<p>Oligodendrocytes, the myelin-producing cells in the central nervous system, derive from oligodendrocyte progenitor cells during both development and remyelination. The intricate process of oligodendrocyte differentiation, which involves several transitional stages before generating fully mature myelin-producing cells, is tightly regulated by extracellular signals. Despite advances in identifying key regulators, the comprehensive network of signaling molecules governing oligodendrocyte maturation in the healthy, and more importantly, the demyelinated brain remains incompletely understood. The endocannabinoid system has been recognized as a key regulator of oligodendroglial lineage progression, contributing to myelin formation and regeneration. In particular, CB₁ cannabinoid receptors are prominent modulators of the initial steps of oligodendrocyte progenitor cell differentiation. However, the potential role of CB₁ receptors in the terminal stages of oligodendrocyte differentiation remains poorly explored. Here, using a new conditional genetic mouse model in which the CB₁ receptor-encoding gene was selectively ablated from differentiated oligodendrocytes, together with the cuprizone diet-induced demyelination paradigm, we demonstrate that CB₁ receptors are essential for the terminal stages of oligodendroglial maturation during myelin regeneration. Specifically, we found that CB₁ receptor gene inactivation in newly regenerated oligodendrocytes hinders oligodendroglial cell maturation and brain remyelination, exacerbates glial activation and axonal damage, and abolishes motor function recovery. Taken together, our findings demonstrate a crucial role for CB₁ receptors in modulating oligodendrocyte maturation during myelin regeneration and supports the notion that appropriate endocannabinoid signaling in the oligodendroglial lineage is essential for achieving efficient remyelination.</p>