Small but Mighty: A Novel Oxytocin Receptor Isoform that Redefines the Oxytocin System 0 views

The canonical oxytocin receptor (OXTR) has been studied for decades as a plasma membrane G-protein coupled receptor. This research has focused primarily on how ligand binding at the cell surface drives downstream signaling linked to social behavior, parental care, and reproductive physiology. However, this single-receptor framework does not fully account for the substantial individual variation observed in oxytocin-dependent phenotypes, nor does it explain how environmental factors such as early life parental care produce lasting changes in OXTR biology through epigenetic modification. The prairie vole (Microtus ochrogaster), a socially monogamous and biparental rodent with a highly conserved Oxtr gene, provides an ideal model system to investigate how transcriptional diversity contributes to cellular function and individual variability. This dissertation investigates whether the transcriptional diversity of Oxtr is biologically meaningful, and if so, through what molecular mechanisms. The prairie vole provides a powerful model to investigate how social experience shapes gene regulation and behavior. Leveraging this system, this dissertation tests the hypothesis that transcriptional diversity at the Oxtr locus generates structurally and functionally distinct receptor isoforms that extend OXTR signaling beyond the plasma membrane. Here, I demonstrate that Oxtr generates structurally distinct transcripts under differential regulatory control, including a novel isoform, OxtrH, which encodes a mitochondria-targeted protein. Expression of OxtrH is associated with cellular bioenergetics, synaptic maturation, and epigenetic aging, revealing a previously unrecognized link between oxytocin signaling and mitochondrial function. Critically, the integrity of a single CpG site within the MT2 regulatory region - known to be sensitive to early-life parental care - is sufficient to regulate OxtrH expression and shift the transcriptomic balance between mitochondrial and synaptic gene programs. Together, these findings reframe the oxytocin receptor as a gene with multiple cellular identities. Oxtr generates structurally distinct transcripts under differential regulatory control where one of which, OxtrH, encodes a mitochondria-targeted protein whose expression is correlated with cellular bioenergetics, synaptic maturation, and biological aging. The integrity of a single CpG site within the MT2 regulatory region, which is known to be sensitive to early life parental care, is sufficient to regulate this isoform and shift the transcriptomic balance between mitochondrial and synaptic programs. These results provide a molecular foundation for understanding how environmental experience shapes not only oxytocin receptor expression, but the subcellular identity and metabolic consequences of the system itself.

PHD (Doctor of Philosophy)

oxytocin receptor; prairie vole; alternative transcripts; mitochondria

English

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2026-04-30