Stress-related brain molecule dampers motivation and energy

Discovery offers insight into debilitating depression symptom.

It’s a familiar scenario: after a stressful day at work, the last thing most people want to do is make a time-consuming dinner. Instead, they’ll choose to eat something quick and low-effort at the expense of taste and nutrition. A recently published paper co-authored by Vancouver Coastal Health Research Scientist Dr. Stan Floresco explains how this type of situation, in which a person chooses the option of least effort for lesser reward rather than greater effort for greater reward, may be influenced by a neuropeptide called corticotropin releasing factor (CRF) released in the brain in response to stress.

The paper builds upon Dr. Floresco and his colleagues' previous research that found that rats, when given a choice, would normally work harder to get a large reward rather than working less for a smaller reward. However, after the researchers introduced stress by placing rats in a more constrained environment, they found that the animals were much lazier and more likely to take the easy way and the smaller reward, rather than working harder to get the large one. 

“This has relevance to stress-related psychiatric disorders such as depression because the major consequence of certain types of depression is anergia – this lack of motivation or effort to get off the couch and do stuff,” explains Dr. Floresco, affiliated researcher with the Djavad Mowafaghian Centre for Brain Health and professor in the Department of Psychology at the University of British Columbia.

Knowing that one of the brain’s responses to stress is the release of CRF, the researchers administered to the stressed rats an experimental drug compound that blocked CRF. As a result, by blocking CRF, the stressed rats chose the large reward requiring more work rather than the less-work-small-reward option.

“What’s more, if we artificially raised the levels of CRF in the rats, we saw the exact same effect where they shifted their bias to just taking the easy road and not working as hard,” says Dr. Floresco. 

“So, we saw that if you gave them a reward on a silver platter, they were fine, but as soon as there was extra effort required, they needed that extra motivation to get over the hump to get that larger reward, and increasing CRF activity blunted that motivation."

The findings highlight the involvement of CRF in regulating effort-related decisions and suggest that increased CRF activity may contribute to motivational impairments and abnormal decision-making associated with stress-related psychiatric disorders such as depression.

“We think the implication of this research is to understand some of the mechanisms that drive this particular anergia symptom in depression,” Dr. Floresco says. 

Discovering CRF’s roll opens possibilities for treatment development

Dr. Floresco and his colleagues' study is the first to show that when animals are given a choice between work-hard-and-win-big versus go-easy-and-win-less, that stress shifts the bias in terms of how hard in individual may want to work.

 “We might be resurrecting a line of research in terms of identifying targets for treating low motivation that we see in disorders like depression.”

“Previously, there have been clinical trials of CRF antagonists whereby the drug worked well, however, the drug also induced liver toxicity, which is a serious side effect,” Dr. Floresco explains. “Perhaps renewing those efforts of finding a molecule that could do the same thing but won’t destroy the liver might be helpful.”

“Really, anergia is one of the most debilitating aspects of depression,” he adds. “Depressed patients will talk about how they feel like a huge weight is on them and they just can’t get up; if that gets lifted and they start engaging, then other aspects of the depression might also be eased.”

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