Concept: Entorhinal cortex
A specific memory is thought to be encoded by a sparse population of neurons. These neurons can be tagged during learning for subsequent identification and manipulation. Moreover, their ablation or inactivation results in reduced memory expression, suggesting their necessity in mnemonic processes. However, the question of sufficiency remains: it is unclear whether it is possible to elicit the behavioural output of a specific memory by directly activating a population of neurons that was active during learning. Here we show in mice that optogenetic reactivation of hippocampal neurons activated during fear conditioning is sufficient to induce freezing behaviour. We labelled a population of hippocampal dentate gyrus neurons activated during fear learning with channelrhodopsin-2 (ChR2) and later optically reactivated these neurons in a different context. The mice showed increased freezing only upon light stimulation, indicating light-induced fear memory recall. This freezing was not detected in non-fear-conditioned mice expressing ChR2 in a similar proportion of cells, nor in fear-conditioned mice with cells labelled by enhanced yellow fluorescent protein instead of ChR2. Finally, activation of cells labelled in a context not associated with fear did not evoke freezing in mice that were previously fear conditioned in a different context, suggesting that light-induced fear memory recall is context specific. Together, our findings indicate that activating a sparse but specific ensemble of hippocampal neurons that contribute to a memory engram is sufficient for the recall of that memory. Moreover, our experimental approach offers a general method of mapping cellular populations bearing memory engrams.
The dentate gyrus (DG) is a region in the hippocampal formation whose function declines in association with human aging and is therefore considered to be a possible source of age-related memory decline. Causal evidence is needed, however, to show that DG-associated memory decline in otherwise healthy elders can be improved by interventions that enhance DG function. We addressed this issue by first using a high-resolution variant of functional magnetic resonance imaging (fMRI) to map the precise site of age-related DG dysfunction and to develop a cognitive task whose function localized to this anatomical site. Then, in a controlled randomized trial, we applied these tools to study healthy 50-69-year-old subjects who consumed either a high or low cocoa-containing diet for 3 months. A high-flavanol intervention was found to enhance DG function, as measured by fMRI and by cognitive testing. Our findings establish that DG dysfunction is a driver of age-related cognitive decline and suggest non-pharmacological means for its amelioration.
Memories can be unreliable. We created a false memory in mice by optogenetically manipulating memory engram-bearing cells in the hippocampus. Dentate gyrus (DG) or CA1 neurons activated by exposure to a particular context were labeled with channelrhodopsin-2. These neurons were later optically reactivated during fear conditioning in a different context. The DG experimental group showed increased freezing in the original context, in which a foot shock was never delivered. The recall of this false memory was context-specific, activated similar downstream regions engaged during natural fear memory recall, and was also capable of driving an active fear response. Our data demonstrate that it is possible to generate an internally represented and behaviorally expressed fear memory via artificial means.
The medial temporal structures, including the hippocampus and the entorhinal cortex, are critical for the ability to transform daily experience into lasting memories. We tested the hypothesis that deep-brain stimulation of the hippocampus or entorhinal cortex alters memory performance.
Adult-born granule cells (GCs), a minor population of cells in the hippocampal dentate gyrus, are highly active during the first few weeks after functional integration into the neuronal network, distinguishing them from less active, older adult-born GCs and the major population of dentate GCs generated developmentally. To ascertain whether young and old GCs perform distinct memory functions, we created a transgenic mouse in which output of old GCs was specifically inhibited while leaving a substantial portion of young GCs intact. These mice exhibited enhanced or normal pattern separation between similar contexts, which was reduced following ablation of young GCs. Furthermore, these mutant mice exhibited deficits in rapid pattern completion. Therefore, pattern separation requires adult-born young GCs but not old GCs, and older GCs contribute to the rapid recall by pattern completion. Our data suggest that as adult-born GCs age, their function switches from pattern separation to rapid pattern completion.
This fMRI study examined recall and familiarity for words and scenes using the novel recognition without cued recall (RWCR) paradigm. Subjects performed a cued recall task in which half of the test cues resembled studied items (and thus were familiar) and half did not. Subjects also judged the familiarity of the cue itself. RWCR is the finding that, among cues for which recall fails, subjects generally rate cues that resemble studied items as more familiar than cues that do not. For words, left and right hippocampal activity increased when recall succeeded relative to when it failed. When recall failed, right hippocampal activity was decreased for familiar relative to unfamiliar cues. In contrast, right Prc activity increased for familiar cues for which recall failed relative to both familiar cues for which recall succeeded and to unfamiliar cues. For scenes, left hippocampal activity increased when recall succeeded relative to when it failed but did not differentiate familiar from unfamiliar cues when recall failed. In contrast, right Prc activity increased for familiar relative to unfamiliar cues when recall failed. Category-specific cortical regions showed effects unique to their respective stimulus types: The visual word form area (VWFA) showed effects for recall vs. familiarity specific to words, and the parahippocampal place area (PPA) showed effects for recall vs. familiarity specific to scenes. In both cases, these effects were such that there was increased activity occurring during recall relative to when recall failed, and decreased activity occurring for familiar relative to unfamiliar cues when recall failed.
Adult hippocampal neurogenesis is considered important for cognition. The integration of newborn dentate gyrus granule cells into the existing network is regulated by afferent neuronal activity of unspecified origin. Here we combine rabies virus-mediated retrograde tracing with retroviral labelling of new granule cells (21, 30, 60, 90 days after injection) to selectively identify and quantify their monosynaptic inputs in vivo. Our results show that newborn granule cells receive afferents from intra-hippocampal cells (interneurons, mossy cells, area CA3 and transiently, mature granule cells) and septal cholinergic cells. Input from distal cortex (perirhinal (PRH) and lateral entorhinal cortex (LEC)) is sparse 21 days after injection and increases over time. Patch-clamp recordings support innervation by the LEC rather than from the medial entorhinal cortex. Mice with excitotoxic PRH/LEC lesions exhibit deficits in pattern separation but not in water maze learning. Thus, PRH/LEC input is an important functional component of new dentate gyrus neuron circuitry.
Researchers have observed unsustainable neurogenesis of the dentate gyrus of the hippocampus, as well as cognitive improvements in short-term imipramine-treated mice following a controlled cortical impact (CCI) model of traumatic brain injury (TBI). But they have yet to investigate the effects of a longer-duration imipramine treatment. In this study, we investigated the effects of a longer treatment regimen on rats following a fluid percussion injury (FPI) model, which creates a brain injury that more closely resembles those incurred by human patients.
The dentate gyrus (DG) in the adult brain maintains the capability to generate new granule neurons throughout life. Neural stem cell-derived new-born neurons emerge to play key functions in the way information is processed in the DG and then conveyed to the CA3 hippocampal area, yet accumulating evidence indicates that both the maturation process and the connectivity pattern of new granule neurons are not prefigured but can be modulated by the activity of local microcircuits and, on a network level, by experience. Although most of the activity- and experience-dependent changes described so far appear to be restricted to critical periods during the development of new granule neurons, it is becoming increasingly clear that the surrounding circuits may play equally key roles in accommodating and perhaps fostering, these changes. Here, we review some of the most recent insights into this almost unique form of plasticity in the adult brain by focusing on those critical periods marked by pronounced changes in structure and function of the new granule neurons and discuss how the activity of putative synaptic partners may contribute to shape the circuit module in which new neurons become finally integrated.
To distinguish age-related memory loss more explicitly from Alzheimer’s disease (AD), we have explored its molecular underpinning in the dentate gyrus (DG), a subregion of the hippocampal formation thought to be targeted by aging. We carried out a gene expression study in human postmortem tissue harvested from both DG and entorhinal cortex (EC), a neighboring subregion unaffected by aging and known to be the site of onset of AD. Using expression in the EC for normalization, we identified 17 genes that manifested reliable age-related changes in the DG. The most significant change was an age-related decline in RbAp48, a histone-binding protein that modifies histone acetylation. To test whether the RbAp48 decline could be responsible for age-related memory loss, we turned to mice and found that, consistent with humans, RbAp48 was less abundant in the DG of old than in young mice. We next generated a transgenic mouse that expressed a dominant-negative inhibitor of RbAp48 in the adult forebrain. Inhibition of RbAp48 in young mice caused hippocampus-dependent memory deficits similar to those associated with aging, as measured by novel object recognition and Morris water maze tests. Functional magnetic resonance imaging studies showed that within the hippocampal formation, dysfunction was selectively observed in the DG, and this corresponded to a regionally selective decrease in histone acetylation. Up-regulation of RbAp48 in the DG of aged wild-type mice ameliorated age-related hippocampus-based memory loss and age-related abnormalities in histone acetylation. Together, these findings show that the DG is a hippocampal subregion targeted by aging, and identify molecular mechanisms of cognitive aging that could serve as valid targets for therapeutic intervention.