Predation Stress Causes Excessive Aggression in Female Mice with Partial Genetic Inactivation of Tryptophan Hydroxylase-2: Evidence for Altered Myelination-Related Processes.

The interaction between brain serotonin (5-HT) deficiency and environmental adversity may predispose females to excessive aggression. Specifically, complete inactivation of the gene encoding tryptophan hydroxylase-2 ( Tph2 ) results in the absence of neuronal 5-HT synthesis and excessive aggressiveness in both male and female null mutant ( Tph2 ^-/- ) mice. In heterozygous male mice ( Tph2 ^+/- ), there is a moderate reduction in brain 5-HT levels, and when they are exposed to stress, they exhibit increased aggression. Here, we exposed female Tph2 ^+/- mice to a five-day rat predation stress paradigm and assessed their emotionality and social interaction/aggression-like behaviors. Tph2 ^+/- females exhibited excessive aggression and increased dominant behavior. Stressed mutants displayed altered gene expression of the 5-HT receptors Htr1a and Htr2a , glycogen synthase kinase-3 β ( GSK-3β ), and c-fos as well as myelination-related transcripts in the prefrontal cortex: myelin basic protein ( Mbp ), proteolipid protein 1 ( Plp1 ), myelin-associated glycoprotein ( Mag ), and myelin oligodendrocyte glycoprotein ( Mog ). The expression of the plasticity markers synaptophysin ( Syp ) and cAMP response element binding protein ( Creb ), but not AMPA receptor subunit A2 ( GluA2 ), were affected by genotype. Moreover, in a separate experiment, naïve female Tph2 ^+/- mice showed signs of enhanced stress resilience in the modified swim test with repeated swimming sessions. Taken together, the combination of a moderate reduction in brain 5-HT with environmental challenges results in behavioral changes in female mice that resemble the aggression-related behavior and resilience seen in stressed male mutants; additionally, the combination is comparable to the phenotype of null mutants lacking neuronal 5-HT. Changes in myelination-associated processes are suspected to underpin the molecular mechanisms leading to aggressive behavior.