Project description DEENESFRITPL Single-cell connectomics to understand human psychiatric diseases Many psychiatric diseases are associated with defects in the connections between neurons. To understand these diseases, we need to know the number and type of connections a single neuron forms, and how these connections are affected in disease. The EU-funded PhenoConnectomics project aims to develop a connectome-by-sequencing assay to chart synaptic networks of thousands of neurons. Change in synaptic connectivity is the main characteristic of autistic disorders, such as Rett syndrome, caused by a mutation in the MECP2 gene, which controls gene expression and the formation of synaptic contacts. Researchers will study Rett syndrome on the transcriptional and connectivity levels using healthy and MECP2-deficient human cortical organoids. This study will establish single-cell connectivity as a disease phenotype, potentially leading to the early detection of psychiatric diseases. Show the project objective Hide the project objective 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? Fields of science natural sciencesbiological sciencesgeneticsmutation Keywords Connectomics Transsynaptic tracing Single-cell multi-omics Organoids Synapse Neural networks Autism Spectrum Disorders (ASD) Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2019 - Individual Fellowships Call for proposal H2020-MSCA-IF-2019 See other projects for this call Funding Scheme MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF) Coordinator INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH Net EU contribution € 174 167,04 Address DR BOHRGASSE 3 1030 Wien Austria See on map Region Ostösterreich Wien Wien Activity type Private for-profit entities (excluding Higher or Secondary Education Establishments) Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 174 167,04