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

Abstract

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.

Understanding the Role of Oxidative Stress, Neuroinflammation and Abnormal Myelination in Excessive Aggression Associated with Depression: Recent Input from Mechanistic Studies

“…Recently, Tph2 +/− mice exposed to predator stress were shown to display excessive aggression, increased anxiety-like behaviours, and altered sociability and compromised brain metabolism of dopamine and noradrenaline [ 95 , 96 ]. The predation stress procedure elicited behavioural and molecular changes in Tph2 +/− mice that were the opposite of those observed in control mice [ 73 , 95 ]. As such, environmentally challenged Tph2 +/− mice may represent a valid model of aggression that recapitulates the role G × E interaction in the mechanisms of stress-related aggression.…”

“…Recently, in a model of stress-induced aggression in Tph2 +/− mice, we have found alterations in Plp1 and myelin basic protein (Mbp) mRNA expression in the medial PFC [ 73 ]. In this study, stressed Tph2 +/− mice with increased aggressive behaviour revealed decreased expression of these genes [ 73 ].…”

“…Recently, in a model of stress-induced aggression in Tph2 +/− mice, we have found alterations in Plp1 and myelin basic protein (Mbp) mRNA expression in the medial PFC [ 73 ]. In this study, stressed Tph2 +/− mice with increased aggressive behaviour revealed decreased expression of these genes [ 73 ]. In another model of stress (stress of “systemic inflammation” or “inflammatory stress”), in which elevated aggression in mice deficient for major brain gangliosides was observed, we also found decreased mRNA and protein expression of Plp1 in the medial prefrontal cortex of both male and female mice.…”

Neurobiology of Aggression—Review of Recent Findings and Relationship with Alcohol and Trauma

“…Despite such a modest effect, modern neuroscientific tools keep pointing towards a serotonergic role in aggression. Since the discovery that the central nervous system has its own enzyme to synthesize serotonin (Tryptophan hydroxylase-2 (Tph-2); [ 106 ]), it was shown that a partial or complete knockdown led to more aggressive behavior in rodents [ 107 , 108 , 109 , 110 ] and could be linked to a diminished 5-HT 1A receptor sensitivity [ 111 ]. On the other hand, highly aggressive wild-derived mice had higher mRNA levels of Tph-2 than other laboratory animals [ 112 ].…”

Molecular signature of excessive female aggression: study of stressed mice with genetic inactivation of neuronal serotonin synthesis

“…We recently described a mouse model of female aggression, in which mice with partial genetic inactivation of Tph2 (heterozygous Tph2 +/− mice) were subjected to predation stress, resulting in pathological aggressive behavior (Svirin et al 2022a ) reminiscent of null mutant ( Tph2 −/− ) mice (Gutknecht et al 2012 , 2015 ). This was accompanied by abnormal expression of 5-HT receptors as well as changes in biomarkers of cellular distress, myelination and neural plasticity (Svirin et al 2022a ). However, these changes were not observed in naïve Tph2 +/− mice.…”