Cannabidiol (CBD) Promotes Post-TBI Astrocyte Viability and Decreases Injury-Induced Glial Stress Responses Across Zebra Finch Song Control Nuclei

Abstract The non-euphorigenic phytocannabinoid cannabidiol (CBD) has demonstrated therapeutic efficacy in childhood-onset epilepsies. Using a songbird preclinical model we have found that CBD promotes recovery of learned vocalizations following focal motor cortical injury. But questions about cellular mechanisms supporting this protection remained. Songbird vocal learning, like human speech, depends on development and maintenance of specialized neural circuits. Partial lesioning (microlesions) of the vocal pre-motor cortical-like song region HVC transiently disrupts song structure and triggers injury-associated cellular stress responses across interconnected song regions. Building on prior findings that CBD reduces neuroinflammation and synaptic loss in zebra finch song circuitry, we investigated potential astrocyte contributions. Here we report that HVC microlesions induce significant cell loss in HVC and its projection targets (vocal motor RA and striatal Area X), with a substantial fraction of apoptotic cells being astrocytes. CBD treatment reduces lesion-induced apoptosis and preserves astrocyte populations, indicating enhanced astrocyte viability as a major factor in CBD-mediated neuroprotection. Microlesions also elevate astrocyte stress, including increased lysosomal burden (LAMP1/LC3 expression) and astrocytic reactivity markers (C3, S100A10, aromatase). CBD attenuates these stress responses while enhancing neuroprotective metabolic and antioxidant mediators (glutamine synthetase [GS], glutamate-cysteine ligase modifier subunit [GCLM]), consistent with improved antioxidant and excitotoxicity resistance. Given that development-dependent sensorimotor skills (e.g. song in songbirds, language and many others in humans) depend on sensitive period establishment and ongoing post-learning maintenance of specialized neural circuits vulnerable to traumatic disruption, the zebra finch model provides a valuable preclinical platform for investigating glial-targeted interventions to promote circuit resilience and functional recovery after TBI. Competing Interest Statement The authors have declared no competing interest.