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Hippocampus-driven feed-forward inhibition of the prefrontal cortex mediates relapse of extinguished fear
Open accessAbstract
The medial prefrontal cortex (mPFC) has been implicated in the extinction of emotional memories, including conditioned fear. We found that ventral hippocampal (vHPC) projections to the infralimbic (IL) cortex recruited parvalbumin-expressing interneurons to counter the expression of extinguished fear and promote fear relapse. Whole-cell recordings ex vivo revealed that optogenetic activation of vHPC input to amygdala-projecting pyramidal neurons in the IL was dominated by feed-forward inhibition. Selectively silencing parvalbumin-expressing, but not somatostatin-expressing, interneurons in the IL eliminated vHPC-mediated inhibition. In behaving rats, pharmacogenetic activation of vHPC→IL projections impaired extinction recall, whereas silencing IL projectors diminished fear renewal. Intra-IL infusion of GABA receptor agonists or antagonists, respectively, reproduced these effects. Together, our findings describe a previously unknown circuit mechanism for the contextual control of fear, and indicate that vHPC-mediated inhibition of IL is an essential neural substrate for fear relapse.
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“The relapse of extinguished fear is found to be mediated by a feedforward inhibitory pathway from ventral hippocampus to IL cortex, which involves the recruitment of PV+ interneurons in IL 43.”
From Mechanisms of synaptic transmission dysregulation in the prefrontal cortex: pathophysiological implications (2022) · cites this paper as [43]
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Metadata
- Authors
- Marek, R., Jin, J., Goode, T. D., Giustino, T. F., Wang, Q., Acca, G. M., Holehonnur, R., Ploski, J. E., Fitzgerald, P. J., Lynagh, T., Lynch, J. W., Maren, S., & Sah, P.
- Affiliations
- The University of Queensland (AU)
- Texas A&M University (US)
- The University of Texas at Dallas (US)
- University of Copenhagen (DK)
- Corresponding author
- Maren, Stephen
- Sah, Pankaj
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2018-02-05
- Volume
- 21
- Issue
- 3
- Pages
- 384-392
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC5957529
- OpenAlex
- W2797856206
- Cited by
- 226
- References
- 59
- Citations by year
- 2026: 17 · 2025: 21 · 2024: 20 · 2023: 22 · 2022: 24 · 2021: 34 · 2020: 34 · 2019: 30 · 2018: 24
- FWCI
- 18.17
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-07-09)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Mental Health (F31MH107113, F31MH112208, R01MH065961)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- fear extinction, fear relapse, ventral hippocampus, infralimbic cortex, medial prefrontal cortex, feedforward inhibition, parvalbumin interneurons, somatostatin interneurons, extinction recall, fear renewal, GABA receptors, optogenetics, pharmacogenetics
- MeSH terms
- Amygdala, Animals, Extinction, Psychological, Fear, Hippocampus, Interneurons, Male, Parvalbumins, Somatostatin, Rats, Wistar, Prefrontal Cortex, Receptors, GABA, Patch-Clamp Techniques, Rats
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