Contralateral Projection of Anterior Cingulate Cortex Contributes to Mirror-Image Pain

Area of Science:

• Neuroscience
• Pain Research
• Central Nervous System

Background:

• Long-term limb nerve injury can cause mirror-image pain (MIP), characterized by pain in the contralateral limb.
• The precise central mechanisms underlying MIP, particularly the role of the anterior cingulate cortex (ACC), remain incompletely understood.

Purpose of the Study:

• To investigate the neural circuit mechanisms in the ACC that contribute to the development and manifestation of MIP.
• To differentiate the roles of distinct ACC neuronal populations in processing pain from the injured limb versus contralateral referred pain.

Main Methods:

• Induction of unilateral chronic constrictive injury (CCI) of the sciatic nerve in male mice to model MIP.
• Viral-mediated projection mapping and c-Fos immunohistochemistry to identify and quantify neuronal activity and connectivity within the ACC.
• Selective chemogenetic inhibition of specific ACC neuronal projection pathways.

Main Results:

• CCI induced MIP and increased neuronal activity (c-Fos expression) in both ipsilateral and contralateral ACC.
• A subset of ACC neurons exhibited cross-callosal projections to the contralateral ACC, with increased activity in MIP-expressing mice.
• Inhibition of cross-callosal ACC projections normalized contralateral limb hypersensitivity (MIP) but not injured limb hypersensitivity.
• Inhibition of non-cross-callosal ACC projections normalized injured limb hypersensitivity but not MIP.

Conclusions:

• A novel circuit mechanism involving cross-callosal ACC projections contributes specifically to mirror-image pain.
• Distinct ACC neuronal populations differentially process nociception from the injured limb and referred contralateral pain.
• These findings provide critical insights into the central processing of chronic pain and contralateral pain migration.