Transcriptomic shifts in Microtus ochrogaster neurogenic niches reveal psychiatric-risk pathways engaged by pair-bond formation

Abstract

Pair bonding (PB) is a stable affiliative relationship that confers profound behavioral and physiological advantages. The prairie vole (Microtus ochrogaster), one of the few socially monogamous mammals, provides a tractable model for dissecting the neurobiological substrates of social interactions. We previously showed that social co-habitation with mating (SCM) increases cell proliferation and neuronal differentiation in the subventricular zone (SVZ) and dentate gyrus (DG), implicating adult neurogenesis in bond formation. Here, we characterized the underlying molecular programs by bulk RNA-seq of the SVZ, DG and nucleus accumbens (NAc) at two time points, 48 h and 120 h, following SCM or isolated (control) housing. Across ∼ 18000 expressed genes, 286 differentially expressed genes (DEGs) emerged in the female SVZ and 540 in the females DG (120 h vs 48 h SCM), whereas male niches displayed markedly fewer transcriptional shifts, confirming pronounced sexual dimorphism. Gene ontology analysis revealed sustained upregulation of mitochondrial and oxidative-phosphorylation modules, coupled with downregulation of neurogenesis, synaptic plasticity, and cell migration pathways in females at 120 h. In vitro, SVZ-derived neurospheres from females mirrored these signatures: SCM increased the sphere number at 48 h, but neuronal output normalized by 120 h, indicating a transient neurogenic surge. Numerous zinc-finger transcripts and unannotated long non-coding RNAs were also regulated, hinting at vole-specific epigenetic controls. Strikingly, > 100 DEGs mapped to human psychiatric-risk loci. Autism disorder spectrum (ADS) and schizophrenia-associated orthologues (e.g., GRIN2A/B, KMT2A, UBE3A) were predominantly downregulated during bond consolidation in females, whereas isolation elevated major depressive disorder (MDD) markers (e.g., CACNA1H) in both sexes. These data suggest that pair-bond formation recruits transcriptional networks that overlap the genetic architecture of neuropsychiatric diseases, and that social isolation elicits an opposing, disorder-linked profile. Together, our results identified sex-specific, temporally phased molecular pathways that couple adult neurogenesis, energy metabolism, and psychiatric-risk gene networks to the establishment of enduring social bonds.