Astrocytic Ensemble at vHip-NAc synapses Modulates Cognitive Impairments Induced by Chronic THC Exposure

Cannabis is the most widely used illicit drug, particularly during adolescence, and its consumption disrupts glutamate homeostasis and synaptic plasticity in the nucleus accumbens (NAc). While astrocytic cannabinoid receptors (CB1Rs) are known to modulate synaptic plasticity and behavior, the extent to which specific astrocytic ensembles drive tetrahydrocannabinol (THC)-induced alterations remains unclear. Here, we identify a functionally distinct accumbal astrocytic ensemble, related to ventral hippocampus-NAc (vHip->NAc) circuit, that is critical for THC-induced synaptic and behavioral impairments. Using fiber photometry, we monitored astrocytic calcium and glutamate dynamics within the NAc of wild-type and p38αMAPK ^−/− (Astrop38α) mice following chronic THC exposure, complemented by electrophysiological and behavioral assessments. Additionally, we employed AstroLight tool to selectively manipulate this astrocytic ensemble. Our findings reveal that: (1) THC increases astrocytic calcium activity and glutamatergic tone within the NAc; (2) the THC-induced glutamatergic alterations are absent in Astrop38α mice, implicating p38αMAPK signaling in astrocyte-mediated plasticity; (3) astrocytic glutamate release within the vHip->NAc ensemble is required for THC-induced cognitive deficits; and (4) targeted attenuation of THC-induced calcium activity in this ensemble prevents both spatial learning and synaptic plasticity impairments. These results highlight a critical role for astrocytic ensembles in shaping behavior and emphasize their potential as therapeutic targets for mitigating the cognitive consequences of THC exposure.