Selective Vulnerability of Parvocellular Oxytocin Neuron in Social Dysfunction

Despite the rapid progress in dissecting neural circuits for social behaviors, it remains unknown whether specific neural cell types are selectively vulnerable in social dysfunction cases often associated with neurodevelopmental disorders. Here, employing a single-cell transcriptome analysis in mice, we show that an embryonic disturbance known to induce social dysfunction preferentially impairs gene expressions crucial for neural functions in parvocellular oxytocin (OT) neurons—a subtype linked to social rewards—while neighboring cell types experience a lesser impact. Chemogenetic stimulation of OT neurons at the neonatal stage ameliorated social deficits, concomitant with a cell-type-specific sustained recovery of the pivotal gene expressions. Our data illuminates the transcriptomic selective vulnerability within the hypothalamic social behavioral center, offering a potential therapeutic target through specific neonatal neurostimulation. Overall design: First, to characterize gene expressions in the paraventricular hypothalamus (PVH) of mice that were embryonically exposed to valproic acid and exhibited social dysfunctions, we administrated sodium valproate at a dosage of 500 mg/kg to pregnant female mice on gestation day 12.5. The PVH samples of male OT-Cre; Ai9 mice at 5 weeks of age were dissected based on the fluorescence of tdTomato subjected to 10X Genomics Chromium platform for single nucleus RNAseq. Age-matched animals of the same genotype but prenatally exposed to saline were used as a control. Second, to analyze the effects of neonatal chemogenetic stimulation of oxytocin neurons on gene expressions in the PVH in later young adulthood, we utilized male OT-Cre; stop-hM3 mice at 5–7 weeks of age that were embryonically exposed to VPA and CNO (or saline as a control) at PND 2. We collected nuclei from PVH areas and subjected them to the 10X Genomics Chromium platform.