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

Roger Marek; Jingji Jin; Travis D. Goode; Thomas F. Giustino; Qian Wang; Gillian M. Acca; Roopashri Holehonnur; Jonathan E. Ploski; Paul J. Fitzgerald; Timothy Lynagh; Joseph W. Lynch; Stephen Maren; Pankaj Sah

doi:10.1038/s41593-018-0073-9

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

Roger Marek, Jingji Jin, Travis D. Goode, Thomas F. Giustino, Qian Wang, Gillian M. Acca, Roopashri Holehonnur, Jonathan E. Ploski, Paul J. Fitzgerald, Timothy Lynagh, Joseph W. Lynch, Stephen Maren, Pankaj Sah^*

^*Corresponding author for this work

75 Citations (Scopus)

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.

Original language	English
Journal	Nature Neuroscience
Volume	21
Pages (from-to)	384-392
Number of pages	9
ISSN	1097-6256
DOIs	https://doi.org/10.1038/s41593-018-0073-9
Publication status	Published - 1 Mar 2018

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title = "Hippocampus-driven feed-forward inhibition of the prefrontal cortex mediates relapse of extinguished fear",

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.",

author = "Roger Marek and Jingji Jin and Goode, {Travis D.} and Giustino, {Thomas F.} and Qian Wang and Acca, {Gillian M.} and Roopashri Holehonnur and Ploski, {Jonathan E.} and Fitzgerald, {Paul J.} and Timothy Lynagh and Lynch, {Joseph W.} and Stephen Maren and Pankaj Sah",

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doi = "10.1038/s41593-018-0073-9",

language = "English",

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journal = "Nature Neuroscience",

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T1 - Hippocampus-driven feed-forward inhibition of the prefrontal cortex mediates relapse of extinguished fear

AU - Marek, Roger

AU - Jin, Jingji

AU - Goode, Travis D.

AU - Giustino, Thomas F.

AU - Wang, Qian

AU - Acca, Gillian M.

AU - Holehonnur, Roopashri

AU - Ploski, Jonathan E.

AU - Fitzgerald, Paul J.

AU - Lynagh, Timothy

AU - Lynch, Joseph W.

AU - Maren, Stephen

AU - Sah, Pankaj

PY - 2018/3/1

Y1 - 2018/3/1

N2 - 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.

AB - 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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DO - 10.1038/s41593-018-0073-9

M3 - Journal article

C2 - 29403033

AN - SCOPUS:85041590623

SN - 1097-6256

VL - 21

SP - 384

EP - 392

JO - Nature Neuroscience

JF - Nature Neuroscience

ER -

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

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