Report
Teaser, summary, work performed and final results
Periodic Reporting for period 1 - MICROGLIA-CIRCUIT (Microglia action towards neuronal circuit formation and function in health and disease)
Teaser
The brain is assembled from thousands of cell types, which are functionally organized in neuronal circuits to collect, encode and process environmental information, resulting in a behavior outcome. The correct circuit assembly is crucial for preventing malfunction. Classical...
Summary
The brain is assembled from thousands of cell types, which are functionally organized in neuronal circuits to collect, encode and process environmental information, resulting in a behavior outcome. The correct circuit assembly is crucial for preventing malfunction. Classical studies have provided important insights into the necessity of correct neuron wiring, but a detailed understanding of the role of microglia is missing. Microglia are traditionally categorized as immune-responsive, but are also involved in cell removal and synapse refinement. The goal of this project is to provide an answer to the important question: How microglia interact with other cell types and sense changes during neuronal circuit development, maintenance and degeneration? Thus, we will elucidate the key molecular and genetic principles underlying microglial phenotype during neuronal circuit formation, identify the circuit components with which microglia are interacting with at a spatial-temporal resolution, pin-point how neuronal activity alters microglial function, and finally differentiate human pluripotent stem cells into microglia to develop a strategy to address microglia-associated disease genes in neurodevelopmental diseases.
The knowledge is fundamental for the society because microglia are frequently found in a phagocytic-associated state in post-mortem human brain of neurodevelopmental disease such as autism spectrum disorder and schizophrenia as well as neurodegenerative diseases. Furthermore, several disease-associated genes are expressed exclusive expressed in microglia 16. Therefore, microglial malfunction could lead to similar devastating effects as neuronal circuit malfunction. It is critical that we know which cell type to address at which time point.
The overall objectives cover to identify the different states of microglial activation on the morphological and transcriptional level. Then, we are manipulating microglia or neurons and see how they impact each other. And finally, we will translate our observations to the human microglia model system.
Work performed
We achieved to generate a library of over 20.000 traced microglial cells at different states during development and disease. We are now applying mathematical modelling to identify underlying principles.
Moreover, we found that microglia show a sex-specific response upon neuron activation. We are currently preparing the manuscript for this.
Final results
We expect that the sex-specific differences in the response upon neuronal stimulation will provide a new research fundament that will be critical for all future studies in this field.
Website & more info
More info: http://sandrasiegert.wixsite.com/laboratory/erc-project.