MATERNAL SEROTONIN SHAPES HYPOTHALAMIC DEVELOPMENT TOWARD SOCIAL NECESSITY PATHWAYS IN RODENTS

Maternal signals can shape offspring social behavior through early developmental plasticity, yet the underlying cellular mechanisms remain unclear. Here, we used a physiological elevation of maternal serotonin via transient 5-HTP administration during peak brain neurogenesis (E11–E14) to examine how pre-neural serotonin modulates social circuits. We found that prenatal serotonin increase did not alter the identity or abundance of known aggression-driving neuronal populations. Instead, social behavior was selectively modified: juvenile offspring exhibited heightened social approach and reduced avoidance without changes in anxiety-like or exploratory behaviors. Single-cell and spatial transcriptomics of the hypothalamus revealed that these effects correspond to robust molecular and regulatory alterations in social-relevance circuits, most prominently within the lateral hypothalamus (LH). LH orexin/hypocretin neurons, a major node in hypothalamic circuits regulating social behavior and social necessity, showed enhanced signaling activity, whereas aggression-associated hypothalamic populations remained unaffected at the transcriptomic and communication levels. Beyond neurons, we identified pronounced and region-specific oligodendrocyte maturation acceleration and lipid metabolic remodeling, particularly in the lateral hypothalamus, in line with myelination-dependent modulation of social circuits. Mechanistically, prenatal serotonin reshaped the hypothalamic regulatory landscape by downregulating NFI transcription factors and engaging Wnt-dependent developmental programs, leading to broad adjustments in synaptic organization and neuron-glia differentiation trajectories. Together, our data identify orexin-linked social necessity pathways - rather than aggression modules - as primary targets of maternal serotonin and uncover a parallel glial mechanism that reshapes hypothalamic network function. These findings reveal a previously unrecognized route through which physiological maternal cues bias the developmental trajectory of social behaviors.