Predation Stress Causes Excessive Aggression in Female Mice with Partial Genetic Inactivation of Tryptophan Hydroxylase-2: Evidence for Altered Myelination-Related Processes
Evgeniy Svirin,
Ekaterina Veniaminova,
João Pedro Costa-Nunes,
Anna Gorlova,
Aleksei Umriukhin,
Allan V. Kalueff,
Andrey Proshin,
Daniel C. Anthony,
Andrey Nedorubov,
Anna Chung Kwan Tse,
Susanne Walitza,
Lee Wei Lim,
Klaus-Peter Lesch,
Tatyana Strekalova
Affiliations
Evgeniy Svirin
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, 6200 MD Maastricht, The Netherlands
Ekaterina Veniaminova
Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov University, 119991 Moscow, Russia
João Pedro Costa-Nunes
Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov University, 119991 Moscow, Russia
Anna Gorlova
Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov University, 119991 Moscow, Russia
Aleksei Umriukhin
Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov University, 119991 Moscow, Russia
Allan V. Kalueff
Neuroscience Program, Sirius University, 354340 Sochi, Russia
Andrey Proshin
P.K. Anokhin Research Institute of Normal Physiology, 125315 Moscow, Russia
Daniel C. Anthony
Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine and Department of Normal Physiology, Sechenov University, 119991 Moscow, Russia
Andrey Nedorubov
Institute of Translational Medicine and Biotechnology, Sechenov University, 119991 Moscow, Russia
Anna Chung Kwan Tse
Li Ka Shing Faculty of Medicine, School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
Susanne Walitza
Department for Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of Zurich, 8032 Zurich, Switzerland
Lee Wei Lim
Li Ka Shing Faculty of Medicine, School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
Klaus-Peter Lesch
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, 6200 MD Maastricht, The Netherlands
Tatyana Strekalova
Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, 6200 MD Maastricht, The Netherlands
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.
