Project description
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.
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 earliest
manifestation.
Disease mechanism:
– How genetic defects affect gene expression, and concurrently the connectome?
– Are all cell types affected the same way?
Fields of science
Not validated
Not validated
Keywords
Programme(s)
Funding Scheme
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinator
1030 Wien
Austria