Cited by 226Memory and Neural MechanismsNeuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on Behavior

Hippocampus-driven feed-forward inhibition of the prefrontal cortex mediates relapse of extinguished fear

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Marek, Roger, Jin, Jingji, Goode, Travis D., Giustino, Thomas F., Wang, Qian, Acca, Gillian M., Holehonnur, Roopashri, Ploski, Jonathan E. +5 more·2018·Nature Neuroscience

Abstract

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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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
Venue
Nature Neuroscience
Published
2018-02-05
Volume
21
Issue
3
Pages
384-392
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
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
Open access
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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