Study of disturbed cells may lead to a better way of "treating excessive anxiety"

Stress is as much an emotional experience as it is a physical one that registers in the body and in the brain. According to findings published Thursday, experiencing chronic, uncontrollable stress can also literally change how our cells function from the inside out — and pinpointing why that happens can lead to a better understanding of what drives anxiety disorders.

Mitochondria help cells do one of their most important jobs: manufacture the energy you need to survive. That’s why they’re called the powerhouses of the cell. However, new research on mice and humans published in PLOS Genetics suggests that chronic stress throws a genetic wrench into the finely tuned mitochondrial energy machine, changing the way it functions, and in some cases, how mitochondria actually look.

Altogether, the findings paint a picture that’s consistent with earlier research done by study co-author Iiris Hovatta, Ph.D., an anxiety researcher at the University of Helsinki. There are lots of tiny molecular events that underpin the overwhelming feeling of chronic stress, and understanding them could point towards new treatments.

“Our findings suggest that mitochondrial function may be altered in some individuals with anxiety disorders,” she tells Inverse. “With this information, we can now investigate mitochondrial function in more detail in anxiety disorders to find out whether modulation of their function could be useful in treating of excessive anxiety.”

These findings are based on two experiments. The first was performed directly on the brains of two strains of mice — one who bred to be more resilient to stress, and another that was predisposed towards being less resilient to stressful experiences.

Then both were exposed to ten days of a “chronic social defeat” situation. That’s a scenario in which young, naive mice are repeatedly bullied by older, aggressive mice until their spirits were broken. That stressful emotional experience has been used to study the effects of depression treatments in mice the past.

In those mice, Hovatta and her team analyzed changes in the cells that make up the bed nucleus of the stria terminalis, a key brain region that takes input from several different brain regions to help regulate emotional responses to stress and anxiety.

The team noted that, in that region, three of the pathways of protein activity, which help the mitochondria make energy, were significantly changed due to exposure to stress. But the mitochondria themselves also were physically different. The stress resilient mice tended to have wider mitochondria than the stress-susceptible mice after they were socially defeated.

These scientists already knew that genetic underpinnings can have a big influence on how mice respond to stress. But this experiment showed one underlying way that stress impacts their bodies is by altering the way that cells produce energy.

That, if confirmed in other work, may help explain a biological underpinning of anxious behavior. Hovatta also says that these “underlying mechanisms” could help examine a key link between the way that cells produce energy during stressful times, and how that manifests in actually anxiety symptoms. Importantly, the human component of this study could be a step in that direction.

In addition to studying stressed mice, Hovatta and her colleagues took blood samples from 21 humans diagnosed with panic disorder, a condition that’s characterized by frequent, crippling panic attacks and persistent fear that they could strike at any time. After analyzing individuals one after they had panic attacks, the team also found differences in their mitochondrial pathways — specifically less expression of genes that impact the way their mitochondria function. The similarities between humans and mice suggest that animals respond to stress similarly, deep in their cells.

These results point towards a better understanding of just how deeply chronic stress can penetrate the body. These tiny changes in the cell may pale in comparison to the physical symptoms of a panic attack or constant anxiety — but they aren’t any less important and could give us clues to how to combat them.

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.