TY - JOUR

T1 - Molecular signature of excessive female aggression: study of stressed mice with genetic inactivation of neuronal serotonin synthesis.

AU - Strekalova, Tatyana

AU - Moskvin, Oleg

AU - Jain, Aayushi Y

AU - Gorbunov, Nikita

AU - Gorlova, Anna

AU - Sadovnik , Daria

AU - Umriukhin, Aleksei

AU - Cespuglio, Raymond C

AU - Yu, Wing Shan

AU - Kwan Tse, Anna Chung

AU - Калуев, Алан Валерьевич

AU - Lesch, Klaus-Peter

AU - Lim , Lee Wei

PY - 2023/9

Y1 - 2023/9

N2 - Aggression is a complex social behavior, critically involving brain serotonin (5-HT) function. The neurobiology of female aggression remains elusive, while the incidence of its manifestations has been increasing. Yet, animal models of female aggression are scarce. We previously proposed a paradigm of female aggression in the context of gene x environment interaction where mice with partial genetic inactivation of tryptophan hydroxylase-2 (Tph2 +/- mice), a key enzyme of neuronal 5-HT synthesis, are subjected to predation stress resulting in pathological aggression. Using deep sequencing and the EBSeq method, we studied the transcriptomic signature of excessive aggression in the prefrontal cortex of female Tph2 +/- mice subjected to rat exposure stress and food deprivation. Challenged mutants, but not other groups, displayed marked aggressive behaviors. We found 26 genes with altered expression in the opposite direction between stressed groups of both Tph2 genotypes. We identified several molecular markers, including Dgkh, Arfgef3, Kcnh7, Grin2a, Tenm1 and Epha6, implicated in neurodevelopmental deficits and psychiatric conditions featuring impaired cognition and emotional dysregulation. Moreover, while 17 regulons, including several relevant to neural plasticity and function, were significantly altered in stressed mutants, no alteration in regulons was detected in stressed wildtype mice. An interplay of the uncovered pathways likely mediates partial Tph2 inactivation in interaction with severe stress experience, thus resulting in excessive female aggression.

AB - Aggression is a complex social behavior, critically involving brain serotonin (5-HT) function. The neurobiology of female aggression remains elusive, while the incidence of its manifestations has been increasing. Yet, animal models of female aggression are scarce. We previously proposed a paradigm of female aggression in the context of gene x environment interaction where mice with partial genetic inactivation of tryptophan hydroxylase-2 (Tph2 +/- mice), a key enzyme of neuronal 5-HT synthesis, are subjected to predation stress resulting in pathological aggression. Using deep sequencing and the EBSeq method, we studied the transcriptomic signature of excessive aggression in the prefrontal cortex of female Tph2 +/- mice subjected to rat exposure stress and food deprivation. Challenged mutants, but not other groups, displayed marked aggressive behaviors. We found 26 genes with altered expression in the opposite direction between stressed groups of both Tph2 genotypes. We identified several molecular markers, including Dgkh, Arfgef3, Kcnh7, Grin2a, Tenm1 and Epha6, implicated in neurodevelopmental deficits and psychiatric conditions featuring impaired cognition and emotional dysregulation. Moreover, while 17 regulons, including several relevant to neural plasticity and function, were significantly altered in stressed mutants, no alteration in regulons was detected in stressed wildtype mice. An interplay of the uncovered pathways likely mediates partial Tph2 inactivation in interaction with severe stress experience, thus resulting in excessive female aggression.

KW - Aggression/physiology

KW - Animals

KW - Brain/metabolism

KW - Female

KW - Mice

KW - Rats

KW - Serotonin/metabolism

KW - Social Behavior

KW - Tryptophan Hydroxylase/genetics

KW - Serotonin

KW - Aggression

KW - Prefrontal cortex

KW - Tryptophan hydroxylase-2 (Tph2)

KW - Predation stress

KW - Deep sequencing (mRNAseq)

UR - https://www.mendeley.com/catalogue/d7fec1d7-90fc-3019-a4f6-7041ef175c36/

U2 - 10.1007/s00702-023-02677-8

DO - 10.1007/s00702-023-02677-8

M3 - Article

C2 - 37542675

VL - 130

SP - 1113

EP - 11132

JO - Acta Neurovegetativa

JF - Acta Neurovegetativa

SN - 0375-9245

IS - 9

ER -