Microglia are cells of the immune system that act as the first defense of the brain against infection and disease. Traditionally, these cells have been thought to be inert unless activated by a pathological event. Recently, it has been discovered that microglia are in fact very active, even in the absence of pathology, and that they can actively participate in important functions in the healthy brain, such as the rewiring of neuronal networks during neurodevelopment and learning. How microglia can sense the activity of neurons is currently unknown, but understanding such a mechanism is critical to unraveling how microglia perform their physiological functions. The experiments proposed determine how neuronal activity affects microglial signaling and physical contacts with neurons by monitoring both neurons and microglia in the living mouse brain. The results will give a wealth of knowledge about how microglia behave in the physiological brain and also give insights into how their functions could impact neurodevelopmental and neurodegenerative disease. In the process of doing the experiments, young scientists are trained for a future in academic and non-academic science, and participate in outreach activities that teach K-5 children about the brain. Additionally, scientists from upstate New York with research programs that focus on glial biology come together to share their new results to build a new vision of how these cells act together with neurons to perform computations.
To understand physiological microglial function, it is necessary to study these cells with minimal perturbation in the living brain. Two-photon microscopy allows the monitoring of signaling within cells in the intact brain, and in this project the investigator images calcium signals in neurons and microglia of anesthetized and of awake mice. Neuronal calcium signaling indicates levels of neuronal activity in a dendrite-specific manner, and the behavior of microglia with respect to more and less active dendrites can be tracked. However, little is known about the function of calcium signaling in microglia. The imaging experiments provide information on whether intracellular calcium is responsible for directed movements of microglial processes and interactions with neurons in vivo. The experiments address how such activity influences microglial contacts with synapses, synapse elimination, and microglial signaling. Taken together, the studies allow for deeper understanding of how microglia and neurons interact in physiological conditions.
