Investigating Astrocyte Heterogeneity in the Brain

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Astrocytes play critical roles in central nervous system (CNS) development and function and are essential for ion/neurotransmitter homeostasis, synaptic transmission/plasticity, metabolic support for neurons, and contributing to the blood brain barrier.  Astrocytes are a heterogeneous cell population with properties that vary depending on developmental origin, cell positioning, and sensitivity to environmental cues. However, precisely how astrocytes molecularly, structurally, and functionally diversify to perform their roles remains poorly understood. In this Discovery Grant, we will investigate this question using advanced cell transplantation techniques that enables us to manipulate and track the properties of astrocytes in the brain. Our long-term research vision is to decipher exactly how, when, and why astrocytes diversify in the CNS. Specific Objectives to be Achieved: Objective 1: Investigate cell-autonomous and non-cell-autonomous mechanisms that promote astrocyte development and diversification. Two broad types of astrocytic heterogeneity are recognized in the brain related to differences in cell populations between brain regions (inter-regional diversity) and within a brain region (intra-regional diversity). However, mechanisms creating such diversity remain unclear. We developed a cell transplantation approach to study how astrocytes integrate, mature, and survive in vivo. Cortical astrocytes transplanted to cortex during development acquire structural/molecular features that resemble host astrocytes including the formation of territories, endfeet on vasculature, and perisynaptic processes. Interestingly, cortical astrocytes transplanted into cerebellum retain cortical astrocyte features. In Objective 1, we will tease apart cell-autonomous (intrinsic) and non-cell-autonomous (environmental) mechanisms that determine the structural/molecular/physiological diversity of transplanted astrocytes. Objective 2: Determine how developmental and epigenetic states impact the ability of transplanted astrocytes to acquire specific molecular and structural features in the CNS. Transcription factor patterning contributes to region-specific astrocytic properties in the CNS. However, the developmental time window for cortical astrocyte specification is unclear. Based upon our results and the timing of astrocytic differentiation/migration/maturation in cortex, we suspect that glial progenitor specification occurs during a late-embryonic/early postnatal period in rodents and establishes cortical astrocyte signatures. In Objective 2, we will investigate how developmental and epigenetic states of cortical astrocytes enable them to acquire region-specific molecular/structural features. CONCLUSION: This grant will provide outstanding conceptual training for students interested in brain cell diversity and technical training in cutting-edge techniques such as cell transplantation, Ca2+ imaging, RNA- and ATAC-seq, bioinformatics, and electrophysiology.