55: Anterior cingulate cross-hemispheric projection to claustrum resolves painful sensory conflict

Topic: Basic Science
Subtopic: Non-specific to any diagnosis (including studies in healthy animals), Electrophysiology, Neurocircuit modulation (could include opto, DREADDs), Behavioral studies

Background and Aims: The anterior cingulate cortex (ACC) is important for processing sensory and affective aspects of pain. Previous study reported that the ACC projects more strongly to the contralateral Claustrum (CLA) than the ipsilateral CLA, which is known as an important negative regulator of cortical activity for a range of functions by connecting with cortical areas including the ACC, but the functions of ACC projection to contralateral CLA have been largely unknown. In this study, we investigated the physiological roles of the ACC cross-hemispheric inputs to CLA using viral-tracing, in vivo and slice electrophysiology and pain behavioral tests.

Methods: Anterograde and retrograde viral strategies were used to selectively manipulate and visualize the ACC to contralateral CLA circuit. To assess the physiological response of ACC neurons projecting contralateral CLA (ACC→contra CLA neurons), in vivo electrophysiological recording with optogenetic tagging were performed from awake mice. Using chemogenetic strategies, we examined the behavioral roles of ACC to contralateral CLA circuit in pain processing.

Results: Using viral-tracing and in vivo and slice electrophysiology, we show that ACC→contraCLA preferentially respond to contralateral mechanical sensory stimulation, and these responses are enhanced during sensory-driven attending behavior. Slice patch-clamp recording results revealed that ACC→contraCLA neurons innervate the CLA neurons projecting to the ACC ipsilateral to CLA. Optogenetic activation of ACC→contraCLA neurons silenced pyramidal neuron activity in the contralateral ACC by recruiting local fast-spiking interneurons via the CLA, and behaviorally suppressed withdrawal responses to ipsilateral mechanical stimuli which are corresponded by contralateral ACC. Sensory-driven attending behaviors inhibited nociceptive responses, and this phenomenon was prevented by chemogenetic inhibition of ACC→contraCLA neurons.

Conclusions: The ACC is involved in assigning salience to sensory events through prioritization and acts as sensory hub to determine appropriate behavioral strategy, but the mechanisms of affective evaluation of pain is not fully understood. This study identifies a novel cross-hemispheric cortical-subcortical-cortical arc allowing the brain to give attentional priority to competing innocuous and noxious inputs. Our findings provide clues to understand why pain hypersensitivity is generally limited to the inflamed or injured side i.e., how pain lateralization is coded in the brain, while the brainstem pain-controlling descending neurons project to both side of spinal cord.

References: Keisuke Koga, Kenta Kobayashi, Makoto Tsuda, Anthony E. Pickering & Hidemasa Furue. Anterior cingulate cross-hemispheric inhibition via the claustrum resolves painful sensory conflict. Commun Biol 7, 330 (2024). https://doi.org/10.1038/s42003-024-06008-9

Presenting Author: Keisuke Koga
Submitting Author: Keisuke Koga

Senior Author: Hidemasa Furue

IASP 2026 Global Year theme of Neuropathic Pain: No

• Kenta Kobayashi: Ph.D. - National Institute for Physiological Sciences
• Makoto Tsuda: Ph.D. - Kyushu University
• Anthony E Pickering: M.D., Ph.D. - University of Bristol
• Hidemasa Furue: Ph.D. - Hyogo Medical University