Author(s): Matias, Sara Pinto dos Santos
Date: 2015
Persistent ID: http://hdl.handle.net/10362/16807
Origin: Repositório Institucional da UNL
Subject(s): Serotonin; Dopamine; Fiber photometry; Reversal learning; Surprise; Domínio/Área Científica::Engenharia e Tecnologia::Engenharia Química
This work was developed in the context of the MIT Portugal Program, area of Bioengineering Systems, in collaboration with the Champalimaud Research Programme, Champalimaud Center for the Unknown, Lisbon, Portugal. The project entitled Dynamics of serotonergic neurons revealed by fiber photometry was carried out at Instituto Gulbenkian de Ciência, Oeiras, Portugal and at the Champalimaud Research Programme, Champalimaud Center for the Unknown, Lisbon, Portugal
Serotonin is an important neuromodulator implicated in the regulation of many physiological and cognitive processes. It is one of the most studied neuromodulators and one of the main targets of psychoactive drugs, since its dysregulation can contribute to altered perception and pathological conditions such as depression and obsessive-compulsive disorder. However, it is still one of the most mysterious and least understood neuromodulatory systems of the brain. In order to study the activity of serotonergic neurons in behaving mice, we used genetically encoded calcium indicators and developed a fiber photometry system to monitor neural activity from genetically defined populations of neurons. This approach was developed to study serotonin neurons but it can be used in any genetically defined neuronal population. To validate our approach, we first confirmed that increased neural activity, induced by electrical microstimulation, indeed produced increases in fluorescence detected by the system. We then used it to monitor activity in the dorsal striatum of freely behaving mice. We show that the two projection pathways of the basal ganglia are both active during spontaneous contraversive turns. Additionally, we show that this balanced activity in the two pathways is needed for such contraversive movements. Finally, we used the fiber photometry system to study the role of serotonin in learning and behavioral control and to compare it to that of dopamine, another important neuromodulator. Dopamine and serotonin are thought to act jointly to orchestrate learning and behavioral control. While dopamine is thought to invigorate behavior and drive learning by signaling reward prediction errors, i.e. better-than-expected outcomes, serotonin has been implicated in behavioral inhibition and aversive processing. More specifically, serotonin has been implicated in preventing perseverative responses in changing environments. However, whether or how serotonin neurons signal such changes is not clear. To investigate these issues, we used a reversal learning task in which mice first learned to associate different odor cues with specific outcomes and then we unexpectedly reversed these associations. We show that dorsal raphe serotonin neurons, like midbrain dopamine neurons, are specifically recruited following prediction errors that occur after reversal. Yet, unlike dopamine neurons, serotonin neurons are similarly activated by surprising events that are both better and worse than expected. Dopamine and serotonin responses both track learned cue-reward associations, but serotonin neurons are slower to adapt to the changes that occur at reversal. The different dynamics of these neurons following reversal creates an imbalance that favors dopamine activity when invigoration is needed to obtain rewards and serotonin activity when behavior should be inhibited. Our data supports a model in which serotonin acts by rapidly reporting erroneous associations, expectations or priors in order to suppress behaviors driven by such errors and enhance plasticity to facilitate error correction. Contrary to prevailing views, it supports a concept of serotonin based on primary functions in prediction, control and learning rather than affect and mood.
