Periodic Reporting for period 2 - SEROTONIN and BEYOND (Serotonin and BEYOND: Brain development research Excelling Young Ones in Neurotechnologies and Discoveries)
Periodo di rendicontazione: 2023-01-01 al 2025-04-30
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.
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.
Serotonin and Beyond hired 15 ESRs and implemented the training and management structure of the project. After a successful online Kick-off in June 2021, all ESRs were appointed and started their research project during autumn/winter 2022. We held a General Assembly meeting on January 2022, to welcome and introduce all ESRs to the consortium and the network. After that all ESRs have developed Personal Career plans and followed the training courses provided by the network and also their institutions. In October 2022 we organized our first network retreat in Paris, which we combined with a workshop on light sheet microscopy. In March 2023 the ESRs and PIs came together in Oxford to discuss their progress and challenges in detail with each other. In June 2023 the second network retreat took place in Berlin, during which the ESRs joined a course from ScienceOpen and from Ascension on technology transfer. In April 2024 the ESRs and PIs met each other again in person, this time in Copenhagen, to discuss progress and challenges. Finally, we held a final conference open to the public in September 2024 in Pisa, which started with a course on grant management and grant writing and ended with European Researcher Night presentations of renowed researchers from Italy. We also had a two-day Wikipedia Edit-a-thon, organised as part of the STEM Wiki User Group / School and University Projects initiative, during which we improved the public visibility and accessibility of scientific knowledge related to the field of serotonin research. All Serotonin & Beyond events as well as other consortium activities (e.g. participation in Open Days and BeOpen days) were disseminated via social media (LinkedIn, X). During the period from end of 2021 till sept 2024 all courses were given. In addition, the ESRs conducted their research at their host institutes and had their secondments with partners of the consortium as well as new partners. It is expected that all ESRs will get their PhD.
Our expected result was to deliver a new generation of high achieving early-stage researchers (ESRs), who will be equipped with a combination of multi-faceted technical skills and a thorough understanding of brain development. This goal was achieved by a unique combination of “hands-on” research training, non-academic placements and courses and workshops on scientific and complementary so-called “soft” skills. Our ESRs laid the groundwork for advances in the fundamental understanding of serotonin-mediated neurodevelopment and the origin of transdiagnostic neuropsychiatric endophenotypes. As 'beyond-state-of-the-art" a key finding of the consortium is that serotonin influences cortical development in a bi-phasic manner with brain and behavioural outcomes being strongly age dependent. Foreseen societal implications involved the identification of risk factors for psychiatric disorders and delivering insight in critical windows for interventions as well as new ideas for future intervention approaches redirecting serotonin-mediated developmental changes. This has the potential to lead to improved prevention of these disorders and promote mental health. At the end of the project, the following concrete impact was achieved so far:
ESR8, Gabriel Ocana Santero became cofounder and CEO of Exin Therapeutics, a company aiming to turn cutting-edge neuroscience into real-world therapies.
The project of ESR15 was followed up by funding from the Dutch government to further develop the homecage touchscreen cages ('Ratpad'), by integrating it with the existing Laboras system of Metris BV. Ratpad is becoming commercially available.
ESR8, Gabriel Ocana Santero became cofounder and CEO of Exin Therapeutics, a company aiming to turn cutting-edge neuroscience into real-world therapies.
The project of ESR15 was followed up by funding from the Dutch government to further develop the homecage touchscreen cages ('Ratpad'), by integrating it with the existing Laboras system of Metris BV. Ratpad is becoming commercially available.