Another step towards understanding how the brain encodes what is good or bad

Neuroscientists at the Institute for Research in Life and Health Sciences (ICVS), at the University of Minho School of Medicine, have made significant progress in understanding how the brain processes positive and negative stimuli. Their findings, published in the prestigious journal Nature Communications, shed new light on the role of neurons in a region of our brain that is key to perceiving pleasure and aversion, the nucleus accumbens. These findings are important because several neuropsychiatric pathologies, including depression and addiction, present alterations in this brain region.

The nucleus accumbens has two types of neurons – D1 and D2 – that have always been thought to be “rivals” in processing pleasure and aversion. In this work, the researchers used miniaturized microscopes to track hundreds of these neurons in real time in rodents exposed to appetitive and aversive stimuli. Contrary to expectations, this study demonstrated that both types of neurons are recruited in response to positive and aversive stimuli.


The researchers then tried to understand how these neurons responded during the learning of positive and negative associations, recreating an experimental paradigm inspired by the famous work of scientist Ivan Pavlov with his dog. Associative learning allows an organism to learn to relate a neutral stimulus (such as a sound) to something meaningful (such as food or an unpleasant event). In this case, scientists trained the animals to associate a specific sound with the delivery of a reward or an aversive stimulus – similar to the way Pavlov conditioned dogs to salivate when they heard a bell. Surprisingly, both D1 and D2 neurons were recruited in a similar manner throughout learning, rather than changing their response over time. However, when the researchers changed the rules of the game, that is, the sound was no longer accompanied by a reward or aversive stimulus, they observed a fascinating nuance: D2 neurons took on a more prominent role than D1 neurons. Using a technique called optogenetics – a millimetre-precise technology that allows specific neurons to be “turned on and off” – the scientists showed that D2 neurons were key to adapting to the new rules. In other words, by inhibiting D2 neurons, they were able to make the animals take longer to “understand the new rules”.

Unraveling how the brain encodes and responds to external cues that predict something positive or aversive is crucial to better understanding certain illnesses such as post-traumatic stress or depression. The same external cue can trigger completely different responses depending on the individual’s context and associated memories. For example, for most people, the sound of party fireworks is associated with festive moments and something positive, but in the case of a soldier with PTSD, it can trigger an anxiety attack, remembering the war, even if he is in a peaceful environment. completely safe. This ability of the brain to reframe external stimuli based on past experiences and adapt to contexts demonstrates the extraordinary complexity of our neural circuits involved in this type of memory.

Left to Right: Carina Cunha, Verónica Domingues, Ana João Rodrigues

For Carina Cunha, one of the researchers who led this work, the research demonstrated the enormous “relevance of these two populations of neurons (D1 and D2) in the response to positive or negative stimuli and to clues that predict these stimuli”. “Although, at certain times, they have different activities, there is also a lot of similarity between these populations and this was something unexpected, which opens many doors for the future.
Within these groups we can see that there is functional segregation, but we still need to know where this segregation comes from. It is something we are going to look for, what differentiates them both in physiological context and in pathology.”

Ana João Rodrigues, who also coordinated this work, mentions that in the next phase of this project the aim is to “find genetic markers that identify the neurons that encode something positive and aversive. That is, understanding what distinguishes these neuron subtypes.” “This way, we can create new tools to manipulate these neurons and see the impact on behavior,” concludes Verónica Domingues, one of the first authors of the article.

This research was supported by funding from the European Research Council (ERC), the La Caixa Foundation, the Foundation for Science and Technology (FCT) and the Bial Foundation.