Glia-mediated cerebellar pain modulation

Clinical studies have revealed that the cerebellum is activated by noxious stimuli or pathological pain, and its removal results in somatosensory dysfunction. However, the neural circuit, cellular and molecular mechanisms underlying pain transmission and modulation in the cerebellum remain unknown. Here, we show that Bergmann glia (BG) relay noradrenaline (NA) signals ascending from the locus coeruleus (LC) to Purkinje cells (PCs), contributing to pain behavior. Using two-photon microscopy and optogenetics in mice, we found that the LC releases NA in the cerebellar cortex during peripheral noxious electrical stimuli, which elevates intracellular calcium in most BG. This global calcium activation of BG, called 'flare', was also elicited during capsaicin-induced pain, and chemogenetic inactivation of BG or LC terminals inhibited not only BG flares but also pain behavior. Pharmacological blockade or genetic knockdown of BG alpha-1 adrenergic receptors (α1-ARs) also suppressed capsaicin-induced BG flares and pain behavior. Electrophysiological recordings indicated that capsaicin-induced pain accompanies the reduction of PC activity, which was mimicked by chemogenetic activation of BG and prevented when flares were blocked by prazosin, an α1-AR blocker. Taken together, our study identified a glia-mediated mechanism of cerebellar pain processing, providing new insights into the cerebellum as an active pain modulator. ### Competing Interest Statement SHK, SKK, SJK hold patent applications related to the contents of this article (10-2021-0180671 in Korea). The other authors declare no conflicts of interest.