Theta-phase-specific modulation of dentate gyrus memory neurons
- Boston University, United States
Abstract
The theta rhythm, a quasi-periodic 4-10 Hz oscillation, is observed during memory processing in the hippocampus, with different phases of theta hypothesized to separate independent streams of information related to the encoding and recall of memories. At the cellular level, the discovery of hippocampal memory cells (engram neurons), as well as the modulation of memory recall through optogenetic activation of these cells, has provided evidence that certain memories are stored, in part, in a sparse ensemble of neurons in the hippocampus. In previous research, however, engram reactivation has been carried out using open loop stimulation at fixed frequencies; the relationship between engram neuron reactivation and ongoing network oscillations has not been taken into consideration. To address this concern, we implemented a closed-loop reactivation of engram neurons that enabled phase-specific stimulation relative to theta oscillations in the local field potential in CA1. Using this real-time approach, we tested the impact of activating dentate gyrus engram neurons during the peak (encoding phase) and trough (recall phase) of theta oscillations. Consistent with previously hypothesized functions of theta oscillations in memory function, we show that stimulating dentate gyrus engram neurons at the trough of theta is more effective in eliciting behavioral recall than either fixed frequency stimulation or stimulation at the peak of theta. Moreover, phase-specific trough stimulation is accompanied by an increase in the coupling between gamma and theta oscillations in CA1 hippocampus. Oure results provide a causal link between phase- specific activation of engram cells and the behavioral expression of memory.
Data availability
Data collected for the purpose of this paper and the custom algorithms that were used in performing the analysis are available at https://dx.doi.org/10.5061/dryad.k0p2ngfc0. The theta-phase detection algorithm is accessible at https://github.com/ndlBU/phase_specific_stim. It can be run using the RTXI platform accessible through http://rtxi.org. Behavioral scoring was done using the ezTrack package available at github.com/DeniseCaiLab/ezTrack.
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Motion and LFP DataDryad Digital Repository, doi:10.5061/dryad.k0p2ngfc0.
Article and author information
Author details
Funding
National Institute of Neurological Disorders and Stroke (R01 NS054281)
- John A White
BU Center for Systems Neuroscience and Neurophotonics Center (Grant)
- Bahar Rahsepar
- Jacob F Norman
- Jad Noueihed
- Steve Ramirez
- John A White
National Institute of Biomedical Imaging and Bioengineering (R01 EB016407)
- John A White
National Institutes of Health (DP5 OD023106-01)
- Steve Ramirez
National Institutes of Health (Transformative R01)
- Steve Ramirez
Ludwig Family Foundation (Research Grant)
- Steve Ramirez
Brain and Behavior Research Foundation (Young Investigator Grant)
- Steve Ramirez
McKnight Foundation (Memory and Cognitive Disorders Award)
- Steve Ramirez
Pew Scholars Program in the Biomedical Science (Grant)
- Steve Ramirez
Air Force Office of Scientific Research (FA9550- 21-1-0310)
- Steve Ramirez
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (PROTO201800599) of Boston University. The protocol was approved by the Committee on the Ethics of Animal Experiments of the University of Minnesota (Permit Number: 27-2956). All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.
Copyright
© 2023, Rahsepar et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Theta-phase-specific modulation of dentate gyrus memory neurons
eLife 12:e82697.
https://doi.org/10.7554/eLife.82697
Further reading
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Synchronous neuronal activity is organized into neuronal oscillations with various frequency and time domains across different brain areas and brain states. For example, hippocampal theta, gamma, and sharp wave oscillations are critical for memory formation and communication between hippocampal subareas and the cortex. In this study, we investigated the neuronal activity of the dentate gyrus (DG) with optical imaging tools during sleep-wake cycles in mice. We found that the activity of major glutamatergic cell populations in the DG is organized into infraslow oscillations (0.01–0.03 Hz) during NREM sleep. Although the DG is considered a sparsely active network during wakefulness, we found that 50% of granule cells and about 25% of mossy cells exhibit increased activity during NREM sleep, compared to that during wakefulness. Further experiments revealed that the infraslow oscillation in the DG was correlated with rhythmic serotonin release during sleep, which oscillates at the same frequency but in an opposite phase. Genetic manipulation of 5-HT receptors revealed that this neuromodulatory regulation is mediated by Htr1a receptors and the knockdown of these receptors leads to memory impairment. Together, our results provide novel mechanistic insights into how the 5-HT system can influence hippocampal activity patterns during sleep.
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