Anna Gorlova1, Gabriela Ortega2, Jonas Waider2, Natalia Bazhenova3, Ekaterina Veniaminova1, Andrey Proshin4, Allan V Kalueff5, Daniel C Anthony6, Klaus-Peter Lesch7, Tatyana Strekalova8. 1. Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia; School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands. 2. Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany. 3. Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia; School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands; Institute of General Pathology and Pathophysiology, Moscow, Russia. 4. PK Anokhin Research Institute of Normal Physiology, Moscow. 5. School of Pharmacy, Southwest University, Chongqing, China with Ural Federal University, Ekaterinburg, Russia; Institute of Translational Biomedicine, St. Petersburg State University and Almazov Medical Research Center, Institute of Experimental Medicine, St. Petersburg Russia. 6. Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia; Department of Pharmacology, Oxford University, Oxford, United Kingdom. 7. Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia; School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands; Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany. 8. Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia; School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands; Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Würzburg, Germany; Institute of General Pathology and Pathophysiology, Moscow, Russia. Electronic address: t.strekalova@maastrichtuniversity.nl.
Abstract
BACKGROUND: The contribution of gene-environment interactions that lead to excessive aggression is poorly understood. Environmental stressors and mutations of the gene encoding tryptophan hydroxylase-2 (TPH2) are known to influence aggression. For example, TPH2 null mutant mice (Tph2-/-) are naturally highly aggressive, while heterozygous mice (Tph2+/-) lack a behavioral phenotype and are considered endophenotypically normal. Here we sought to discover whether an environmental stressor would affect the phenotype of the genetically 'susceptible' heterozygous mice (Tph2+/-). METHODS: Tph2+/- male mice or Tph2+/+ controls were subjected to a five-day long rat exposure stress paradigm. Brain serotonin metabolism and the expression of selected genes encoding serotonin receptors, AMPA receptors, and stress markers were studied. RESULTS: Stressed Tph2+/- mice displayed increased levels of aggression and social dominance, whereas Tph2+/+ animals became less aggressive and less dominant. Brain tissue concentrations of serotonin, its precursor hydroxytryptophan and its metabolite 5-hydroxyindoleacetic acid were significantly altered in all groups in the prefrontal cortex, striatum, amygdala, hippocampus and dorsal raphe after stress. Compared to non-stressed animals, the concentration of 5-hydroxytryptophan was elevated in the amygdala though decreased in the other brain structures. The overexpression of the AMPA receptor subunit, GluA2, and downregulation of 5-HT6 receptor, as well as overexpression of c-fos and glycogen-synthase-kinase-3β (GSK3-β), were found in most structures of the stressed Tph2+/- mice. LIMITATIONS: Rescue experiments would help to verify causal relationships of reported changes. CONCLUSIONS: The interaction of a partial TPH2 gene deficit with stress results in pathological aggression and molecular changes, and suggests that the presence of genetic susceptibility can augment aggression in seemingly resistant phenotypes.
BACKGROUND: The contribution of gene-environment interactions that lead to excessive aggression is poorly understood. Environmental stressors and mutations of the gene encoding tryptophan hydroxylase-2 (TPH2) are known to influence aggression. For example, TPH2 null mutant mice (Tph2-/-) are naturally highly aggressive, while heterozygous mice (Tph2+/-) lack a behavioral phenotype and are considered endophenotypically normal. Here we sought to discover whether an environmental stressor would affect the phenotype of the genetically 'susceptible' heterozygous mice (Tph2+/-). METHODS: Tph2+/- male mice or Tph2+/+ controls were subjected to a five-day long rat exposure stress paradigm. Brain serotonin metabolism and the expression of selected genes encoding serotonin receptors, AMPA receptors, and stress markers were studied. RESULTS: Stressed Tph2+/- mice displayed increased levels of aggression and social dominance, whereas Tph2+/+ animals became less aggressive and less dominant. Brain tissue concentrations of serotonin, its precursor hydroxytryptophan and its metabolite 5-hydroxyindoleacetic acid were significantly altered in all groups in the prefrontal cortex, striatum, amygdala, hippocampus and dorsal raphe after stress. Compared to non-stressed animals, the concentration of 5-hydroxytryptophan was elevated in the amygdala though decreased in the other brain structures. The overexpression of the AMPA receptor subunit, GluA2, and downregulation of 5-HT6 receptor, as well as overexpression of c-fos and glycogen-synthase-kinase-3β (GSK3-β), were found in most structures of the stressed Tph2+/- mice. LIMITATIONS: Rescue experiments would help to verify causal relationships of reported changes. CONCLUSIONS: The interaction of a partial TPH2 gene deficit with stress results in pathological aggression and molecular changes, and suggests that the presence of genetic susceptibility can augment aggression in seemingly resistant phenotypes.
Authors: Johannes de Munter; Dmitrii Pavlov; Anna Gorlova; Michael Sicker; Andrey Proshin; Allan V Kalueff; Andrey Svistunov; Daniel Kiselev; Andrey Nedorubov; Sergey Morozov; Aleksei Umriukhin; Klaus-Peter Lesch; Tatyana Strekalova; Careen A Schroeter Journal: Front Nutr Date: 2021-04-15
Authors: Kajol V Sontate; Mohammad Rahim Kamaluddin; Isa Naina Mohamed; Rashidi Mohamed Pakri Mohamed; Mohd Farooq Shaikh; Haziq Kamal; Jaya Kumar Journal: Front Psychol Date: 2021-12-20
Authors: 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 Journal: Cells Date: 2022-03-18 Impact factor: 6.600