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Distinct hippocampal engrams control extinction and relapse of fear memory

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Lacagnina, Anthony F., Brockway, Emma T., Crovetti, Chelsea R., Shue, Francis, McCarty, Meredith J., Sattler, Kevin P., Lim, Sean C., Santos, Sofia Leal, Denny, Christine A., Drew, Michael R.·2019·Nature Neuroscience

DOI 10.1038/s41593-019-0361-zPMC PMC6705137

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Abstract

Learned fear often relapses after extinction, suggesting that extinction training generates a new memory that coexists with the original fear memory; however, the mechanisms governing the expression of competing fear and extinction memories remain unclear. We used activity-dependent neural tagging to investigate representations of fear and extinction memories in the dentate gyrus. We demonstrate that extinction training suppresses reactivation of contextual fear engram cells while activating a second ensemble, a putative extinction engram. Optogenetic inhibition of neurons that were active during extinction training increased fear after extinction training, whereas silencing neurons that were active during fear training reduced spontaneous recovery of fear. Optogenetic stimulation of fear acquisition neurons increased fear, while stimulation of extinction neurons suppressed fear and prevented spontaneous recovery. Our results indicate that the hippocampus generates a fear extinction representation and that interactions between hippocampal fear and extinction representations govern the suppression and relapse of fear after extinction.

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Authors: Lacagnina, A. F., Brockway, E. T., Crovetti, C. R., Shue, F., McCarty, M. J., Sattler, K. P., Lim, S. C., Santos, S. L., Denny, C. A., & Drew, M. R.
Affiliations: The University of Texas at Austin (US)
Research Foundation For Mental Hygiene (US)
Corresponding author: Drew, Michael R.
ORCID: Lacagnina, Anthony F.
Brockway, Emma T.
Shue, Francis
McCarty, Meredith J.
Sattler, Kevin P.
Lim, Sean C.
Santos, Sofia Leal
Denny, Christine A.
Drew, Michael R.
Venue: Nature Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 2019-04-01
Volume: 22
Issue: 5
Pages: 753-761
ISSN: 1097-6256 (ISSN-L)
1546-1726
DOI: 10.1038/s41593-019-0361-z
PMC: PMC6705137
OpenAlex: W2935468986
Cited by: 311
References: 52
Citations by year: 2026: 30 · 2025: 48 · 2024: 48 · 2023: 44 · 2022: 42 · 2021: 53 · 2020: 24 · 2019: 20
FWCI: 20.20
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Neuroscience (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, cc-by-nc-nd)
Funders: National Institutes of Health (DP5OD017908)
National Institute of Mental Health (F31MH111243, R01MH117426, R01MH102595, T32MH106454)
National Eye Institute (R21EY026446)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD101402)
Topics: Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Life Sciences › Neuroscience › Cognitive Neuroscience › Memory Processes and Influences
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords: fear extinction, fear memory, hippocampus, dentate gyrus, engram cells, contextual fear, spontaneous recovery, optogenetic silencing, optogenetic stimulation, memory reactivation
MeSH terms: Animals, Conditioning, Classical, Extinction, Psychological, Fear, Female, Male, Memory, Mice, Transgenic, Neurons, Mental Recall, Dentate Gyrus, Optogenetics

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Distinct hippocampal engrams control extinction and relapse of fear memory

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