TACHD · Treatment of depression and cognitive decline in Huntington's Disease: Cannabinoids as a Dual Therapeutic Approach

The proposed MSCA Postdoctoral Fellowship project investigates the potential of early cannabinoid-based therapies to alleviate psychiatric and cognitive symptoms in Huntington’s Disease (HD), a fatal neurodegenerative condition characterized by progressive motor, psychiatric, and cognitive decline. The research, to be hosted at IDIBAPS in Barcelona under the supervision of Prof. Silvia Ginés, integrates behavioral phenotyping, cell-type-specific transcriptomics, and functional brain imaging to assess whether cannabidiol (CBD) or combined CBD:THC interventions can modulate early neuroinflammatory and synaptic dysfunctions in HD. Previous studies show that the endocannabinoid system is dysregulated early in HD, especially with reduced CB1 receptor expression in mood and memory-related brain regions. Preclinical evidence suggests that phytocannabinoids, particularly CBD and THC, might alleviate these early non-motor symptoms, though mechanisms remain unclear. This project hypothesizes that targeted cannabinoid therapies could delay or reverse depressive behaviors and cognitive impairments in HD by acting on neuroinflammation and synaptic plasticity, thereby potentially altering the disease trajectory. The approach will utilize two well-characterized mouse models (R6/1 and HdhQ111), treating animals at both adolescent and young-adult stages with escalating doses of CBD and CBD:THC in different ratios. Behavioral outcomes will be measured using validated paradigms for depression (Forced Swim Test, Tail Suspension Test, Sucrose Preference) and cognition (Y-maze, Novel Object Location, Novel Object Recognition). At the molecular level, transcriptomic profiling will be performed using RiboTag mice to isolate mRNA from specific neuronal populations (glutamatergic and GABAergic), identifying gene expression changes linked to treatment, with a focus on inflammatory markers and CB1R-mediated pathways. Neuroimaging studies will involve resting-state fMRI scans analyzed for conne