Periodic Reporting for period 1 - FLEX5 (Establishing the dual role of serotonergic neurons of the dorsal raphe in flexible behaviors) Reporting period: 2020-09-01 to 2022-08-31 Summary of the context and overall objectives of the project Is serotonin the molecule of happiness or the molecule of restraint? This neuromodulator is involved in many psychological disorders such as depression, anxiety, obsessive compulsive disorders, impulsivity, and addiction. However, how serotonin does this remains elusive. Understanding the role of serotonin in behaviour can therefore greatly help the development of new therapeutic strategies. FLEX5 aimed to define the role of the serotoninergic neurons within its network in reinforcement and restraint. The project demonstrated the general role of serotonin in reinforcement, in agreement with studies showing serotonin implication in anhedonia (inability to feel pleasure) and aboulia (inability to seek pleasure) but a specific role of one of its receptors in the repetition of deceiving reinforcement, agreeing previous studies of serotonin implication in behaviour inhibition. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far The project activities centred around monitoring and manipulating the neurons of one of the main sources of serotoninergic neurons, the dorsal raphe nucleus (DRN). A series of behavioural experiments were carried out to probe reinforcement that is beneficial in the long term or reinforcement that is either deceiving in the long term or aversive and that subjects learn to refrain from repeating. We found that while serotoninergic neurons of the DRN (DRN5-HT) respond generally to reward and is necessary for the animals to repeat rewarded action, neighbouring dopaminergic neurons of the DRN (DRNDA) respond generally to aversive stimuli. We also found that the response of DRN5-HT neurons to reward is conserved in a structure involved in reinforcement that is the dorsolateral striatum, and that this signal is necessary for repeating the experience of reinforcement whether beneficial or deceiving. While this suggest that serotonin seems generally involved in reinforcement, we found that blocking one receptor of serotonin (5HT4) specifically reduced the repetition of deceiving reinforcement suggesting a selective role of serotonin receptors in restraint and reinforcement.The results of FLEX5 were presented at four international conferences (European Brain and Behavioural Society forum 2021, Society For Neuroscience forum 2021, Basal Ganglia Gordon’s Conference 2022 and Federation of European Neuroscience Society 2022) and two further presentations are planned, after completion of the FLEX5 Project, at the Australasian neuroscience society forum 2022 and at the winter brain conference 2023. Furthermore, two scientific publications are in development and will be submitted to open access journals in 2023. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) The FLEX5 project data provides new insight in how serotonin works in the brain, reconciling previous theories regarding the role of serotonin and its implication in so many different psychopathologies. The project: 1. Demonstrated that dopaminergic neurons of the DRN respond differently to reinforcement and restraint stimuli.2. Discovered that inhibition of serotonin receptors modifies the behavioural response of subjects to reinforcement stimuli.3. Developed novel tools, based on viral vectors, to record the activity of serotoninergic terminals in the output structures of DRN. These results have also paved the way for future research into the functional role of serotonin. In particular, the knowledge generated by FLEX5 will help to inform future studies into the treatment of depression, at the new laboratory of the FLEX5 researcher, Yann Pelloux, at the Université Paris Saclay. schematic of the experiments
