Claustrum projections to the anterior cingulate modulate nociceptive and pain-associated behavior

Christian A Faig; Gloria H K Kim; Alison D Do; Zoë Dworsky-Fried; Jesse Jackson; Anna M W Taylor

doi:10.1016/j.cub.2024.03.044

Claustrum projections to the anterior cingulate modulate nociceptive and pain-associated behavior

Curr Biol. 2024 May 6;34(9):1987-1995.e4. doi: 10.1016/j.cub.2024.03.044. Epub 2024 Apr 12.

Authors

Christian A Faig¹, Gloria H K Kim², Alison D Do³, Zoë Dworsky-Fried⁴, Jesse Jackson⁵, Anna M W Taylor⁶

Affiliations

¹ Department of Pharmacology, University of Alberta, 8613 114 Street NW, Edmonton, AB T6G 2R3, Canada; Neuroscience and Mental Health Institute, University of Alberta, 11315 87 Avenue NW, Edmonton, AB T6G 2E1, Canada.
² Neuroscience and Mental Health Institute, University of Alberta, 11315 87 Avenue NW, Edmonton, AB T6G 2E1, Canada.
³ Department of Physiology, University of Alberta, 8613 114 Street NW, Edmonton, AB T6G 2R3, Canada.
⁴ Department of Pharmacology, University of Alberta, 8613 114 Street NW, Edmonton, AB T6G 2R3, Canada.
⁵ Neuroscience and Mental Health Institute, University of Alberta, 11315 87 Avenue NW, Edmonton, AB T6G 2E1, Canada; Department of Physiology, University of Alberta, 8613 114 Street NW, Edmonton, AB T6G 2R3, Canada. Electronic address: jackson4@ualberta.ca.
⁶ Department of Pharmacology, University of Alberta, 8613 114 Street NW, Edmonton, AB T6G 2R3, Canada; Neuroscience and Mental Health Institute, University of Alberta, 11315 87 Avenue NW, Edmonton, AB T6G 2E1, Canada; Cancer Research Institute of Northern Alberta, University of Alberta, 11315 87 Avenue NW, Edmonton, AB T6G 2E1, Canada; Department of Anesthesiology and Pain Medicine, University of Alberta, 8440 112 Street NW, Edmonton, AB T6G 2B7, Canada. Electronic address: ataylor1@ualberta.ca.

PMID: 38614081
DOI: 10.1016/j.cub.2024.03.044

Abstract

The anterior cingulate cortex (ACC) is critical for the perception and unpleasantness of pain.¹^,²^,³^,⁴^,⁵^,⁶ It receives nociceptive information from regions such as the thalamus and amygdala and projects to several cortical and subcortical regions of the pain neuromatrix.⁷^,⁸ ACC hyperexcitability is one of many functional changes associated with chronic pain, and experimental activation of ACC pyramidal cells produces hypersensitivity to innocuous stimuli (i.e., allodynia).⁹^,¹⁰^,¹¹^,¹²^,¹³^,¹⁴ A less-well-studied projection to the ACC arises from a small forebrain region, the claustrum.¹⁵^,¹⁶^,¹⁷^,¹⁸^,¹⁹^,²⁰ Stimulation of excitatory claustrum projection neurons preferentially activates GABAergic interneurons, generating feed-forward inhibition onto excitatory cortical networks.²¹^,²²^,²³^,²⁴ Previous work has shown that claustrocingulate projections display altered activity in prolonged pain²⁵^,²⁶^,²⁷; however, it remains unclear whether and how the claustrum participates in nociceptive processing and high-order pain behaviors. Inhibition of ACC activity reverses mechanical allodynia in animal models of persistent and neuropathic pain,¹^,⁹^,²⁸ suggesting claustrum inputs may function to attenuate pain processing. In this study, we sought to define claustrum function in acute and chronic pain. We found enhanced claustrum activity after a painful stimulus that was attenuated in chronic inflammatory pain. Selective inhibition of claustrocingulate projection neurons enhanced acute nociception but blocked pain learning. Inversely, chemogenetic activation of claustrocingulate neurons had no effect on basal nociception but rescued inflammation-induced mechanical allodynia. Together, these results suggest that claustrocingulate neurons are a critical component of the pain neuromatrix, and dysregulation of this connection may contribute to chronic pain.

Keywords: anterior cingulate cortex; chronic pain; claustrum; nociception.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Claustrum* / physiology
Gyrus Cinguli* / physiology
Gyrus Cinguli* / physiopathology
Male
Mice
Mice, Inbred C57BL
Neural Pathways / physiology
Neural Pathways / physiopathology
Nociception / physiology
Pain / physiopathology