Serotonin deficiency caused by inactivation of Tph2 in mice leads to widespread sex-dependent changes in cerebral oxidative metabolic activity.

Tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme of serotonin synthesis in the CNS, has been associated with numerous behavioural traits and psychiatric disorders. Tph2 modified mice present altered sensitivity to stress, and excessively aggressive behaviour that develops even in female animals. We have measured histochemically the activity of cytochrome c oxidase (COX) in 106 brain regions in wildtype, Tph2 heterozygous and total knockout male and female mice (n=78). In addition to direct comparisons by sex and genotype, COX activity co-variation in putative aggression networks was examined. Overall, female mice have higher COX activity than males. In regions affected by Tph2 inactivation a consistent pattern emerged, where Tph2± mice had the lowest, Tph2-/- mice had the highest COX activities, and Tph2+/+ in-between. Tph2 inactivation induced broad changes and an extensive reorganisation of neural activity as revealed by regional activity co-variation matrices of COX. These patterns of inter-regional correlations differed between sexes. Co-variation of COX activity also differed between males and females in the proposed networks for aggressiveness. In male mice, Tph2 inactivation disrupted co-variation of COX activity of the dorsal raphe and the periaqueductal grey matter with limbic regions. The septum appears as a hub of altered connectivity in females but not in males. Serotonin deficiency is associated with altered regional neural activity patterns as revealed by COX histochemistry. These alterations are profoundly different in male and female mice, and suggest that serotonin plays a partly sex-dependent role in the regulation of behaviour.