TY - JOUR
T1 - Predation Stress Causes Excessive Aggression in Female Mice with Partial Genetic Inactivation of Tryptophan Hydroxylase-2
T2 - Evidence for Altered Myelination-Related Processes
AU - Svirin, Evgeniy
AU - Veniaminova, Ekaterina
AU - Costa-Nunes, João Pedro
AU - Gorlova, Anna
AU - Umriukhin, Aleksei
AU - Kalueff, Allan V
AU - Proshin, Andrey
AU - Anthony, Daniel C
AU - Nedorubov, Andrey
AU - Tse, Anna Chung Kwan
AU - Walitza, Susanne
AU - Lim, Lee Wei
AU - Lesch, Klaus-Peter
AU - Strekalova, Tatyana
N1 - Funding Information:
Funding: The authors’ animal work reported here was supported by Deutsche Forschungsgemein-schaft (DFG:CRC TRR58A1/A5), the European Union’s Seventh Framework Programme (FP7/2007– 2013) under Grant No. 602805 (Aggressotype), the Horizon 2020 Research and Innovation Programme under Grant No. 728018 (Eat2beNice) (to K.P.L. and T.S.) and Grant No. 101007642 (PhytoAPP) (to D.A. and T.S.), and Swiss-Russian Cooperation grant RPG Russia 2020 (to S.W. and K.P.L.). Molecular data analysis was supported by RAS N0520-2019-0031 (to E.S. and T.S.). The sponsors had no role in study design, in the collection, analysis, and interpretation of data; in the writing of the report, and in the decision to submit the article for publication.
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/3/18
Y1 - 2022/3/18
N2 - 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.
AB - 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.
KW - Aggression/physiology
KW - Animals
KW - Female
KW - Glycogen Synthase Kinase 3 beta
KW - Male
KW - Mice
KW - Predatory Behavior
KW - Rats
KW - Serotonin/metabolism
KW - Tryptophan Hydroxylase/genetics
KW - TRANSCRIPTION FACTOR-1 MYT1
KW - female aggression
KW - 5-HT receptors
KW - glycogen synthase kinase-3 beta (GSK-3 beta)
KW - SOCIAL DEFEAT
KW - MOUSE MODEL
KW - SEROTONIN
KW - INDUCED ANHEDONIA
KW - HIPPOCAMPAL NEUROGENESIS
KW - C57BL/6 MICE
KW - PREFRONTAL CORTEX
KW - predation stress
KW - MATERNAL SEPARATION
KW - TREADMILL EXERCISE
KW - tryptophan hydroxylase-2 (Tph2)
KW - myelination
U2 - 10.3390/cells11061036
DO - 10.3390/cells11061036
M3 - Article
C2 - 35326487
SN - 2073-4409
VL - 11
JO - Cells
JF - Cells
IS - 6
M1 - 1036
ER -