Anterior cingulate cross-hemispheric projection to the claustrum determines prioritization in painful sensory conflict

The anterior cingulate cortex (ACC) is important for both sensory integration and the processing of affective aspects of pain to coordinate appropriate behavioral reactions. However, the role of the projections of ACC neurons to subcortical areas and their influence on sensory processing are not fully understood. Here, we identified that ACC neurons preferentially project to the contralateral claustrum (CLA). Extracellular recordings in awake mice showed that ACC neurons projecting to the contralateral claustrum (ACC→contraCLA) preferentially respond to contralateral mechanical sensory stimulation, and these sensory responses were enhanced during attending behavior. Optogenetic activation of ACC→contraCLA neurons silenced pyramidal neurons in the contralateral ACC by activation of fast-spiking interneurons via the CLA and inhibited the ipsilateral sensory responses. Sensory-driven attending behavior inhibited nociceptive responses, and this was prevented by chemogenetic silencing of the cross-hemispheric circuit. Our findings identify a novel cross-hemispheric cortical-subcortical-cortical arc allowing the brain to allocate attentional priority between competing innocuous and noxious inputs.