Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Memory Consolidation Engrams and Circuits


Science  07 Apr 2017: Vol. 356, Issue 6333, pp. 73-78

Engrams and circuits crucial for systems consolidation of a memory

Takashi Kitamura,

RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Departments of Biology and Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.


Episodic memories initially require rapid synaptic plasticity within the hippocampus for their formation and are gradually consolidated in neocortical networks for permanent storage. However, the engrams and circuits that support neocortical memory consolidation have thus far been unknown. We found that neocortical prefrontal memory engram cells, which are critical for remote contextual fear memory, were rapidly generated during initial learning through inputs from both the hippocampal–entorhinal cortex network and the basolateral amygdala. After their generation, the prefrontal engram cells, with support from hippocampal memory engram cells, became functionally mature with time. Whereas hippocampal engram cells    gradually became silent with time,    engram cells in the basolateral amygdala, which were necessary for fear memory, were maintained. Our data provide new insights into the functional reorganization of engrams and circuits underlying systems consolidation of memory.

Memories are thought to be initially stored within the hippocampal–entorhinal cortex (HPC-EC) network (recent memory) and, over time, slowly consolidated within the neocortex for permanent storage (remote memory). Systems memory consolidation models suggest that the interaction between the HPC-EC network and the neocortex during and after an experience is crucial. Experimentally, prolonged inhibition of hippocampal or neocortical networks during the consolidation period produces deficits in remote memory formation. However, little is known regarding specific neural circuit mechanisms underlying the formation and maturation of neocortical memories through interactions with the HPC-EC network. Using activity-dependent cell-labeling technology, combined with viral vector–based transgenic, anatomical, and optogenetic strategies for circuit-specific manipulations and in vivo calcium imaging, we investigated the nature and dynamics of neocortical and subcortical memory engram cells [a population of neurons that are activated by learning, have enduring cellular changes, and are reactivated by a part of the original stimuli for recall] and their circuits for systems consolidation of memory.

We first traced entorhinal projections to frontal cortical structures [the medial prefrontal cortex (PFC),    caudal anterior cingulate cortex (cACC),    and retrosplenial cortex (RSC)] involved in contextual fear memory, as well as to the basolateral amygdala (BLA), with injections of the retrograde tracer cholera toxin subunit B–Alexa555 (hereafter, CTB injections) into these regions. CTB injections resulted in labeling in the medial entorhinal cortex (MEC), specifically in cells in layer Va, indicating that MEC-Va cells have extensive projections to the neocortex and BLA. We then sought to inhibit these specific projections by bilaterally injecting adeno-associated virus 8 (AAV8)–calcium/calmodulin-dependent protein kinase II (CaMKII):eArchT–enhanced yellow fluorescent protein (eYFP) in the deep layers of the MEC in wild-type (WT) mice with bilaterally implanted optic fibers above the PFC, cACC, or RSC. Expression of eArchT-eYFP was abundant in MEC-Va terminals located in each of these regions. These mice were then subjected to contextual fear conditioning (CFC) while we delivered green light bilaterally to the different cortical areas that have MEC-Va projections during either the conditioning period (day 1) (fig. S2E) or the recall test period (days 2, 8, 15, and 22). Axon terminal inhibition with optogenetics of MEC-Va cells within the PFC during day 1 of CFC disrupted memory at days 15 and 22, but not at days 2 or 8. Terminal inhibition during memory recall tests did not affect memory retrieval. Last, terminal inhibition in the cACC or RSC during CFC or recall had no effect on memory throughout these periods.

In this study, we found that PFC memory engram cells for CFC were rapidly formed during day 1 training through inputs from both the MEC-Va and the BLA, but they were not retrievable with natural recall cues. The immature PFC engram cells functionally, structurally, and physiologically matured during the subsequent few weeks, and this process required inputs from HPC engram cells, presumably through the MEC-Va. In contrast to their formation on day 1, retrieval of the PFC engram at a remote time did not require MEC-Va input. HPC engram cells that formed during training became silent with time; they were not retrieved on day 14 by natural recall cues but were still reactivatable optogenetically for recall. However, fear memory BLA engrams that formed during training were functionally maintained, even after the consolidation-mediated switch in recall circuits.

Our model introduces the concept that the prefrontal memory engram is already generated, albeit in an immature form, on day 1 of training through inputs from both the HPC-EC network and the BLA. The standard model hypothesizes that remote memory is formed in the cortex by a slow transfer of hippocampal memory. In contrast, in our study, the role of the hippocampus in cortical memory is in the rapid generation of immature engram cells in the PFC during training and in the subsequent functional maturation of these preexisting engram cells. The immature PFC engram may correspond to the cortical “tagging” suggested in an earlier study. In a previous study, the BLA was found to be crucial for both recent and remote fear memory expression. Our results demonstrate an overlapping set of BLA engram cells for both recent and remote fear memory retrieval, which were quickly formed during training. However, the source of input into the BLA engrams for retrieval    shifts from the MEC-Va at recent time points    to the PFC engram at remote time points. The route through which contextual stimuli    activate the mature PFC engram is unknown. Most likely, the information processed in a variety of sensory cortices reaches the PFC via the thalamus. Supporting this idea, PFC engram cells receive monosynaptic input from both the medial-dorsal and anteromedial thalamus.

Our finding of the lasting hippocampal engrams is consistent with multiple trace theory. However, at the postconsolidation stage, the hippocampal engrams were not activatable by natural recall cues, but rather by optogenetic stimulation. A similar state of hippocampal engrams has previously been observed in anisomycin-induced amnesia and mouse models of early Alzheimer’s disease, and the early (day 2) PFC engram cells showed a similar property. Although we did not determine how long after encoding this “silent state” of the hippocampal engram lasts, we speculate that the hippocampal engram    eventually loses the original memory information. Alternatively, the silent engram cells may still participate in the successful remote recall of discrete episodic details.

As in previous studies, we observed that training resulted in widespread neuronal activation in the neocortex, including the ACC and RSC. However, whereas the activation of PFC neurons is crucial for formation of remote memory, MEC-Va input into the cACC or RSC is dispensable for this process. For remote memory, the PFC may thus have a distinctive role in integrating multiple sensory information stored in various cortical areas. Last, our data show that the remote memory expressed by the PFC engram is conditioned-context specific, suggesting that it is episodic-like.

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