Single-Nucleus Transcriptomics of the Nucleus Accumbens Reveals Cell-Type-Specific Dysregulation in Adolescent Macaques with Depressive-Like Behaviors

Adolescent depression is increasingly recognized as a serious mental health disorder with distinct clinical and molecular features. Using single-nucleus RNA sequencing, we identified cell-specific transcriptomic changes in the nucleus accumbens (NAc), particularly in astrocytes, of adolescent macaques exhibiting depressive-like behaviors. The level of diacylglycerol kinase beta was significantly reduced in neurons and glial cells of depressed macaques, while FKBP5 levels increased in glial cells. Disruption of GABAergic synapses and disruption of D-glutamine and D-glutamate metabolism were linked to depressive phenotypes in medium spiny neurons (MSNs) and subtypes of astrocytes. Communication pathways between astrocytes and D1/D2-MSNs were also disrupted, involving factors like bone morphogenetic protein-6 and Erb-B2 receptor tyrosine kinase-4. Bulk transcriptomic and proteomic analyses corroborated these findings, and FKBP5 upregulation was confirmed by qRT-PCR, western blotting, and immunofluorescence in the NAc of rats and macaques with chronic unpredictable mild stress. Our results highlight the specific roles of different cell types in adolescent depression in the NAc, offering potential targets for new antidepressant therapies.