Single-Nucleus Transcriptomics of the Mouse Medial Preoptic Area Reveals Sex-Dependent Molecular Signatures of Social...

Social dominance hierarchies are a common form of social organization across animal species. We have previously shown that both male and female CD-1 mice form highly linear dominance hierarchies. In mice and other vertebrates, the medial preoptic area (mPOA) is a key hypothalamic sub-region regulating aggressive and defensive behaviors that support hierarchical social structures, but the transcriptional mechanisms in mPOA neurons underlying dominance behaviors and the influence of sex on these neuron populations in the context of social dominance hierarchies remain largely unresolved. Using single-nucleus RNA sequencing (snRNA-seq) to profile mPOA neurons from dominant and subordinate mice, we identified highly consistent social status-dependent changes in the transcriptomes of neuronal nuclei expressing neuropeptide transcripts. Oxytocin expression was remarkably widespread across mPOA neurons, and we found it to be the primary driver of group differences in neuropeptide co-expression networks. Overall, dominant males and females exhibited markedly decreased expression of oxytocin and vasopressin and had a lower proportion of neurons co-expressing multiple neuropeptide transcripts compared to subordinate individuals. In contrast, subordinates displayed widespread reorganization of the transcriptomic neuropeptidome and strikingly enhanced coupling of neuropeptide expression in mPOA neurons. Despite the strong pattern of concordant gene expression in dominant and subordinate individuals, the number of genes that were differentially expressed by status was substantially reduced in males compared to females. In sum, these results demonstrate that maintenance of social status dynamically reconfigures hypothalamic transcriptomic neuropeptidome in a sex-dependent manner and establishes how social status is encoded at a single-cell resolution.