Astrocytic Bestrophin1 in the Anterior Cingulate Cortex Modulates the Formation and Persistence of Morphine Addiction Memory

Abstract

Emerging evidence indicates that astrocytes play a vital role in both the establishment and preservation of memories. However, their specific contribution to addiction-related memory remains largely unresolved. In this study, we observed alterations in Ca²⁺ dynamics within astrocytes of the anterior cingulate cortex (ACC) during the acquisition, recent retrieval, and remote retrieval phases of morphine-conditioned place preference (CPP). Selective activation of Gi signaling in ACC astrocytes during the acquisition phase, rather than during retrieval or transfer phases, led to a significant and prolonged increase in the morphine CPP score. In contrast, activation of Gq signaling led to a reduction in the CPP score, which was both diminished and shortened. Additionally, we noted a significant increase in astrocytic Bestrophin 1 (BEST1) expression in the ACC during the morphine CPP acquisition phase. Selective knockdown of BEST1 from ACC astrocytes elevated astrocytic Ca²⁺ dynamics, expanded astrocytic coverage, alleviated astrocytic glutamate release, and altered the density of synapses between the dorsal hippocampus (dCA1) and ACC within the astrocytic microdomains. Mice lacking astrocytic BEST1 displayed impaired activity in ACC^dCA1 neurons and decreased CPP scores. These findings suggest that ACC astrocytes modulate the connectivity between dCA1 and ACC neurons, possibly through extrasynaptic glutamate activity, thereby regulating the strength and persistence of morphine-associated memory.