Tph2 deficiency shapes neurodevelopmental behavioral trajectories through interactions with the maternal environment, sex, and the gut microbiome

Abstract Serotonin (5-HT) is critical for neurodevelopment, influencing brain maturation, emotional regulation, and social behavior. Tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme for central 5-HT synthesis, causes lifelong 5-HT depletion when disrupted. While early-life 5-HT perturbations are linked to neuropsychiatric vulnerability, it remains unclear how lifelong depletion shapes behavioral trajectories across development, or how sex and postnatal environment influence these effects. Here, we provide a longitudinal characterization of Tph2 -deficient male and female rats, assessing reflex development, sensorimotor coordination, anxiety-like behavior, recognition memory, social interaction, and aggression across the first two months of life. To investigate environmental and microbial modulators, we quantified maternal care (e.g., licking/grooming, nursing, nest proximity) through daily observations during the first postnatal week and profiled adult gut microbiota via 16S rRNA sequencing. The association between maternal care and behavioral outcomes was assessed to identify environmental modulators of the Tph2 phenotype, while principal component analysis (PCA) visualized genotype- and sex-specific microbial clustering. Tph2 −/− rats exhibited delayed sensorimotor maturation, altered emotional regulation, reduced object-directed exploration and sociability, and increased aggression, particularly in males. Sensorimotor and exploratory outcomes were positively associated with maternal care, reinforcing its role in shaping behavioral trajectories. Microbiota analysis revealed genotype- and sex-dependent alterations, with Tph2 +/− males showing the most pronounced shifts, including increased microbial richness and taxonomic divergence. Together, our findings demonstrate that 5-HT depletion disrupts behavioral neurodevelopmental trajectories via interactions between genetic, environmental, and ecological factors, highlighting the importance of accounting for sex, environment, and developmental timing in translational research.