Processing of pain and itch information by modality-specific neurons within the anterior cingulate cortex in mice

Hyoung-Gon Ko^1,2,  Hyunsu Jung^#3,4,  Seunghyo Han^#5,  Dong Il Choi^#4,  Chiwoo Lee^#4,  Ja Eun Choi⁴,  Jihae Oh⁴,  Chuljung Kwak³,  Dae Hee Han³,  Jun-Nyeong Kim⁵,  Sanghyun Ye⁴,  Jiah Lee⁴,  Jaehyun Lee⁴,  Kyungmin Lee⁶,  Jae-Hyung Lee⁷,  Min Zhuo^8,9 &  Bong-Kiun Kaang^10,11

¹Department of Anatomy and Neurobiology, School of Dentistry, Brain Science and Engineering Institute, Kyungpook National University, 2177 Dalgubeol-daero, Daegu, South Korea. hgko@khu.ac.kr.²Department of Oral Anatomy and Developmental Biology, Kyung Hee University College of Dentistry, Seoul, South Korea. hgko@khu.ac.kr.³Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon, 34126, South Korea.⁴Department of Biological Sciences, College of Natural Sciences, Seoul National University, 1 Gwanangno, Seoul, South Korea.⁵Department of Anatomy and Neurobiology, School of Dentistry, Brain Science and Engineering Institute, Kyungpook National University, 2177 Dalgubeol-daero, Daegu, South Korea.⁶Laboratory for Behavioral Neural Circuitry and Physiology, Department of Anatomy, Brain Science and Engineering Institute, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Daegu, South Korea.⁷Department of Oral Microbiology, College of Dentistry, Kyung Hee University, 26 Kyungheedae-ro, Seoul, South Korea.⁸Department of Physiology, Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto, Ontario, Canada.⁹International Institute for Brain Research, Qingdao International Academician Park, Qingdao, China.¹⁰Center for Cognition and Sociality, Institute for Basic Science (IBS), Daejeon, 34126, South Korea. kaang@ibs.re.kr.¹¹Department of Biological Sciences, College of Natural Sciences, Seoul National University, 1 Gwanangno, Seoul, South Korea. kaang@ibs.re.kr.^#Contributed equally.

• PMID: 40038260
• PMCID: PMC11880300
• DOI: 10.1038/s41467-025-57041-z

Abstract

Pain and itch are aversive sensations with distinct qualities, processed in overlapping pathways and brain regions, including the anterior cingulate cortex (ACC), which is critical for their affective dimensions. However, the cellular mechanisms underlying their processing in the ACC remain unclear. Here, we identify modality-specific neuronal populations in layer II/III of the ACC in mice involved in pain and itch processing. Using a synapse labeling tool, we show that pain- and itch-related neurons selectively receive synaptic inputs from mediodorsal thalamic neurons activated by pain and itch stimuli, respectively. Chemogenetic inhibition of these neurons reduced pruriception or nociception without affecting the opposite modality. Conversely, activation of these neurons did not enhance stimulus-specific responses but commonly increased freezing-like behavior. These findings reveal that the processing of itch and pain information in the ACC involves activity-dependent and modality-specific neuronal populations, and that pain and itch are processed by functionally distinct ACC neuronal subsets.