Anterior cingulate cortex glutamatergic projection neurons modulate motion sickness susceptibility via a cortico-vestibular circuit.

Motion sickness (MS) is a prevalent and debilitating vestibular disorder with limited therapeutic options, yet the cortical mechanisms governing individual susceptibility remain elusive. Using a biaxial rotation mouse model, we investigated the role of the anterior cingulate cortex (ACC) in MS by integrating morphology, calcium imaging, electrophysiology, cell ablation, chemogenetics, and optogenetics. Biaxial rotation induced hypothermia, anorexia, taste avoidance, locomotor hypoactivity, and gait incoordination. ACC pyramidal neurons exhibited enhanced activation and increased intrinsic excitability following vestibular stimulation. Ablation of ACC CaMKII+ neurons alleviated MS symptoms, and bidirectional chemogenetic manipulation demonstrated that ACC glutamatergic projection neurons are both necessary and sufficient for MS behaviors. Furthermore, the ACC to medial vestibular nuclei parvicellular part (MVePC) projection was identified as a previously uncharacterized cortico-vestibular circuit that bidirectionally mediates MS susceptibility. Whole-brain projectome analysis further revealed anatomically heterogeneous projection subtypes of ACC-medial vestibular neurons. These findings advance our understanding of the cortical mechanisms underlying MS and establish the ACC-MVePC pathway as a mechanistic entry point for future neuromodulatory strategies.