Abstract
Stressful life events are major environmental risk factors for anxiety disorders, although not all individuals exposed to stress develop clinical anxiety. The molecular mechanisms underlying the influence of environmental effects on anxiety are largely unknown. To identify biological pathways mediating stress-related anxiety and resilience to it, we used the chronic social defeat stress (CSDS) paradigm in male mice of two inbred strains, C57BL/6NCrl (B6) and DBA/2NCrl (D2), that differ in their susceptibility to stress. Using a multi-omics approach, we identified differential mRNA, miRNA and protein expression changes in the bed nucleus of the stria terminalis (BNST) and blood cells after chronic stress. Integrative gene set enrichment analysis revealed enrichment of mitochondrial-related genes in the BNST and blood of stressed mice. To translate these results to human anxiety, we investigated blood gene expression changes associated with exposure-induced panic attacks. Remarkably, we found reduced expression of mitochondrial-related genes in D2 stress-susceptible mice and in exposure-induced panic attacks in humans, but increased expression of these genes in B6 stress-susceptible mice. Moreover, stress-susceptible vs. stress-resilient B6 mice displayed more mitochondrial cross-sections in the post-synaptic compartment after CSDS. Our findings demonstrate mitochondrial-related alterations in gene expression as an evolutionarily conserved response in stress-related behaviors and validate the use of cross-species approaches in investigating the biological mechanisms underlying anxiety disorders.
Highlights
Chronic stress is a significant risk factor for human anxiety disorders [1], yet not all individuals exposed to stress develop a clinically relevant anxiety symptomatology
To identify biological pathways involved in psychosocial stress-induced anxiety and resilience to it, we used a well-characterized mouse model of chronic social defeat stress (CSDS) in two inbred mouse strains, C57BL/6NCrl (B6) and DBA/2NCrl (D2), which differ in their susceptibility to stress
We focused on the bed nucleus of the stria terminalis, a key brain region behind stress-response and anxiety, and carried out genome-wide analysis of mRNA, and miRNA expression, and protein abundance
Summary
Chronic stress is a significant risk factor for human anxiety disorders [1], yet not all individuals exposed to stress develop a clinically relevant anxiety symptomatology. The underlying reasons for these differences are not yet fully understood but involve an interaction of complex genetic and environmental factors that vary among individuals resulting in stress susceptibility or resilience. The chronic social defeat stress (CSDS) model is a well-established mouse paradigm of psychosocial stress, with construct, face, discriminative, and predictive validity for stressrelated disorders [2,3,4]. It involves 10 days of brief daily confrontation of two conspecific male mice, a resident-aggressor and an intruder who reacts with defensive, flight, or submissive behavior [5, 6]. We have previously shown that genetic factors strongly affect the behavioral outcome of the CSDS, since different inbred mouse strains vary in the proportion of susceptible and resilient animals as well as in their stress coping behaviors [4]
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