Previous studies show that chronic stress induces synaptic structural alterations in brain regions involved in emotional processing such as the prefrontal cortex (PFC) and the basolateral amygdala ...(BLA). Yet, these studies are based mainly in animal exposure to unpredictable stressors or to restraint stress. On the other hand, studies using the chronic social defeat stress (CSDS), a relevant model of depression based on social conflict, are lacking. Here we aim to study the acute (24 h after CSDS) and long-term (one month after CSDS) effects of CSDS on dendritic and synaptic structures in the PFC and BLA of C57BL/6 mice. Specifically, BLA and PFC dendritic spine densities as well as BLA arborisation were analysed. Subsequently, we investigate in these regions the synaptic response to a friendly (interaction with a same strain mouse) or a fearful (interaction with a dominant strain mouse) social stimulus.
Spine densities of the apical dendrites from the PFC pyramidal neurons were decreased by CSDS in the long-term (one month after CSDS). In addition, CSDS increased BLA stellate neurons spine density in the short-term (24 h after CSDS) and dendritic arborisation in the long-term. Moreover, long-term CSDS mice exposed to a fearful stimulus experienced a marked social avoidance and showed a significant increase in the expression of the immature form of the brain derived neurotrophic factor (proBDNF) in the amygdala.
Taken together these results suggest the existence of persistent neuronal adaptations in the PFC and BLA in socially defeated mice. Specifically, spine density retraction in the PFC and increased BLA dendritic arborisation could represent an adaptive structural change allowing rapid expression of synaptic markers in response to fearful experiences.
Rationale
Chronic social defeat stress (CSDS) has been proposed as a model of depression. However, most CSDS studies rely only on the analysis of stress-induced social avoidance. Moreover, the ...predictive validity of the model has been poorly analyzed, let alone its interaction with biological risk factors.
Objectives
Here, we explore the validity of CSDS as a depression model. Further, the effect of decreased vesicular glutamate transporter 1 (VGLUT1), as a potential factor enhancing a depressive-like phenotype, was studied.
Methods
Mice were exposed to CSDS (10 days) followed by saline, venlafaxine, fluoxetine, or tianeptine treatment (30 days). The battery of behaviors included motor activity, memory, anxiety, social interaction, helplessness, and anhedonic-like behavior. Moreover, the behavioral effect of CSDS in VGLUT1 heterozygous (VGLUT1+/−) mice was studied, as well as the regulation of VGLUT1 mRNA.
Results
CSDS induced anhedonia, helplessness, hyperactivity, anxiety, social avoidance, and freezing, as well as downregulation of VGLUT1 mRNA in the amygdala. Repeated venlafaxine showed antidepressant-like activity and both venlafaxine and tianeptine behaved as effective anxiolytics. CSDS-induced social avoidance was reverted by tianeptine. Fluoxetine failed to revert most of the behavioral alterations. VGLUT1+/− mice showed an enhanced vulnerability to stress-induced social avoidance.
Conclusion
We suggest that CSDS is not a pure model of depression. Indeed, it addresses relevant aspects of anxiety-related disorders. Firstly, CSDS-induced anhedonia and social avoidance are not associated in this model. Moreover, CSDS might be affecting brain areas mainly involved in the processing of social behavior, such as the amygdala, where the glutamatergic mechanism could play a key role.
Many studies suggest that the prefrontal cortex (PFC) is a target limbic region for stress response because a dysfunction here is linked to anhedonia, a decrease in reactivity to rewards, and to ...anxiety. It is suggested that stress-induced persistent molecular changes in this brain region could bring some light on the mechanisms perpetuating depressive episodes. In order to address this issue, here we have studied the long-term PFC gene expression pattern and behavioral effects induced by a chronic mild stress (CMS) model and antidepressant treatment in mice. CMS was applied to mice for six weeks and imipramine (10mg/kg, i.p.) or saline treatment was administered for five weeks starting from the third week of CMS. Mice were sacrificed one month after CMS and following two weeks after the discontinuation of drug treatment and the PFC was dissected and prepared for gene (mRNA) and protein expression studies. Using the same experimental design, a separate group of mice was tested for anhedonia, recognition memory, social interaction and anxiety. CMS induced a long-term altered gene expression profile in the PFC that was partially reverted by imipramine. Specifically, the circadian rhythm signaling pathway and functions such as gene expression, cell proliferation, survival and apoptosis as well as neurological and psychiatric disorders were affected. Of these, some changes of the circadian rhythm pathway (Hdac5, Per1, and Per2) were validated by RT-PCR and western-blot. Moreover, CMS induced long-lasting anhedonia that was reverted by imipramine treatment. Impaired memory, decreased social interaction and anxiety behavior were also induced by chronic stress. We have identified in the PFC molecular targets oppositely regulated by CMS and imipramine that could be relevant for chronic depression and antidepressant action. Among these, a possible candidate for further investigation could be the circadian rhythm pathway.
•Chronic mild stress (CMS) alters cortical gene expression in the long term.•CMS downregulation of Per1, Per2, Bhlhe40 and Pdgfb was reverted by imipramine.•Circadian rhythm could be a key regulator of depression and antidepressant action.
Abstract Major depression is a mental disorder often preceded by exposure to chronic stress or stressful life events. Recently, animal models based on social conflict such as chronic social defeat ...stress (CSDS) are proposed to be more relevant to stress-induced human psychopathology compared to environmental models like the chronic mild stress (CMS). However, while CMS reproduces specifically core depressive symptoms such as anhedonia and helplessness, CSDS studies rely on the analysis of stress-induced social avoidance, addressing different neuropsychiatric disorders. Here, we study comparatively the two models from a behavioural and neurochemical approach and their possible relevance to human depression. Mice (C57BL/6) were exposed to CMS or CSDS for six weeks and ten days. Anhedonia was periodically evaluated. A battery of test applied during the fourth week after the stress procedure included motor activity, memory, anxiety, social interaction and helplessness. Subsequently, we examined glutamate, GABA, 5-HT and dopamine levels in the prefrontal cortex, hippocampus and brainstem. CMS induced a clear depressive-like profile including anhedonia, helplessness and memory impairment. CSDS induced anhedonia, hyperactivity, anxiety and social avoidance, signs also common to anxiety and posttraumatic stress disorders. While both models disrupted the excitatory inhibitory balance in the prefrontal cortex, CMS altered importantly this balance in the brainstem. Moreover, CSDS decreased dopamine in the prefrontal cortex and brainstem. We suggests that while depressive-like behaviours might be associated to altered aminoacid neurotransmission in cortical and brain stem areas, CSDS induced anxiety behaviours might be linked to specific alteration of dopaminergic pathways involved in rewarding processes.
Abstract Major depression might originate from both environmental and genetic risk factors. The environmental chronic mild stress (CMS) model mimics some environmental factors contributing to human ...depression and induces anhedonia and helplessness. Mice heterozygous for the synaptic vesicle protein (SVP) vesicular glutamate transporter 1 (VGLUT1) have been proposed as a genetic model of deficient glutamate function linked to depressive-like behaviour. Here, we aimed to identify, in these two experimental models, gene expression changes in the frontal cortex, common to stress and impaired glutamate function. Both VGLUT1+/− and CMS mice showed helpless and anhedonic-like behavior. Microarray studies in VGLUT1+/− mice revealed regulation of genes involved in apoptosis, neurogenesis, synaptic transmission, protein metabolic process or learning and memory. In addition, RT-PCR studies confirmed gene expression changes in several glutamate, GABA, dopamine and serotonin neurotransmitter receptors. On the other hand, CMS affected the regulation of 147 transcripts, some of them involved in response to stress and oxidoreductase activity. Interestingly, 52 genes were similarly regulated in both models. Specifically, a dowregulation in genes that promote cell proliferation (Anapc7), cell growth (CsnK1g1), cell survival (Hdac3), and inhibition of apoptosis (Dido1) was observed. Genes linked to cytoskeleton (Hspg2, Invs), psychiatric disorders (Grin1, MapK12) or an antioxidant enzyme (Gpx2) were also downregulated. Moreover, genes that inhibit the MAPK pathways (Dusp14), stimulate oxidative metabolism (Eif4a2) and enhance glutamate transmission (Rab8b) were upregulated. We suggest that these genes could form part of the altered “molecular context” underlying depressive-like behaviour in animal models. The clinical relevance of these findings is discussed.
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