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

Abstract

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.

Resilience and Vulnerability to Stress-Induced Anhedonia: Unveiling Brain Gene Expression and Mitochondrial Dynamics in a Mouse Chronic Stress Depression Model

“…In this study, mice were subjected to three different stressors (rat exposure, restraint stress, and social defeat) over 2 weeks, as described elsewhere [77,78]. For rat exposure stress, mice were introduced to a transparent glass cylinder (15 cm high × Ø 8 cm) and placed into the rat cage (15 h exposures were performed between 18:00 and 09:00), as described previously [87,88]. During restraint stress, mice were placed into a small container (50 mL Falcon Tube) with space for breathing but no space for free movement.…”

“…This assay was carried out as described elsewhere [88]. All mice were scored for their coat state prior to stress and 15 h after the termination of the last stressor (5-excellent condition, 1-poor condition).…”