Layer 5 anterior cingulate cortical neurons engage dorsolateral periaqueductal gray excitatory neurons to facilitate the affective component of pain
- 1University of North Carolina at Chapel Hill
Abstract
Pain is a conscious perceptual experience characterized by its aversive quality and consequent motivation to quench pain perception. The anterior cingulate cortex (ACC) critically contributes to the emotional dimension of pain. In both humans and rodents, ACC neural activity increases during acute and chronic pain, whereas ACC lesioning or excitability reduction decreases emotional reactivity during pain. However, the ACC is connected to many brain regions and is engaged during experiences beyond pain. Thus, it remains unclear through which circuit mechanisms the ACC shapes pain experience, and how specific those circuits are to nociception. Here, we show that excitatory input from the ACC to the dorsolateral periaqueductal gray (dlPAG) facilitates the affective-motivational dimension of pain. We first examined ACC[->]dlPAG connectivity using histology, optogenetics, and electrophysiology. We found that the axons of layer 5 ACC neurons terminate in the dlPAG and monosynaptically excite Slc17a6+ (VGLUT2-expressing) dlPAG neurons. Second, we genetically targeted ACC[->]dlPAG neurons with viral vectors to express the inhibitory DREADD hM4Di and then exposed the animals to an array of pain tests. We found that, across acute and chronic pain states, inhibition of the ACC[->]dlPAG pathway reduced affective-motivational but not reflexive pain behaviors. Third, we used fiber photometry to record neural calcium activity in the ACC in behaving mice and found that ACC[->]dlPAG neurons are engaged during a broad array of aversive experiences, rather than exclusively during pain, and exhibit task-specific activity patterns. Collectively, these results uncover the direct contribution of ACC[->]dlPAG neural activity to pain unpleasantness and the necessity of this pathway for generating aversive behavioral responses in general, rather than specifically for encoding the unpleasant quality of noxious stimuli.
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BibTeX
@misc{kaslow2026layer,
title = {{Layer 5 anterior cingulate cortical neurons engage dorsolateral periaqueductal gray excitatory neurons to facilitate the affective component of pain}},
author = {J. Kaslow and W. M. McCallum and A. Francois and G. Corder and E. J. Kremer and K. D. Ritola and N. Mercer Lindsay and G. Scherrer},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.24.746788},
url = {https://www.biorxiv.org/content/10.64898/2026.08.24.746788v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Layer 5 anterior cingulate cortical neurons engage dorsolateral periaqueductal gray excitatory neurons to facilitate the affective component of pain
AU - J. Kaslow
AU - W. M. McCallum
AU - A. Francois
AU - G. Corder
AU - E. J. Kremer
AU - K. D. Ritola
AU - N. Mercer Lindsay
AU - G. Scherrer
PY - 2026
DA - 2026/08/24
PB - bioRxiv
DO - 10.64898/2026.08.24.746788
UR - https://www.biorxiv.org/content/10.64898/2026.08.24.746788v1
AB - Pain is a conscious perceptual experience characterized by its aversive quality and consequent motivation to quench pain perception. The anterior cingulate cortex (ACC) critically contributes to the emotional dimension of pain. In both humans and rodents, ACC neural activity increases during acute and chronic pain, whereas ACC lesioning or excitability reduction decreases emotional reactivity during pain. However, the ACC is connected to many brain regions and is engaged during experiences beyond pain. Thus, it remains unclear through which circuit mechanisms the ACC shapes pain experience, and how specific those circuits are to nociception. Here, we show that excitatory input from the ACC to the dorsolateral periaqueductal gray (dlPAG) facilitates the affective-motivational dimension of pain. We first examined ACC[->]dlPAG connectivity using histology, optogenetics, and electrophysiology. We found that the axons of layer 5 ACC neurons terminate in the dlPAG and monosynaptically excite Slc17a6+ (VGLUT2-expressing) dlPAG neurons. Second, we genetically targeted ACC[->]dlPAG neurons with viral vectors to express the inhibitory DREADD hM4Di and then exposed the animals to an array of pain tests. We found that, across acute and chronic pain states, inhibition of the ACC[->]dlPAG pathway reduced affective-motivational but not reflexive pain behaviors. Third, we used fiber photometry to record neural calcium activity in the ACC in behaving mice and found that ACC[->]dlPAG neurons are engaged during a broad array of aversive experiences, rather than exclusively during pain, and exhibit task-specific activity patterns. Collectively, these results uncover the direct contribution of ACC[->]dlPAG neural activity to pain unpleasantness and the necessity of this pathway for generating aversive behavioral responses in general, rather than specifically for encoding the unpleasant quality of noxious stimuli.
ER -