Abstract
Placebo effects are striking demonstrations of mind-body interactions 1,2. During pain perception, in the absence of any treatment, an expectation of pain relief can reduce the experience of pain, a phenomenon known as placebo analgesia 3–6. However, despite the strength of placebo effects and their impact on everyday human experience and failure of clinical trials for new therapeutics 7, the neural circuit basis of placebo effects has remained elusive. Here, we show that analgesia from the expectation of pain relief is mediated by rostral anterior cingulate cortex (rACC) neurons that project to the pontine nucleus (rACC→Pn), a pre-cerebellar nucleus with no established function in pain. We created a behavioral assay that generates placebo-like anticipatory pain relief in mice. In vivo calcium imaging of neural activity and electrophysiological recordings in brain slices showed that expectations of pain relief boost the activity of rACC→Pn neurons and potentiate neurotransmission in this pathway. Transcriptomic studies of Pn neurons revealed an abundance of opioid receptors, further suggesting a role in pain modulation. Inhibition of the rACC→Pn pathway disrupted placebo analgesia and decreased pain thresholds, whereas activation elicited analgesia in the absence of placebo conditioning. Finally, Purkinje cells exhibited activity patterns resembling those of rACC→Pn neurons during pain relief expectation, providing cellular-level evidence of a role for the cerebellum in cognitive pain modulation. These findings open the possibility of targeting this prefrontal cortico-ponto-cerebellar pathway with drugs or neurostimulation to treat pain.
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Authors and Affiliations
Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Chong Chen,Jesse K. Niehaus,Karen L. Huang,Alexander L. Barnette,Adrien Tassou,Adam Hantman&Grégory Scherrer
UNC Neuroscience Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Chong Chen,Jesse K. Niehaus,Karen L. Huang,Alexander L. Barnette,Adrien Tassou,Kimberly Ritola,Adam Hantman&Grégory Scherrer
Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Chong Chen,Jesse K. Niehaus,Karen L. Huang,Alexander L. Barnette,Adrien Tassou,Kimberly Ritola&Grégory Scherrer
Department of Neurobiology, Harvard Medical School, Boston, MA, USA
S. Andrew Shuster
Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA
Lihua Wang&Andrew Lemire
Department of Neurology, Columbia University, New York, NY, USA
Vilas Menon
Allen Institute for Brain Science, Seattle, WA, USA
Hongkui Zeng
James H. Clark Center for Biomedical Engineering & Sciences, Stanford University, Stanford, CA, USA
Mark J. Schnitzer
CNC Program, Stanford University, Stanford, CA, USA
Fatih Dinc&Mark J. Schnitzer
Department of Biology, Stanford University, Stanford, CA, USA
Mark J. Schnitzer
Department of Applied Physics, Stanford University, Stanford, CA, USA
Fatih Dinc&Mark J. Schnitzer
Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA
Mark J. Schnitzer
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- Chong Chen
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- Jesse K. Niehaus
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- Fatih Dinc
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- Karen L. Huang
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- Alexander L. Barnette
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- Adrien Tassou
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- S. Andrew Shuster
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- Lihua Wang
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- Andrew Lemire
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- Vilas Menon
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- Kimberly Ritola
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- Adam Hantman
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- Hongkui Zeng
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- Mark J. Schnitzer
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- Grégory Scherrer
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Correspondence to Grégory Scherrer.
Supplementary information
Supplementary Table 1
Marker genes for each Pn neuron cluster (related to Fig.5). The spreadsheet contains 10 tabs, each corresponding to a cluster of Pn neurons classified in Fig.5b. In each tab, genes with a log effect size greater than 0.5 are listed.
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Chen, C., Niehaus, J.K., Dinc, F. et al. Neural circuit basis of placebo pain relief. Nature (2024). https://doi.org/10.1038/s41586-024-07816-z
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DOI: https://doi.org/10.1038/s41586-024-07816-z
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