Chemical imaging and manipulation of the brain's astrocytes

The active participation of the brain's astrocytes in normal and pathological brain function is now well established. Astrocytes adjust synaptic strength, mediate synaptogenesis, and participate directly in neural signaling on a breadth of timescales that would be otherwise inaccessible via neuron‐centric signaling. Gaining a better understanding of astrocyte function will have wide‐ranging implications for human health. The technologies for visualizing and manipulating astrocytes generally, and neuron‐to‐astrocyte interactions in particular, are few, especially in comparison to the repertoire of strategies for visualizing neuronal anatomy and physiology. By bridging the fields of chemistry and neuroscience, we have designed a novel chemical strategy that will enable the direct visualization and manipulation of astrocytes globally, and potentially of neural‐astrocyte connectivity specifically. Our strategy for chemical imaging of astrocytes and neuron‐astrocyte interactions employs a chemical tag that, when appended to structurally diverse chemical scaffolds, targets the molecule to astrocytes when delivered systemically. Here, we discuss the capabilities of this astrocyte targeting tag, for example, delivering fluorescent reporters of cell physiology, drugs for modulating astrocyte function, or transcription activators to control gene expression, directly to astrocytes. We describe alterations to the neuron‐glia label's chemical structure in order to explore possibilities for astrocyte specific drug delivery, cell‐type specific labeling, transgene expression in labeled glial populations, and optical control of labeling. Finally, we discuss recent results exploring direct introduction of the astrocyte targeting tag into sensory neurons of larval zebrafish. We report transfer of the molecules to proximal radial astrocytes in live zebrafish, potentially serving as a marker for the population of astrocytes that interact with a given neuron. Ultimately, the ability to interrogate astrocytes with tunable chemical scaffolds, and, specifically, to visualize select neuron‐astrocyte interactions will be a valuable tool for understanding the brain.