Research Article

Ventromedial prefrontal area 14 provides opposing regulation of threat and reward-elicited responses in the common marmoset

Zuzanna M. Stawicka, Roohollah Massoudi, Nicole K. Horst, Ken Koda, Philip L. R. Gaskin, Laith Alexander, Andrea M. Santangelo, Lauren McIver, Gemma J. Cockcroft, Christian M. Wood, and Angela C. Roberts
PNAS October 6, 2020 117 (40) 25116-25127; first published September 21, 2020; https://doi.org/10.1073/pnas.2009657117

  1. Edited by Robert Desimone, Massachusetts Institute of Technology, Cambridge, MA, and approved August 24, 2020 (received for review June 11, 2020)

Significance

Ventromedial prefrontal cortex is a large heterogenous region, which is dysfunctional in mood and anxiety disorders. Unfortunately, neuroimaging and focal lesion studies in humans have failed to resolve this heterogeneity, especially in relation to the symptom domains of enhanced negative emotion, blunted positive emotion, and autonomic dysfunction. We address this issue in marmoset monkeys, which have similar prefrontal organization to humans. By comparing inactivation and overactivation of area 14 within rostral ventromedial prefrontal cortex (vmPFC) across threatening and rewarding contexts, we reveal how area 14 overactivation heightens responsivity to distal threat and blunts appetitive arousal. Its lack of effect on basal cardiovascular reactivity and expression and extinction of certain proximal threat highlight its distinct profile of effects within the vmPFC.

Abstract

The ventromedial prefrontal cortex (vmPFC) is a key brain structure implicated in mood and anxiety disorders, based primarily on evidence from correlational neuroimaging studies. Composed of a number of brain regions with distinct architecture and connectivity, dissecting its functional heterogeneity will provide key insights into the symptomatology of these disorders. Focusing on area 14, lying on the medial and orbital surfaces of the gyrus rectus, this study addresses a key question of causality. Do changes in area 14 activity induce changes in threat- and reward-elicited responses within the nonhuman primate, the common marmoset, similar to that seen in mood and anxiety disorders? Area 14 overactivation was found to induce heightened responsivity to uncertain, low-imminence threat while blunting cardiovascular and behavioral anticipatory arousal to high-value food reward. Conversely, inactivation enhanced the arousal to high-value reward cues while dampening the acquisition of cardiovascular and behavioral responses to a Pavlovian threat cue. Basal cardiovascular activity, including heart rate variability and sympathovagal balance, which are dysfunctional in mood and anxiety disorders, are insensitive to alterations in area 14 activity as is the extinction of conditioned threat responses. The distinct pattern of dysregulation compared to neighboring region area 25 highlights the heterogeneity of function within vmPFC and reveals how the effects of area 14 overactivation on positive and negative reactivity mirror symptoms of anhedonia and anxiety that are so often comorbid in mood disorders.

Footnotes

  • ↵1Z.M.S. and R.M. contributed equally to this work.

  • ↵2Present address: Pain and Neurology, Discovery Research Laboratory for Core Therapeutic Areas, Shionogi and Co. Ltd., Osaka 541-0045, Japan.

  • ↵3Present address: Biological Sciences, BenevolentAI, London W1T 5HD, United Kingdom.

  • ↵4Present address: St. Thomas’ Hospital, London SE1 7EH, United Kingdom.

  • ↵5C.M.W. and A.C.R. contributed equally to this work.

  • ↵6To whom correspondence may be addressed. Email: cmw84{at}cam.ac.uk or acr4{at}cam.ac.uk.

  • Author contributions: R.M., L.A., and A.C.R. designed research; R.M., N.K.H., K.K., P.L.R.G., A.M.S., L.M., G.J.C., C.M.W., and A.C.R. performed research; Z.M.S., R.M., and C.M.W. analyzed data; and Z.M.S., C.M.W., and A.C.R. wrote the paper.

  • The authors declare no competing interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2009657117/-/DCSupplemental.

Data Availability.

Behavioral and cardiovascular data have been deposited at the Mendeley Data repository, http://dx.doi.org/10.17632/76c2j7bbbd.1 (81).

Published under the PNAS license.

View Full Text

Log in through your institution

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
Back to top
Article Alerts
Email Article
Citation Tools
Request Permissions
Ventromedial prefrontal area 14 provides opposing regulation of threat and reward-elicited responses in the common marmoset
Zuzanna M. Stawicka, Roohollah Massoudi, Nicole K. Horst, Ken Koda, Philip L. R. Gaskin, Laith Alexander, Andrea M. Santangelo, Lauren McIver, Gemma J. Cockcroft, Christian M. Wood, Angela C. Roberts
Proceedings of the National Academy of Sciences Oct 2020, 117 (40) 25116-25127; DOI: 10.1073/pnas.2009657117
Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
Proceedings of the National Academy of Sciences: 117 (40)
Table of Contents

Submit

Article Classifications

Jump to section

You May Also be Interested in

Large piece of gold
News Feature: Tracing gold's cosmic origins
Astronomers thought they’d finally figured out where gold and other heavy elements in the universe came from. In light of recent results, they’re not so sure.
Image credit: Science Source/Tom McHugh.

Similar Articles