A new avenue to explore to combat depressive behaviors

You have probably experienced anxiety while waiting for medical results. The effect you feel immediately after being informed that everything is okay is difficult to describe in all its dimensions, but this relief has a euphoric effect. What is happening in your brain at that moment? And what would happen if your brain was not capable of making you feel this state? These are the two main questions that a team of Chinese researchers wanted to answer in an article recently published in the journal Neuron. To analyze it in detail, we interviewed François Tronche, research director at the National Center for Scientific Research (CNRS) at Sorbonne University, specializing in the study of the role of gene expression in adaptive behaviors. He is particularly interested in the impact of stress hormones on dopaminoceptive neurons and the consequences on social behavior.

From the study of addiction to that of relief

Historically, the detailed study of dopaminergic neurons of the ventral tegmental area (VTA) has mainly been carried out to answer questions linked to addictions: “VTA neurons were initially studied in the context of the response to drugs, probably because it fascinated scientists to understand how addiction to certain molecules could modify some of our behaviors in the long term. The regions studied in this research article are, however, involved in the modulation of numerous behaviors. explains François Tronche. It is likely that the historical context of the “war on drugs” in the United States also played a role in the funding and dominance of this area of ​​study.

Since then, biological engineering techniques have taken a giant step forward: “ Today, we can manipulate almost all of the parameters of a living organism, for example through genetic editing targeted on a single cell, by controlling the production of a protein of interest, by injecting viruses activator or inhibitor of certain neurons, by causing the activation of certain molecules to respond to a light source, etc. “, specifies François Tronche. From now on, the field of neurobehavioral studies is diversifying and exploring new phenomena previously neglected such as the effect of stress relief.

The Rewarding Effect of Stress Relief

In our nervous system there is a network of brain structures, including the striatum, and the ventral tegmental area which participates in reward mechanisms during certain situations. For example, when you eat, socialize or consume certain substances. The nature of this reward is biological and is expressed in chemical form. It is not reduced to the presence of dopamine, which is often called the pleasure neurotransmitter because it plays a central role in these processes.

The researchers wanted to know if the relief that an animal can feel immediately after stress affects this reward system. It’s the case. Take two coins that a mouse can easily distinguish. If, just after stress, in this case being confined in a narrow tube, you systematically release her into the same room, she will develop a preference for this space. You can observe him by giving him the choice, a few days later, to go freely, this time, in one or the other room. She will choose the one in which she was usually released. With control mice, which have not been stressed, this preference does not develop: “ This type of experiment, called “conditioned place preference,” has been widely used to study drug addiction. For example, give morphine to a mouse, and place it in one of the two chambers, several times in a row and then give it the choice of walking in one or the other chamber. She will spend a lot more time in the one where she had this pleasant experience of receiving morphine. In the article, the authors also compare the two. Taking morphine and stopping unpleasant stress cause a similar place preference. They also show that the time window which allows this conditioning effect is short; you have to do it within five minutes of the stress stopping, after that it’s too late,” analyzes François Tronche.

The (incomplete) neural mapping of stress relief

After verifying that stress relief resulted in reward, the researchers dissected the underlying neural mechanisms. They showed that pharmacologically blocking the action of dopamine stems this effect. So they focused on the dopamine system. It includes the ventral tegmental area (VTA), the dopaminergic neurons which project to the nucleus accumbens in which they release dopamine.

If you repeatedly expose individuals to repeated stress, such as that of restraint, used here in mice, you will induce depressive-type behaviors in some of them such as resignation or loss of pleasure: “ By juggling tools to precisely target a cell type (Cre/loxP system), to control neuronal activity (optogenetics), to measure dopamine release in vivo using fluorescent probes, etc., this team demonstrates that stress relief activates dopaminergic neurons in the VTA and that this activation correlates with the magnitude of conditioned place preference. The projections of these neurons onto subregions of the nucleus accumbens will, for some, block the appearance of resignation, and for others, the loss of pleasure. enthuses François Tronche about the beauty of this experimental manipulation.

There is therefore a behavioral specificity of these different neuronal pathways. However, given the beauty of these results, François Tronche warns us, with humor, against too hasty conclusions: “ It is not because these two regions respond well to the tests carried out that we have mapped all the ins and outs of stress relief. It’s a bit like the joke of the guy who lost his keys in the street at night and who only looks for them under streetlights because that’s the only place where there is light. It’s a bit the same thing here. This study shows that these two regions are necessary, but not that they are necessarily sufficient.”

Strengthen the effects of relief to combat depression?

Repeated stress, such as that used here, induces depressive-like behavior in some individuals while others are resilient. The mechanism described in this study could contribute to this interindividual variation. A strong reward, just after stress has stopped, could perhaps facilitate resilience. This appears to be the case. Just after stress, give them sugared water or chocolate, which they really like, and you will reduce depressive symptoms. Behavioral strategies could prevent the appearance of depressive-type behaviors. Would this work in humans? To know this, clinical trials will need to look into the issue by evaluating the nature of the rewards used and the type of population. This preclinical study suggests it’s worth a try.