Dataset Information

Artificial association of memory events by optogenetic stimulation of hippocampal CA3 cell ensembles.

ABSTRACT: Previous gain-of-function studies using an optogenetic technique showed that manipulation of the hippocampal dentate gyrus or CA1 cell ensembles is important for memory reactivation and to generate synthetic or false memory. However, gain-of-function study manipulating CA3 cell ensembles has not been reported. The CA3 area of the hippocampus comprises a recurrent excitatory circuit, which is thought to be important for the generation of associations among the stored information within one brain region. We investigated whether the coincident firing of cell ensembles in one brain region, hippocampal CA3, associates distinct events. CA3 cell ensembles responding to context exploration and during contextual fear conditioning were labeled with channelrhodopsin-2 (ChR2)-mCherry. The synchronous activation of these ensembles induced freezing behavior in mice in a neutral context, in which a foot shock had never been delivered. The recall of this artificial associative fear memory was context specific. In vivo electrophysiological recordings showed that 20-Hz optical stimulation of ChR2-mCherry-expressing CA3 neurons, which is the same stimulation protocol used in behavioral experiment, induced long-term potentiation at CA3-CA3 synapses. Altogether, these results demonstrate that the synchronous activation of ensembles in one brain region, CA3 of the hippocampus, is sufficient for the association of distinct events. The results of our electrophysiology potentially suggest that this artificial association of memory events might be induced by the strengthening of synaptic efficacy between CA3 ensembles via recurrent circuit.

SUBMITTER: Oishi N

PROVIDER: S-EPMC6323779 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Artificial association of memory events by optogenetic stimulation of hippocampal CA3 cell ensembles.

Oishi Naoya N Nomoto Masanori M Ohkawa Noriaki N Saitoh Yoshito Y Sano Yoshitake Y Tsujimura Shuhei S Nishizono Hirofumi H Matsuo Mina M Muramatsu Shin-Ichi SI Inokuchi Kaoru K

Molecular brain 20190108 1

Previous gain-of-function studies using an optogenetic technique showed that manipulation of the hippocampal dentate gyrus or CA1 cell ensembles is important for memory reactivation and to generate synthetic or false memory. However, gain-of-function study manipulating CA3 cell ensembles has not been reported. The CA3 area of the hippocampus comprises a recurrent excitatory circuit, which is thought to be important for the generation of associations among the stored information within one brain ...[more]

PMID: 30621738

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Project description: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.

Project description:BackgroundHippocampal oscillations play a critical role in the ontogeny of allocentric memory in rodents. During the critical period for memory development, hippocampal theta is the driving force behind the temporal coordination of neuronal ensembles underpinning spatial memory. While known that hippocampal oscillations are necessary for normal spatial cognition, whether disrupted hippocampal oscillatory activity during the critical period impairs long-term spatial memory is unknown. Here we investigated whether disruption of normal hippocampal rhythms during the critical period have enduring effects on allocentric memory in rodents.Objective/hypothesisWe hypothesized that disruption of hippocampal oscillations via artificial regulation of the medial septum during the critical period for memory development results in long-standing deficits in spatial cognition.MethodsAfter demonstrating that pan-neuronal medial septum (MS) optogenetic stimulation (465 nm activated) regulated hippocampal oscillations in weanling rats we used a random pattern of stimulation frequencies to disrupt hippocampal theta rhythms for either 1Hr or 5hr a day between postnatal (P) days 21-25. Non-stimulated and yellow light-stimulated (590 nm) rats served as controls. At P50-60 all rats were tested for spatial cognition in the active avoidance task. Rats were then sacrificed, and the MS and hippocampus assessed for cell loss. Power spectrum density of the MS and hippocampus, coherences and voltage correlations between MS and hippocampus were evaluated at baseline for a range of stimulation frequencies from 0.5 to 110 Hz and during disruptive hippocampal stimulation. Unpaired t-tests and ANOVA were used to compare oscillatory parameters, behavior and cell density in all animals.ResultsNon-selective optogenetic stimulation of the MS in P21 rats resulted in precise regulation of hippocampal oscillations with 1:1 entrainment between stimulation frequency (0.5-110 Hz) and hippocampal local field potentials. Across bandwidths MS stimulation increased power, coherence and voltage correlation at all frequencies whereas the disruptive stimulation increased power and reduced coherence and voltage correlations with most statistical measures highly significant (p < 0.001, following correction for false detection). Rats receiving disruptive hippocampal stimulation during the critical period for memory development for either 1Hr or 5hr had marked impairment in spatial learning as measured in active avoidance test compared to non-stimulated or yellow light-control rats (p < 0.001). No cell loss was measured between the blue-stimulated and non-stimulated or yellow light-stimulated controls in either the MS or hippocampus.ConclusionThe results demonstrated that robust regulation of hippocampal oscillations can be achieved with non-selective optogenetic stimulation of the MS in rat pups. A disruptive hippocampal stimulation protocol, which markedly increases power and reduces coherence and voltage correlations between the MS and hippocampus during the critical period of memory development, results in long-standing spatial cognitive deficits. This spatial cognitive impairment is not a result of optogenetic stimulation-induced cell loss.

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Artificial association of memory events by optogenetic stimulation of hippocampal CA3 cell ensembles.

Publications

Artificial association of memory events by optogenetic stimulation of hippocampal CA3 cell ensembles.

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