Ventromedial prefrontal area 14 provides opposing regulation of threat and reward-elicited responses in the common marmoset

New study published in the Proceedings of the National Academy of Sciences this week shows how overactivity of an area in the frontal lobes, called area 14, that shows altered activity in depression, can flatten anticipatory excitement in marmoset monkeys and cause an acute state of anxiety-like behaviour.

Anhedonia is a loss of pleasure and is a core symptom of depression. Anxiety states are also found to accompany depression in many people. Here, researchers in PDN including Dr Yoolla Massoudi, PhD student, Zuzanna Stawicka and senior author, Dr Christian Wood, under the leadership of Professor Angela Roberts have shown that both states can be induced by the same brain manipulation. Moreover, the increase in activity that induces these symptoms in marmosets mirrors those changes in activity that have been reported to occur in a similar region when imaging the brains of people with depression.

Imaging depression has shown us that there are many changes in activity in the brain associated with this condition but which of these changes is related to which symptom is unclear. Moreover, whether these changes cause the symptoms or are a result of the symptoms is also unclear. These are important questions because over 30% of people with depression are not effectively treated by current therapies, and even when people are effectively treated we don’t know how, or why, one therapy works in one person but not another. One of the most likely explanations is that the underlying changes in the brain causing depression and anxiety differ between individuals, and thus more individualised treatment strategies are required to ameliorate these different causes. Intervention studies, such as the one described here in monkeys, can help to inform this issue by dissecting out the specific role that these different changes in the brain have in causing the variety of symptoms associated with depression.

This study establishes that an increase in activity in one particular part of the frontal lobes can enhance reactivity to the presence, for just two minutes, of an unknown human. The mild anxiety that is induced in such a situation is considerably heightened following the acute activation of area 14. But this increased reactivity to threat is only seen when the threat is uncertain. It would appear that this area of the brain is not engaged when the threat is more imminent and certain. It is proposed that only when threat is uncertain and more distal is there time to engage in more complex strategies that would appear to be dependent, in part, on area 14 within the frontal lobes. In contrast to this heightening of reactivity to uncertain threat, activation of area 14 reduced the behavioural and cardiovascular arousal that accompanies the excitement a monkey shows to a sound that they have learned predicts access to a box of marshmallows.

By comparing these effects to those induced by manipulations in neighbouring regions of the frontal lobe, also implicated in depression, the Roberts lab are beginning to separate out the distinct contributions made by these different brain regions to the symptoms of depression and anxiety. This will provide insight into the varied nature of these disorders and help to explain the individual differences in sensitivity to treatments.

Reference: Ventromedial prefrontal area 14 provides opposing regulation of threat and reward-elicited responses in the common marmoset, Zuzanna M. Stawicka, Roohollah Massoudi, Nicole K. Horst, Ken Koda, Philip L. R. Gaskin, Laith Alexander, Andrea M. Santangelo, Lauren McIver, Gemma J. Cockcroft, Christian M. Wood, and Angela C. Roberts, PNAS https://doi.org/10.1073/pnas.2009657117