 100 and some year-old memory engram theory (Semon, 1904). In the contemporary version of this theory, formation of memory starts with learning-induced activation of a specific population of neurons, followed by an establishment of enduring physical or chemical changes in these neurons, referred to as an engram, which is the brain representation of the acquired memory. Furthermore, subsequent recall of the memory is evoked by reactivation of these engram-holding neurons by recall cues. Our approach took advantage of the activation of an immediate early gene, c-fos, in a specific population of neurons upon experiencing a certain episode. These neurons can be labelled upon learning with a light-sensitive protein like channelrhodopsin-2 (ChR2) in a transgenic mouse in which the promotor of the c-fos promoter controls the expression of ChR2 (Liu et al, 2012). Using this genetic technology, the memory engram cell population in the hippocampus could be identified, and their subsequent reactivation by light of a specific wavelength was sufficient for eliciting recall of the specific memory. Furthermore, these engram cell populations were shown to be essential for natural memory recall (Tonegawa et al, 2015).

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