Font noteworthy bold11/4/2023 We report reproducible alterations affecting hundreds of microglia-, astrocyte- and oligodendroglia-associated transcripts. Here, we present our findings from a transcriptomic study at single nuclei resolution in the VM, built from two independent opioid misuse-control cohorts (totaling 95 subjects) from different geographical areas in the U.S. This approach thus lends itself to an in-depth characterization of opioid-related changes in gene expression in these relatively under-studied glial cell types in human VM. In contrast, DA and GABA neurons taken together contributed only a very minor (< 4%) share of nuclei in this type of single nuclei RNA-seq assay 12, 13. Of note, in recent pilot studies exploring adult postmortem human VM single cell genomics (by 10x chromium single nuclei transcriptomic profiling Smajic and colleagues 12, and others 13, reported very high recovery rates of glial and other non-neuronal nuclei in these ‘dopaminergic’ brain structures, with >95–96% of the total population of nuclei recovered from the SN contributed by prototypical glia, including ODCs and their precursors, astrocytes, and microglia. Further, RNA-seq profiling of VM bulk tissue is insufficient to disentangle cell type-specific contributions in neuropsychiatric disease 11. However, to date, with the exception of a single study profiling RNA from VM bulk tissue in a limited cohort of opioid users and controls 10, no knowledge exists about genome-scale dysregulation associated with chronic opioid exposure and overdose. This task is particularly urgent for opioid use disorder (OUD), considering that opioid overdose (OD) is now the leading cause of accidental deaths in the United States, with ~70,000 deaths annually reflecting a >8-fold increase over the course of just two decades 9. To this end, cell-specific transcriptomic profiling of VM dissected from human post-mortem brain could deliver critical insights. However, despite these intriguing mechanistic studies in animal models, the functional and clinical significance of VM glial populations in subjects diagnosed with substance use disorder remains unexplored. Finally, oligodendrogenesis in VM is essential for morphine-mediated reward behavior, and proliferation and differentiation of VM oligodendrocytes (ODCs) is regulated by the firing activity of their surrounding dopaminergic neurons 8. Likewise, VM astrocytes play an essential role in drug-induced synaptic plasticity in DA neurons 6, a reflection of astrocytic regulation of neuronal glutamine supply and glutamatergic neurotransmission 7. To mention just three representative examples, excessive activation of VM microglia is thought to disrupt chloride homeostasis in GABA neurons, which in turn, negatively affects opioid and stimulant-induced dopamine release and associated reward behaviors 5. It has become increasingly clear in recent years that, in addition to the well-established roles of DA and non-DA (e.g., GABAergic) neurons, the VM’s glial and other non-neuronal populations may play an important role for drug responsiveness and substance use. Ventral midbrain (VM), including the ventral tegmental area (VTA) and substantia nigra (SN) 1, 2, is important for mediating habitual behaviors and salience of cues associated with drug use, as well as withdrawal-related anhedonia and dysphoria 3, 4. Ventral midbrain transcriptomic reprogramming in the context of chronic opioid exposure included 325 genes that previous genome-wide studies had linked to risk of substance use traits in the broader population, thereby pointing to heritable risk architectures in the genomic organization of the brain’s reward circuitry. Genes associated with activation of the immune response including interferon, NFkB signaling, and cell motility pathways were upregulated, contrasting with down-regulated expression of synaptic signaling and plasticity genes in ventral midbrain non-dopaminergic neurons. Chronic exposure to opioids was not associated with change in proportions of glial and neuronal subtypes, however glial transcriptomes were broadly altered, involving 9.5 − 6.2% of expressed genes within microglia, oligodendrocytes, and astrocytes. We studied gene expression in 212,713 ventral midbrain single nuclei from 95 individuals with history of opioid misuse, and individuals without drug exposure. Dynamic interactions of neurons and glia in the ventral midbrain mediate reward and addiction behavior.
0 Comments
Leave a Reply.AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |