Control of fear extinction by hypothalamic melanin-concentrating hormone–expressing neurons

Learning to fear danger is essential for survival. However, overactive, relapsing fear behavior in the absence of danger is a hallmark of disabling anxiety disorders that affect millions of people. Its suppression is thus of great interest, but the necessary brain components remain incompletely iden...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 117; no. 36; pp. 22514 - 22521
Main Authors Concetti, Cristina, Bracey, Edward F., Peleg-Raibstein, Daria, Burdakov, Denis
Format Journal Article
LanguageEnglish
Published Washington National Academy of Sciences 08.09.2020
Subjects
Anxiety disorders
Biological Sciences
Brain
Disruption
Extinction
Extinction behavior
Fear
Fear conditioning
Hypothalamus
Learning
Melanin
Melanin-concentrating hormone
Neurons
Safety
Substrate inhibition
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Summary:Learning to fear danger is essential for survival. However, overactive, relapsing fear behavior in the absence of danger is a hallmark of disabling anxiety disorders that affect millions of people. Its suppression is thus of great interest, but the necessary brain components remain incompletely identified. We studied fear suppression through a procedure in which, after acquiring fear of aversive events (fear learning), subjects were exposed to fear-eliciting cues without aversive events (safety learning), leading to suppression of fear behavior (fear extinction). Here we show that inappropriate, learning-resistant fear behavior results from disruption of brain components not previously implicated in this disorder: hypothalamic melanin-concentrating hormone–expressing neurons (MNs). Using real-time recordings of MNs across fear learning and extinction, we provide evidence that fear-inducing aversive events elevate MN activity. We find that optogenetic disruption of this MN activity profoundly impairs safety learning, abnormally slowing down fear extinction and exacerbating fear relapse. Importantly, we demonstrate that the MN disruption impairs neither fear learning nor related sensory responses, indicating that MNs differentially control safety and fear learning. Thus, we identify a neural substrate for inhibition of excessive fear behavior.
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Author contributions: C.C., D.P.-R., and D.B. designed research; C.C. and E.F.B. performed research; C.C. analyzed data; and D.P.-R. and D.B. wrote the paper.
Edited by Nathaniel Heintz, Rockefeller University, New York, NY, and approved July 28, 2020 (received for review April 24, 2020)
1D.P.-R. and D.B. contributed equally to this work.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.2007993117