Spatial transcriptome mapping to decode Cannabinoid-mediated neuroprotection in HIV-1 gp120—induced degenerating mouse brain 2255864

Abstract Introduction HIV-associated neurocognitive disorders (HAND) remain a major complication in AIDS patients and are thought to arise from chronic neuroinflammation. Our previous work established that Δ9-tetrahydrocannabinol (THC) exerts neuroprotective effects in HIV gp120 transgenic (Tg) mice by downregulating gp120 expression and reducing astrocytic activation. Methods In this study, we employed spatial transcriptomics to map the neuroimmune landscape of the gp120 Tg brain and to define the regional effects of THC treatment. Results Soluble gp120 protein was distributed throughout the hippocampus, corpus callosum, cortex, and thalamus, coinciding with increased reactive astrocytes–an effect markedly diminished by THC. While reactive microglia were evenly distributed across brain regions, THC treatment enhanced oligodendrocyte populations and induced IL-33 expression in the corpus callosum and stria. Notably, THC increased excitatory neurons in the cortex and thalamus but decreased inhibitory neurons primarily in the hypothalamus, suggesting restoration of neural balance underlying cognition and memory. T cells and dendritic cells localized around the subfornical organ and lateral ventricles decreased after THC exposure. Conclusion These spatial data align with our prior single-cell RNA-seq findings, collectively revealing that THC modulates the neuroimmune and cellular architecture of the HIV-compromised brain. Our findings highlight spatial transcriptomics as a powerful approach to uncover region-specific neuroimmune remodeling and support the therapeutic potential of cannabinoids in HAND. Funding Source Supported by NIH grants P20GM103641, P30GM154631, R01ES030144, and R01AI160896 Topic Categories Neuroimmunology (NEUR)