PhenoConnectomics · Pheno-connectomics of human neurodevelopmental diseases
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-09-01 → 2023-08-31
- EU contribution
- €174,167
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Pheno-connectomics of human neurodevelopmental diseases
The brain, with its myriad of neurons, operates like a vast, intricate network. Each neuron in this network connects to several others, forming the very essence of our thoughts, behaviors, and emotions. However, understanding precisely how each neuron connects and communicates with its counterparts remains a daunting challenge. This gap in our knowledge is of great societal significance because many psychiatric illnesses, from depression to autism, are deeply intertwined with abnormalities in these connections. Addressing this profound challenge, the project embarked on a journey to develop a novel method that can map these neural connections on a single-cell level. Using advanced techniques like single-cell mRNA sequencing, viral tracing, and barcoding, the aim was not only to chart the 'roads' each neuron takes but also to understand the 'language' they speak – their gene expression. The project's ultimate objective was fourfold. Firstly, to pioneer a new technological assay that can unravel the synaptic networks spanning thousands of neurons. Secondly, to delve into the basic biology of neurons, questioning the nature and number of connections each neuron forms and whether their connectivity influences their genetic expression. The third goal was conceptual, introducing the idea of viewing the connectome at a single-cell level as a unique phenotype, coined "pheno-connectomics", which holds the key to understanding various diseases at their most foundational level. Lastly, the project aimed to decode how genetic anomalies can simultaneously influence a neuron's gene expression and its connections, and whether this impact is uniformly distributed across different neuron types. In conclusion, this project holds the promise of bridging the gap between genetic expression and neural connectivity. Its success has the potential to reshape our understanding of psychiatric diseases at a fundamental level.
Data: CORDIS, © European Union
Project objective
There is much we don't know about how neurons connect in our brains, but we know that their connectivity is essential for brain function in health and disease. Many psychiatric diseases coincide with the miswiring of the brain: to understand these, we need to know how neurons connect in each condition. I will develop a new approach to map single-cell synaptic connectivity, and use it to study joint connectome & transcriptome changes in an established monogenic autism spectrum disorder (ASD) organoid model. Change in synaptic connectivity is a key feature of ASDs, such as Rett-syndrome, which is caused by a mutation of the epigenetic regulator, MECP2. To understand how Rett-syndrome manifests on both transcriptional and connectivity levels, I will compare healthy & MECP2-KO human cortical organoids. I will combine single-cell mRNA sequencing and transsynaptic viral tracing techniques with barcoding. I will subsequently develop the required computational analysis entailing multi-omics integration and network analysis, and use statistical reconstructions to study the global properties of the organoid connectome. In essence, the project aims at four advances: Technology: – Develop a connectome-by-sequencing assay to chart synaptic networks of thousands of neurons.Basic biology: – Find out how many, and what kind of connections do single neurons form? – Do ‘lonely’ neurons have a different transcriptome than highly connected ones?Concept: – Introduce single-cell connectomics as a phenotype (pheno-connectomics) to understand diseases, and find their earliestmanifestation.Disease mechanism: – How genetic defects affect gene expression, and concurrently the connectome? – Are all cell types affected the same way?
Original text from CORDIS.
Participants
- INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH · WienCoordinatorAustria
Links
Data: CORDIS, © European Union