ASTROGLIAL CANNABINOID TYPE 1 RECEPTOR TUNES LOCOMOTOR ACTIVITY AND AVERSION THROUGH EXTERNAL GLOBUS PALLIDUS CIRCUITS

The external Globus Pallidus (GPe) and the Subthalamic Nucleus (STN) are Basal Ganglia (BG) nuclei involved in motor control, action selection and motivation, whose dysfunction contributes to addiction and neurodegenerative disorders, such as Parkinson’s disease. The GPe is characterized by a high astrocyte-to-neuron ratio and a strong enrichment in cannabinoid type-1 receptors (CB1R). We hypothesized that astrocytes, and astroglial endocannabinoid signaling, could causally influence GPe neuronal activity by integrating contextual information from the environment and from interconnected nuclei such as the STN. We first studied the behavioral role of astroglial CB1R in the GPe by combining behavioral assays with fiber photometry recording of astroglial Ca²⁺ activity in CB1R-deleted mice. Astroglial CB1R deletion in the GPe disrupted locomotion-coupled astrocytic Ca²⁺ signals and prevented the THC-induced impairment of fine locomotor coordination in an open arena, quantified using machine learning–based locomotion segmentation. These results indicate a context-dependent role of astroglial CB1R in shaping BG circuit functions. We next identified the STN as a potential source of endocannabinoids acting on GPe astroglial CB1R using ex vivo Ca²⁺ imaging. This motivated us to test the STN–(astrocytes)–GPe circuit in vivo, by combining optogenetic stimulation of STN projections with selective astroglial CB1R deletion in the GPe. Optogenetic activation elicited aversive behavior only in CB1R-deleted mice, suggesting that astroglial CB1R provides an on-demand compensatory mechanism during preference and aversion learning. Overall, these findings reveal an unrecognized role of astroglial CB1R in GPe circuit function and in the regulation of motor and motivated behaviors.