Delineation of astrocyte microdomain calcium events during cortical activity

点击翻译按钮获取中文摘要

Astrocytes, a type of brain glial cell, are important for normal neuronal function. They are known to support neurons in many ways: by supplying energy, removing wastes, and maintaining an environment for proper neuronal activity. There is also evidence that astrocytes sense neuronal activity and actively release molecules to change neuronal function. The long-term goal of my research program is to determine the nature of neuron-astrocyte communication and define how astrocytes can change neuronal activity within sensory circuits to influence cortical information processing. Neuronal activity causes local increases in astrocyte calcium, termed "microdomain calcium events" (MCEs). These MCEs have become an important biomarker of astrocyte activity, since they are necessary for astrocyte signaling back to neurons. Therefore, in order to understand the functional roles of astrocytes, it is important that we fully characterize astrocyte MCEs. My HQP will use novel genetic tools and cutting-edge in vivo two-photon microscopy in awake animals during somatosensory stimulation to study astrocyte MCEs and nearby neurons within intact circuits. First, we will correlate cortical astrocyte MCEs with nearby neuronal activity to determine the neuronal type (excitatory vs. inhibitory) and subcellular compartment (soma vs. dendrite) that induces astrocyte MCEs, particularly during physiological whisker stimulation. Next, we will examine astrocyte MCE recruitment during neuronal reorganization during a sensory deprivation paradigm, which will provide insight into how astrocytes respond to and possibly tune neuronal population changes. Finally, my preliminary data shows that astrocyte N-methyl-D-aspartate receptors, ionotropic receptors activated by excitatory glutamate, play an important role in astrocyte MCEs and affect nearby neuronal activity. My group will further investigate the functional role of these astrocyte receptors, including in how they influence excitatory or inhibitory neuronal populations and ultimately affect mouse sensory perception.  Overall, results will provide an important characterization of several unknown aspects of cortical astrocyte MCEs, including identification of specific mechanisms and neuronal contributions that evoke these astrocyte signals and conversely, the influence these localized signals have on nearby synaptic transmission. This will advance current concepts of astrocytes in directions that provide a more solid foundation for understanding neuron-astrocyte communication and how astrocytes are integrated into brain circuits. This is directly relevant for our understanding of synaptic level microcircuits but also has broader implications for large-scale brain system connectivity. The training environment created by this research program will provide cutting-edge technical and transferable skills for a minimum of two graduate students and ten undergraduate students in this 5-year cycle.