Cannabidiol Inhibits Neuroinflammatory Responses and Circuit-Associated Synaptic Loss Following Damage to a Songbird Vocal Pre-motor Cortical-Like Region

Abstract

Abstract The non-euphorigenic phytocannabinoid cannabidiol (CBD) has been used successfully to treat childhood-onset epilepsies. These conditions are associated with developmental delays that often include vocal learning. Zebra finch song, like language, is a complex behavior learned during a sensitive period of development. Song quality is maintained through continuous sensorimotor refinement involving circuits that control learning and production. Within the vocal motor circuit, HVC is a cortical-like region that when partially lesioned temporarily disrupts song structure. We previously found CBD (10 mg/kg/day) improves post-lesion vocal recovery. The present studies were done to understand mechanisms underlying CBD vocal protection. We found CBD-improved vocal recovery is accompanied by reduced expression of inflammatory mediators and oxidative stress markers. These effects were associated with regionally-reduced expression of the microglia marker TMEM119. As microglia are key regulators of synaptic reorganization, we measured synapse densities, finding significant lesion-induced circuit-wide decreases that were largely reversed by CBD. Synaptic protection was accompanied by NRF2 activation and BDNF/ARC/ARG3.1/MSK1 expression implicating mechanisms important to song circuit node mitigation of oxidative stress and promotion of synaptic homeostasis. Our findings indicate CBD improves post-lesion recovery of a complex learned behavior through an array of neuroprotective processes consistent with modulation of multiple cell signaling systems.