Distinct hippocampal engrams control extinction and relapse of fear memory
Open accessAbstract
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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Threat conditioning and extinction memories exist in separate populations of neurons within the hippocampus.
“Activity-tagging coupled with optogenetic inhibition suggests that threat conditioning and extinction memories exist in separate populations of neurons within the hippocampus [44]”
From Prefrontal cortex, amygdala, and threat processing: implications for PTSD (2022) · cites this paper as [44]
Fetal growth rate involves coordinated epigenetic modifications to modulate DNA chromatin structure in the liver, skeletal muscle, adipose tissue, and hypothalamus.
“For example, fetal growth rate involves coordinated epigenetic modifications to modulate the DNA chromatin structure in the liver, skeletal muscle, adipose tissue, and hypothalamus.”
From Revisiting Epigenetics Fundamentals and Its Biomedical Implications (2024) · cites this paper as [95]
The Introduction and Results discuss hippocampal neurons involved in fear extinction and relapse, while Methods > Subjects describes experiments in adult mice (page numbers unavailable). Searches for fetal growth, epigenetic modifications, chromatin structure, and the named tissues found no passage addressing the claim. (LLM, conf=0.78)
Experimental — accuracy not yet measuredModels of nutritional restriction and uteroplacental insufficiency suggest that the gestational environment influences the postnatal phenotype, which may increase susceptibility to childhood obesity through metabolic reprogramming.
“Other investigations with models of nutritional restriction and uteroplacental insufficiency suggest that the gestational environment influences the postnatal phenotype, which may increase susceptibility to childhood obesity through metabolic reprogramming [95].”
From Revisiting Epigenetics Fundamentals and Its Biomedical Implications (2024) · cites this paper as [95]
The Results passages describe hippocampal neurons involved in fear conditioning and extinction, not gestational influences on postnatal phenotype. Searches for nutritional restriction, uteroplacental insufficiency, childhood obesity, and metabolic reprogramming found no passage addressing the claim. (LLM, conf=0.78)
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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
- Venue
- Nature Neuroscience
- Published
- 2019-04-01
- Volume
- 22
- Issue
- 5
- Pages
- 753-761
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- 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 · 2014: 1
- 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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