Serotonin is an important neurotransmitter playing a key role in neuropsychiatric disorders. It is most commonly used drugs in psychiatry target serotonin neurotransmission. However, it is becoming increasingly clear that the efficacy of these drugs is suboptimal. A new wave of research revealed that serotonin has powerful neurotrophic and neurodevelopmental actions. It is well possible that the suboptimal efficacy of serotonergic medication is because origins of neuropsychiatric disorders do not per se lie in disturbed serotonin neurotransmission, but rather in serotonin-mediated neurodevelopmental changes. We hypothesised that it are the serotonin-mediated downstream changes in brain development and maturation that confer risk to serotonin-related neuropsychiatric disorders.
The overarching objective of this ETN was to provide high-level training in the field of serotonin, neurodevelopment, neuropsychiatry and neurotechnologies. The specific scientific objectives of this ETN involved the following 4 objectives:
1.To determine the role of serotonin in perinatal raphe-PFC network formation
2.To define the role of serotonin in postnatal raphe-PFC network maturation
3.To elucidate how serotonin-mediated neurodevelopmental changes translate to psychiatric endophenotypes and respond to environmental stimuli
4.Optimize new technologies to measure serotonin-mediated neurodevelopmental changes and cognition.
1: We identified the placental compartments and components of the serotonergic machinery involved in the transport and metabolism of serotonin within the placenta (ESR1). We mapped the wiring-specific serotonergic connectome in early postnatal mice, revealing topographic projections to limbic structures (ESR2). We found that early fluoxetine exposure led to long-lasting changes in prefrontal cortex activity and its connectivity with the mediodorsal thalamus, which were linked to impaired cognitive flexibility (ESR3). We uncovered a key role for the dorsal raphe serotonin system in regulating nesting behavior, which was modulated by serotonergic signaling (ESR4). Finally, we elucidated the contribution of the serotonergic system to the excitatory/inhibitory (E/I) imbalance using human iPSC-derived cortical neurons (ESR5).
2: We found that the growth retardation of rats lacking serotonin in the brain (Tph2 knockout) could be rescued by monoamine oxidase-A inhibition and by 5-HTP treatment (ESR6). We showed that Tph2 knockout rats exhibit substantial deficits in motor and sensory reflex development (ESR7). We also found that serotonin signaling changes across life as a function of early fluoxetine exposure (ESR8) and that serotonin in adolescence shapes the dorsal raphe-hypothalamus neural pathway mediating aggression (ESR9). Finally, we applied computational modeling to theorize how serotonin influences precision in the predictive brain (ESR10).
3: ESR11 revealed that the interplay between genes and environment is happening early on during development. Corroborating evidence was obtained in human studies: ESR12 showed that this interplay is at work even prenatally, and ESR13 found that there is a link between peripheral DNA methylation of SLC6A4 and TPH2 and brain levels of 5-HTT and 5-HT4, as well as with measures of early life stress and depressive symptoms. Finally, ESR14 showed that maternal serotonergic genotype affects offspring brain development, behaviour and cognition, together with the role of the microbiome herein.
4: ESR15 built the ‘social ratpad’ system allowing cognitive testing in the homepage under social conditions and the identification of cognitive developmental milestones in rats with early perturbations in serotonin levels.
