![]() This proved that, firstly, the memory is maintained and, secondly, the cells responsible for encoding the original memory are not properly reactivated in early-stage AD models ( Roy et al., 2016 Perusini et al., 2017). Using the engram tagging approach in this model, animals with amnesia due to early-stage AD were able to remember a contextual memory through optogenetic stimulation of the labelled engram neurons. ![]() The fact that this kind of amnesia is retrograde (because the initial short-term memory is observed) indicates that the engram might still be present in the brain. In the APP/PS1 mouse model, short-term memories (minutes to hours) are intact, whereas long-term memories (a day or more) are compromised, indicating a consolidation deficit as a cause of the amnesia ( Kilgore et al., 2010 Ryan et al., 2015). Although these studies show that certain activities and interventions can ameliorate the deterioration of memory, they do not show whether the engram itself survives amnesia. Photonic stimulation of the visual cortex by chronic application of light in frequencies of 40 Hz improved contextual and fear memory, and significantly reduced amyloid-β plaque deposition ( Iaccarino et al., 2016). Environmental enrichment was shown to be beneficial by stimulation of synaptic activity ( Jankowsky et al., 2005 Lazarov et al., 2005 Fischer et al., 2007). The APP/PS1 mouse model recapitulates many of the hallmarks of human AD, including deficits in spatial, social and cognitive memory ( Gong et al., 2004 Lalonde et al., 2005), but some strategies have successfully improved cognition in these models. As a consequence of these aggregates, synapses are compromised, and there is selective neuronal death and a decrease in specific neurotransmitters (reviewed in Masters et al., 2015). AD is associated with the deposition of amyloid-β peptide in extracellular plaques and with the aggregation of the microtubule-associated protein tau in neurofibrillary tangles inside neurons ( Braak and Braak, 1991). The same methodological approach was subsequently applied to models of early AD – the major neurodegenerative disease that affects memory storage ( Roy et al., 2016 Perusini et al., 2017). This approach demonstrated that direct activation of engram neurons for contextual memories associated with fear/threat is sufficient ( Liu et al., 2012 Ramirez et al., 2013), as well as necessary ( Denny et al., 2014 Tanaka et al., 2014 Trouche et al., 2016), to recall this specific episodic memory. Temporal control is allowed by the tetracycline-controlled transactivator (tTA)-tetracycline response element (TRE) system, inducible by the removal of the antibiotic doxycycline so that it only labels the neurons that are responding to the controlled contextual experience. In its first demonstration, a promoter of the IEG c-fos was used to drive the expression of channelrhodopsin (ChR2), a light-responsive ion channel, in hippocampal dentate gyrus neurons that were activated by a target contextual experience ( Fig. 1). Developed originally by Tonegawa and colleagues, the technology integrates optogenetics and immediate early gene (IEG) labelling to drive the expression of a transgene in cells that specifically respond to an experience ( Boyden et al., 2005 Reijmers et al., 2007 Tonegawa et al., 2015a, b). ![]() Memory engram technology is based on the combination of transgenic, optogenetic, behavioural and electrophysiological approaches. Recently, we have begun to make progress in our understanding of both memory and amnesia through the development of memory engram technology. The general approach is to interfere with a brain region, physiological process or gene that we hypothesize is important for memory, and then look for experimental amnesia in a given behavioural paradigm ( McGaugh, 2000). To understand the mechanisms of engram formation, we have primarily relied on indirect methodological approaches, for example, by studying amnesia. Reactivation of these engram cells will result in the recall of that particular memory ( Semon, 1904). In 1904, Richard Semon postulated that experiences provoke long-lasting changes in specific neurons that result in an enduring memory trace – an engram of the acquired information. Understanding memory, and its mechanisms, is a central goal of modern neuroscience. Knowledge learnt by animals alters their brain and modulates how the brain then regulates future behaviour. Memory is the ability to store information of past experiences in the brain.
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