Tripson, Mark Andrew2023-06-052023-06-052023-052023-04-27May 2023http://hdl.handle.net/10342/12841The non-euphorigenic phytocannabinoid CBD has been found to be effective in treating childhood-onset epilepsies, conditions that are often associated with developmental delays, including vocal communication. Zebra finch song is a complex behavior that is learned during a sensitive period of vocal development, making it a promising model for understanding the mechanisms responsible for potential CBD-related improvements in vocal learning. Like language, the quality of adult zebra finch song is maintained through continuous sensorimotor maintenance and refinement, involving brain regions that control vocal learning and production. One of these brain regions, HVC, is a pre-vocal motor cortical-like region that when partially lesioned temporarily disrupts vocal behavior. Recovery from HVC microlesions typically takes about seven days without treatment. However, treatment with CBD has been shown to both speed recovery and reduce the acute magnitude of disruptions. Given the anti-inflammatory properties of CBD in seizure and other models, we suspected involvement of similar mechanisms in vocal recovery. To test this, we investigated CBD modulation of post-lesion expression of inflammatory cytokines, markers of neuronal stress, microglial migration, and changes in synaptic densities within relevant song control regions. Results indicate that CBD-improved vocal recovery is associated with reduced oxidative stress and anti-inflammatory activity. This decrease in inflammation and stress marker expression was associated with reduced density of microglia staining within song regions afferent to the lesion target, HVC (including learning-essential Area X [basal ganglia] and vocal motor RA [motor cortex]). Furthermore, we measured densities of excitatory synapses within Area X and RA, finding significant lesion-related decreases that were largely reversed by CBD. This synaptic protection was associated with BDNF/Arc/MSK1 upregulation, implicating mechanisms important to homeostatic synaptic scaling. Overall, this work indicates that CBD improves post-CNS damage recovery of learned vocal behavior by promoting multiple homeostatic mechanisms. This efficacy may generalize to sensorimotor skills learned by other vertebrates and suggests potential application to TBI and related disorders.application/pdfenNeurosciencePharmacologyLearning and MemoryNeural CircuitsSynaptic PlasticityInflammationPhytocannabinoidsCannabidiolZebra finchNeuroprotectionDoctoral Dissertation2023-06-02