Stanford Advisors

All Publications

  • Accurate quantification of astrocyte and neurotransmitter fluorescence dynamics for single-cell and population-level physiology. Nature neuroscience Wang, Y., DelRosso, N. V., Vaidyanathan, T. V., Cahill, M. K., Reitman, M. E., Pittolo, S., Mi, X., Yu, G., Poskanzer, K. E. 2019; 22 (11): 1936-1944


    Recent work examining astrocytic physiology centers on fluorescence imaging, due to development of sensitive fluorescent indicators and observation of spatiotemporally complex calcium activity. However, the field remains hindered in characterizing these dynamics, both within single cells and at the population level, because of the insufficiency of current region-of-interest-based approaches to describe activity that is often spatially unfixed, size-varying and propagative. Here we present an analytical framework that releases astrocyte biologists from region-of-interest-based tools. The Astrocyte Quantitative Analysis (AQuA) software takes an event-based perspective to model and accurately quantify complex calcium and neurotransmitter activity in fluorescence imaging datasets. We apply AQuA to a range of ex vivo and in vivo imaging data and use physiologically relevant parameters to comprehensively describe the data. Since AQuA is data-driven and based on machine learning principles, it can be applied across model organisms, fluorescent indicators, experimental modes, and imaging resolutions and speeds, enabling researchers to elucidate fundamental neural physiology.

    View details for DOI 10.1038/s41593-019-0492-2

    View details for PubMedID 31570865

    View details for PubMedCentralID PMC6858541

  • Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation CELL Lui, H., Zhang, J., Makinson, S. R., Cahill, M. K., Kelley, K. W., Huang, H., Shang, Y., Oldham, M. C., Martens, L. H., Gao, F., Coppola, G., Sloan, S. A., Hsieh, C. L., Kim, C. C., Bigio, E. H., Weintraub, S., Mesulam, M., Rademakers, R., Mackenzie, I. R., Seeley, W. W., Karydas, A., Miller, B. L., Borroni, B., Ghidoni, R., Farese, R. V., Paz, J. T., Barres, B. A., Huang, E. J. 2016; 165 (4): 921-935


    Microglia maintain homeostasis in the brain, but whether aberrant microglial activation can cause neurodegeneration remains controversial. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive upregulation of lysosomal and innate immunity genes, increased complement production, and enhanced synaptic pruning in microglia. During aging, Grn(-/-) mice show profound microglia infiltration and preferential elimination of inhibitory synapses in the ventral thalamus, which lead to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, deleting C1qa gene significantly reduces synaptic pruning by Grn(-/-) microglia and mitigates neurodegeneration, behavioral phenotypes, and premature mortality in Grn(-/-) mice. Together, our results uncover a previously unrecognized role of progranulin in suppressing aberrant microglia activation during aging. These results represent an important conceptual advance that complement activation and microglia-mediated synaptic pruning are major drivers, rather than consequences, of neurodegeneration caused by progranulin deficiency.

    View details for DOI 10.1016/j.cell.2016.04.001

    View details for Web of Science ID 000375800300019

    View details for PubMedID 27114033

    View details for PubMedCentralID PMC4860138