Multi-omics analysis identifies mitochondrial pathways associated with anxiety-related behavior, 2019, Hovatta et al

[Andy]

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.

Author summary
Genetic and environmental factors contribute to the etiology of psychiatric diseases but the underlying mechanisms are poorly understood. Chronic psychosocial stress is a well-known risk factor for anxiety disorders. 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. Bioinformatic integration of these data supported differences in mitochondrial pathways as a major stress response. To translate these findings to human anxiety, we investigated blood cell gene expression in mice and in panic disorder patients exposed to fearful situations and experiencing panic attacks. Concurring with our brain findings, expression of mitochondrial pathways was also affected in mouse and human blood cells, suggesting that the observed stress response mechanisms are evolutionarily conserved. Therefore, chronic stress may critically affect cellular energy metabolism, a finding that may offer new targets for therapeutic interventions of stress-related diseases.

Open access at https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1008358

 

[Trish]

Research done in mice.

Spoiler: Stressed mouse

 

[Mithriel]

Basic biology is highly conserved so most of what we know about the behaviour of genes has come from animal studies, including fruit flies and planarian worms so it may have relevance to humans.

As it stands, psychology treats anxiety as an emotional problem - healthy stress system not working because of wrong thoughts that can be fixed by changing thoughts with CBT whereas I believe that many people with anxiety disorders have a faulty stress system which reacts badly to a stress level that a healthy system could cope with.

If your system is broken then any psychological therapy should be tailored to that not just CBT which assumes that you are doing something wrong. It should be treated as an illness in the same way as coeliac disease, say, where people are not blamed and a way is found to deal with a broken system.

 

[Midnattsol]

Basic biology is highly conserved so most of what we know about the behaviour of genes has come from animal studies, including fruit flies and planarian worms so it may have relevance to humans.

As it stands, psychology treats anxiety as an emotional problem - healthy stress system not working because of wrong thoughts that can be fixed by changing thoughts with CBT whereas I believe that many people with anxiety disorders have a faulty stress system which reacts badly to a stress level that a healthy system could cope with.

If your system is broken then any psychological therapy should be tailored to that not just CBT which assumes that you are doing something wrong. It should be treated as an illness in the same way as coeliac disease, say, where people are not blamed and a way is found to deal with a broken system.

This. A hundred times this.

 

[rvallee]

It sounds a lot more likely that what we commonly refer to as anxiety is a range of biological and psychological processes but that we cannot tell them apart, even in cases of zero psychological involvement. We know for a fact that purely physiological processes can cause behavioral changes indistinguishable from the definition of psychologically-induced anxiety, from brain tumors to caffeine overdose.

We cannot test for anxiety and only have vague definitions of it. Claims about anxiety should be moderated with that in mind. Because if we follow the logic that ME does not exist because we cannot test for it, then anxiety does not exist either. Which is not a true statement. There is too much uncertainty and vague, hollow models about indeterminate concepts are not at all helpful.

The same can be said of depression. We only have a vague definition for it and no means to test for it. Arbitrary double standards are not the way to solve complex problems, especially when it leads to paradoxes like "this disease cannot be real since we cannot test for it therefore it must only and strictly be this vague, indeterminate concept we cannot test for and is superficially indistinguishable from other unrelated health problems".