For more information, visit the Tian Laboratory website.
The goal of our research is to invent new molecular tools for analyzing and engineering functional neural circuits. We also leverage these tools, combined with optical imaging techniques, to study molecular mechanisms of neurological disorders at system level and to empower searching for novel therapeutic treatments.
One of the primary challenges in neuroscience is to link complex neural phenomena to the structure and function of their composite neural circuits. Addressing this problem requires a thorough understanding of patterns of neural activity, and the ability to relate this to physiological processes, behavior and disease states. An essential step towards this goal is the simultaneous recording of neural activity in large, defined populations, ideally in intact circuitry. Traditional electrophysiological approaches provide excellent sensitivity and temporal resolution, but are limited in the number of cells that can be recorded simultaneously.
Fluorescent protein based biosensors can transfer changes in neural state (e.g. membrane potential or essential ion flux or enzyme activity) to fluorescence observables. They are genetically encoded, and can thus be used to label large populations of defined cell types and/or sub-cellular compartments. Combined with modern fluorescence imaging techniques, these probes allow us observe and track how neural networks are established or modified in time and space and find out what goes wrong in diseases. Our lab used a variety of techniques (computational protein engineering, rational design, molecular evolution, chemical synthesis) to develop genetically encoded imaging probes, such as calcium indicators, neurotransmitter sensors and kinase sensors. We also explore strategies for better targeting these sensors to small compartments in the nervous system, such as axon terminals, and for longer expression with reduced cytotoxicity in vivo.
Chemical probes are also essential tools in biology for measuring and manipulating cellular properties. Evan wit high molecular specificity, however, their application in complex biological environments is frequency limited by poor cellular specificity. Our previous research has demonstrated a straightforward approach for the identification of orthogonal ester-esterase pairs that are stable to endogenous esterase activity and can be directed to specific cell types. We will utilize different chemistries in future work to develop tissue-specific probes for drug or metabolite localization and activity in cells, tissues, or model organisms.
We also integrate our imaging probes to induced pluripotent stem cells (iPSCs)-derived neurons and glias to create a platform for studying psychiatric diseases in vitro. Such cultured human neuronal networks will enable us to visulize how the precise, guided communication in neurons develops, and how it breaks down in diseases. With this system we can test a library of drugs to identify ones that can correct the communications defects in a patient-specific manner; such a drug screening would not be possible on living patients.
My research program will provide interdisciplinary trainings for graduate students and postdoc fellows.
Marvin J, Borghuis B, Tian L, Cichon J, Looger L, “An optimized fluorescent probe for visualizing glutamate neurotransmission”, Nature Methods, 10:162, Feb, 2013.
Petreanu L, Gutnisky DA, Huber D, O’Connor H, Xu NL, Tian L, Looger L and Svoboda K, “Activity in motor-sensory projections reveals distributed coding in somatosensation”, Nature, 489,299-303, 2012.
Huber D, Gutnisky DA, Person S, O’Connor H., Tian L, Looger L and Svoboda K, “Multiple dynamic representations in the motor cortex during sensorimotor learning”, Nature, 484:473, 2012.
Tian L, Yang Y, Wysocki, L, Sternson S, Looger L and Luke L, “A general approach for targeting small molecules with cellular specificity”, Proceedings of the National Academy of Sciences, 109(13):4756-61, 2012. Evaluated article by F1000 in the field of chemical biology of the cell.
Tian L and Looger L, “Optogenetic approaches to control and monitoring neuronal activities”, Progress in Brain Research, corresponding author, 196:79, 2012.
Zariwala HA, Borghuis BG, Hoogland TM, Madisen L, Tian L, Hongkui Zeng, Loren L. Looger, Karel Svoboda, Tsai-Wen Chen, “A Cre-dependent GCaMP3 reporter mouse for neuronal imaging in vivo”, accepted, Journal of Neuroscience, 32:3131, 2011.
Tian L, Hires A, Looger L, “Imaging neural activity with genetically encoded calcium indicator”, Imaging in Neuroscience: A Laboratory Mannual, Cold Spring Harbor Laboratory Press, May, 2011.
Bart B, Tian L, Xu Y, Nikonov S, Vardi Noga, Zemelman B & Looger L, “Imaging light responses of targeted neuron populations in the rodent retina”, Journal of Neuroscience, 31:2855, 2011.
Dombeck D, Harvey C, Tian L, Looger L, Tank D, “Functional imaging of hippocampal place cells at cellular resolution during virtual navigation”, Nature Neuroscience 13:1433, 2010.
Tian L, Hires A, Mao TY, Huber D, Chiappe E, Chalasani S, Petreanu L, Akerboom J, McKinney S, Bargmann C, Jayaraman V, Svoboda K & Looger L, “Imaging neural activity in worms, flies and mice with improved GCaMP calcium indicators”, Nature Methods, 6:875-884, 2009. Cited by 192, a systematic optimization of calcium indicator to facilitate neuroscience application
Akerboom J, Rivera J, Guibe M, Malave E, Hernandez H, Tian L, Hires A, Looger L and Schreiter E, “Crystal structures of the GCaMP calcium sensor reveal the mechanism of fluorescence signal change and aid rational design”, Journal of Biological Chemistry, 284:6455, 2009.
Tian L and Looger L, “Genetic encoded fluorescence sensors for studying healthy and diseased nervous system”, Drug Discovery Today: Disease Models special issue on nervous system disorders, 5:27-35, 2008.
Hires A, Tian L and Looger L, “Reporting Neuronal activity using genetic encoded calcium indicators”, Brain Cell Biology, 36:69-86, 2008.
Tian L and Matouschek A, “Where to start and when to stop”, Nature Structural& Molecular Biology, 13:668-670, 2006.
Tian L, Holmgren R, and Matouschek A, “A conserved processing mechanism regulates the activity of transcription factors Cubitus interruptus and NF-kB”, Nature Structural & Molecular Biology, 12:1045-1053, 2005.
Prakash S, Tian L, Ratliff K, Lehotzky R and Matouschek A, “An unstructured initiation site is required for efficient proteasome-mediated degradation”, Nature Structural & Molecular Biology, 11:830-837, 2004.