Medial Preoptic Nucleus to Periaqueductal Gray GABAergic Pathway Underlies Individual Differences in Consolation-Like Behavior in Mice

INTRODUCTION: Consolation is a complex empathic behavior that varies considerably across individuals, yet the neural basis of this heterogeneity remains poorly understood. The medial preoptic area is a key hub for instinctive social behaviors, but it remains unclear which of its subregions - the medial preoptic nucleus (MPN) versus the surrounding area (MPA) - or which neuronal subtypes (GABAergic, glutamatergic, or galanin-expressing) contribute to individual differences in consolation. METHODS: We used a social defeat-induced consolation paradigm in male mice and categorized them into low- and high-consolation groups based on allogrooming duration toward distressed partners. We performed c-Fos immunofluorescence to compare neuronal activation in the MPN versus MPA, and to identify the specific neuronal subtypes activated in each group. We then used chemogenetic approaches to manipulate MPN GABAergic neurons, as well as their projection to the periaqueductal gray (PAG), and examined the effects on consolation behavior, sociability, and anxiety. RESULTS: High-consolation mice showed selective c-Fos activation in the MPN, but not in the MPA, and this activation was specific to GABAergic neurons. Chemogenetic inhibition of MPN GABAergic neurons or the MPNGABA-PAG pathway selectively reduced allogrooming in high-consolation mice without affecting sociability or anxiety. CONCLUSION: The MPNGABA-PAG pathway is a critical modulator of individual variation in consolation-like behavior in mice, revealing a subregion- and cell-type-specific circuit mechanism underlying empathic heterogeneity.