Dissecting the morpho-functional relationship of microglia

Our brain has been in constant exchange with the environment. Specialized neurons pick up the signals such as incoming light photons, process the information into electrical signals, and then exchange the information across different brain areas to generate a visual picture. To perform this task, neurons depend on glial cells that optimize signal processing, supply nutrients, and remove waste products. Microglia, traditionally classified as immune- responsive cells, have been mostly associated to the latter because they are frequently associated with neurological diseases. Yet, surprisingly little is known about how microglia maintain the day-to-day brain function and how deviation from this task will induce disease onset. The morphological branching complexity of the microglia provides a first intuition on their intrinsic state; massively reduced branching is commonly found in severe pathological conditions and indicates phagocytic activity. However, attempts to morphologically classify microglia before reaching this extreme condition have been unsatisfactory. In our line of research, we noticed that strategies to simplify the branching tree cause loss of discriminative information. Thus, we developed our algorithm morphOMICs, which is based on principles of topological data analysis and prove to be robust to quantify subtle yet functionally informative morphological adaptations. In this proposal, we are now interested to connect microglia morphology to a defined functional state and in this way establish a morpho-functional relationship. The retina offers an ideal model system because microglia are spatially confined in defined compartments with distinct signal processing features. First, we will establish which morphological features of the microglia alter upon defined environmental changes and indicate an early response to a stimulus. Then, we will investigate how the intracellular distribution of organelles influence microglia morphology. Specifically, we will focus how the intracellular organization of the energy-providing mitochondria influence energy-expensive morphological remodeling. Finally, we will resolve the molecular signature of the microglia associated to a particular morphology. The results of this study will provide a valuable resource to predict the microglia functional signature in a living organism beyond the immediate requirements of single-cell transcriptomics. It will establish microglia as a sensor for the physiological state of the brain and as an early indicator for environmental changes.