Silent memory engrams as the basis for retrograde amnesia

Abstract

Recent studies identified neuronal ensembles and circuits that hold specific memory information (memory engrams). Memory engrams are retained under protein synthesis inhibition-induced retrograde amnesia. These engram cells can be activated by optogenetic stimulation for full-fledged recall, but not by stimulation using natural recall cues (thus, amnesia). We call this state of engrams "silent engrams" and the cells bearing them "silent engram cells." The retention of memory information under amnesia suggests that the time-limited protein synthesis following learning is dispensable for memory storage, but may be necessary for effective memory retrieval processes. Here, we show that the fullfledged optogenetic recall persists at least 8 d after learning under protein synthesis inhibition-induced amnesia. This long-term retention of memory information correlates with equally persistent retention of functional engram cell-to-engram cell connectivity. Furthermore, inactivation of the connectivity of engram cell ensembles with its downstream counterparts, but not upstream ones, prevents optogenetic memory recall. Consistent with the previously reported lack of retention of augmented synaptic strength and reduced spine density in silent engram cells, optogenetic memory recall under amnesia is stimulation strength-dependent, with low-power stimulation eliciting only partial recall. Finally, the silent engram cells can be converted to active engram cells by overexpression of α-p-21-activated kinase 1, which increases spine density in engram cells. These results indicate that memory information is retained in a form of silent engram under protein synthesis inhibition-induced retrograde amnesia and support the hypothesis that memory is stored as the specific connectivity between engram cells.A memory engram is the enduring physical or chemical changes that occur in brain networks upon learning, representing the acquired memory information. Memory engrams are held by a set of neuronal ensembles that are activated by learning, and reactivation of these neurons gives rise to recall of the specific memory (1-3). A combination of immediate early genes, transgenics, and optogenetic techniques has recently provided the long-sought gain-of-function evidence for engram cells in the dentate gyrus of the hippocampus (4-6). This evidence has been complemented by loss-of-function evidence in the lateral amygdala (7,8). Further studies identified and investigated memory engram cells in various brain areas under a variety of mnemonically relevant behavioral protocols (9-18). Furthermore, optogenetic manipulations of specific engram cells in vivo permitted unprecedented investigations of the relationship between memory representations and animal cognition or behaviors, allowing inception of a false memory (5), switching memory valence (19,20), ameliorating depression-like behaviors (21), and restoring a memory impairment in early Alzheimer's mice (22).Another important benefit of engram cell identification is that it permits investigation...

Brain-wide mapping of contextual fear memory engram ensembles supports the dispersed engram complex hypothesis

“…Most known brain regions that have previously been demonstrated to hold engrams by optogenetic and other manipulations (e.g., hippocampal dentate gyrus, CA3, and basolateral amygdala) showed high engram index values, supporting our hypothesis that a brain region with a high index is likely to hold an engram cell ensemble. One limitation of this index, however, is that it cannot be used to identify silent engram cells, which are formed in certain brain regions during encoding but are not reactivated by natural recall cues for recall although they can be optogenetically reactivated (Roy et al, 2017a;Ryan et al, 2015;Tonegawa et al, 2018). A second limitation of this index is that it is limited to brain regions in which cFos is expressed, which clearly is the case for the majority of regions.…”

“…Several studies have identified engram cells for different memories in many brain regions including the hippocampus (Liu et al, 2012;Ohkawa et al, 2015;Roy et al, 2016), amygdala (Han et al, 2009;Redondo et al, 2014), retrosplenial cortex (Cowansage et al, 2014), and prefrontal cortex (Kitamura et al, 2017). In particular, by performing engram cell connectivity and engram cell reactivation experiments, it has been demonstrated that a given memory is stored in a specific set of engram cell ensembles that exhibit enduring cellular changes and are functionally connected (Roy et al, 2017a;Ryan et al, 2015). While these findings have enhanced our understanding of engrams and their dynamics, a thorough mapping of engram cell ensemble circuits for a specific memory has not been accomplished.…”

Modulating reconsolidation and extinction to regulate drug reward memory

“…Direct optogenetic activation of the 'silent engrams', the amnesic engram cells that did not show learning-induced augmented synaptic strength after a protein synthesis inhibitor-induced retrograde amnesia, could restore memory recall in amnesic animals (Ryan et al, 2015;Roy et al, 2017). These results support that retrograde amnesia induced by the protein synthesis inhibitor in the consolidation process inhibited memory retrieval rather than disrupted memory storage, suggesting that the consolidation of memory was essential for memory retrieval but not storage (Roy et al, 2017). An alternative explanation is that the intact memory traces could be responsible for the information of the CS stored in the brain, but the association between the CS and the UCS was erased by the protein synthesis inhibitor in the animals.…”

High capacity and dynamic accessibility in associative memory networks with context-dependent neuronal and synaptic gating

“…Furthermore, our model provides a direct mechanistic basis for memory failure due to loss of accessibility rather than forgetting 39 . Such a hypothesis has been put forth in the context of different types of amnesia 39,42,43 . Therefore, our model may have specific implications for the understanding of memory access in healthy and disease states.…”

“…Finally, how accessible each memory is (during recall) may limit the theoretically achievable storage capacity 39,40 , which is often ignored in mechanistic memory models. For example, it has been posited that some cases of memory forgetting, such as amnesia, may be partially due to deficits in memory accessibility rather than decay of the memories themselves [41][42][43] . Here too, context dependence may control memory expression and search 8,10 , for example, by directing retrieval towards particular memories, through gating or biasing of memory strength 44 .…”