Haining Zhong, Ph.D.
Haining Zhong earned his B.A. in Biological Science and Biotechnology, and B.Eng. in Electronics and Computer Science from Tsinghua University in Beijing, China in 1996. He received his Ph.D. in Neuroscience from the Johns Hopkins University School of Medicine in 2002. Zhong did postdoctoral training at the Cold Spring Harbor Laboratory and then at the Janelia Farm Research Campus of the Howard Hughes Medical Institute. In 2009 he was appointed as an assistant scientist at the Vollum Institute and was promoted to scientist in 2015.
Summary of Current Research
Our brain is a complex network consisting of billions of neurons. These neurons communicate with one another through trillions of very specialized connections called chemical synapses. These synapses and their experience-dependent plasticity are thought to be the fundamental mechanisms underlying animal’s behavior, adaptation, learning and memory. We are interested in the mechanisms by which the strength of a synapse is set and regulated at the cellular and molecular level.
Synaptic function and plasticity require the regulation and interaction of myriad synaptic proteins. Merely knowing the identity of these players is not sufficient to understand their roles in synaptic functions. As many of these proteins are strategically and dynamically organized in neurons, an investigation of their spatiotemporal organization is necessary to understand how neuronal communication works. Our current focus, then, is to systematically characterize the abundance, stoichiometry, localization and activity of critical synaptic proteins and how they are modulated by neuronal activity.
Because the scale of protein architecture can span several orders of magnitude, from a few nanometers to tens of micrometers, we use several complementary imaging approaches. Two-photon microscopy allows us to examine protein distribution in live neurons in cortical slices at diffraction-limited resolution (~ 0.5 µm); super-resolution, photoactivated localization microscopy (PALM) enables the examination of protein distribution and movement at 20 nm resolution; and two-photon fluorescence lifetime imaging microscopy (2PFLIM), which quantifies FRET, is used to examine the activity of signaling reporters and protein-protein interactions at a scale less than 8 nm. These imaging approaches are combined with electrophysiological recording, genetic labeling and manipulation of individual neurons, and novel optical and optogenetic tools for physiologically-relevant stimuli. The goal is to provide an architectural basis of the synapse for understanding synaptic function and plasticity.
On-going studies include how protein kinase A (PKA), a broad spectrum kinase that regulates many aspects of neuronal functions, is strategically positioned to achieve their function and specificity. We are also interested in how PKA is activated and inactivated by various forms of neuronal activity. Finally, we are examining the structure and experience-dependent dynamics of the postsynaptic density using a PSD95-GFP knock-in mouse.
Patriarchi T, Cho JR, Merten K, Howe MW, Marley A, Xiong WH, Folk RW, Broussard GJ, Liang R, Jang MJ, Zhong H, Dombeck D, von Zastrow M, Nimmerjahn A, Gradinaru V, Williams JT, and Tian L. (2018) Ultrafast neuronal imaging of dopamine dynamics with designed genetically encoded sensors. Science 360:eaat4422.
Ma L, Jongbloets BC, Xiong WH, Melander JB, Qin M, Lameyer TJ, Harrison MF, Zemelman BV, Mao T*, and Zhong H*. (2018) A highly sensitive A-kinase activity reporter for imaging neuromodulatory events in awake mice. Neuron 99:665-679.e5. *Co-senior authorship
Tillo SE, Xiong WH, Takahashi M, Miao S, Andrade AL, Fortin DA, Yang G, Qin M, Smoody BF, Stork PJS, and Zhong H. (2017) Liberated PKA catalytic subunits associate with the membrane via myristoylation to preferentially phosphorylate membrane substrates. Cell Reports 19:617-629.
Shi W, Xianyu A, Han Z, Tang X, Li Z, Zhong H, Mao T, Huang K, and Shi SH. (2017) Ontogenetic establishment of order-specific nuclear organization in the mammalian thalamus. Nature Neurosci. 20:516-528.
Hunnicutt BJ, Jongbloets BC, Birdsong WT, Gertz KJ, Zhong H, and Mao T. (2016) A comprehensive excitatory input map of the striatum reveals novel functional organization. Elife 5:e19103.
Zhong H. (2015) Applying superresolution localization-based microscopy to neurons. Synapse 69:283-294.
Fortin DA, Tillo SE, Yang G, Rah JC, Melander JB, Bai S, Soler-Cedeño O, Qin M, Zemelman BV, Guo C, Mao T*, and Zhong H*. (2014) Live imaging of endogenous PSD-95 using ENABLED: a conditional strategy to fluorescently label endogenous proteins. J. Neurosci. 34:16698-16712. *Co-senior authorship
Hunnicutt BJ, Long BR, Kusefoglu D, Gertz KJ, Zhong H*, and Mao T*. (2014) A comprehensive thalamocortical projection map at the mesoscopic level. Nature Neurosci. 17:1276-1285. *Co-senior authorship
Zhong H. (2010) Photoactivated localization microscopy (PALM): an optical technique for achieving ~10-nm resolution. Cold Spring Harb. Protoc. 2010(12):pdb.top91.
Zhong H, Sia GM, Sato TR, Gray NW, Mao T, Khuchua Z, Huganir RL, and Svoboda K. (2009) Subcellular dynamics of type II PKA in neurons. Neuron 62:363-374.
Do MT, Kang SH, Xue T, Zhong H, Liao HW, Bergles DE, and Yau KW. (2009) Photon capture and signaling by melanopsin retinal ganglion cells. Nature 457:281-287.
Ji N, Shroff H, Zhong H, and Betzig E. (2008) Advances in the speed and resolution of light microscopy. Curr. Opin. Neurobiol. 18:605-616.
Harvey CD, Yasuda R, Zhong H, and Svoboda K. (2008) The spread of Ras activity triggered by activation of a single dendritic spine. Science 321:136-140.
Yasuda R, Harvey CD, Zhong H, Sobczyk A, van Aelst L, and Svoboda K. (2006) Supersensitive Ras activation in dendrites and spines revealed by two-photon fluorescence lifetime imaging. Nature Neurosci. 9:283-291.
Fu Y, Zhong H, Wang MH, Luo DG, Liao HW, Maeda H, Hattar S, Frishman LJ, and Yau KW. (2005) Intrinsically photosensitive retinal ganglion cells detect light with a vitamin A-based photopigment, melanopsin. Proc. Natl. Acad. Sci. USA 102:10339-10344.
Zhong H, Lai J, and Yau KW. (2003) Selective heteromeric assembly of cyclic nucleotide-gated channels. Proc. Natl. Acad. Sci. USA 100:5509-5513.
Zhong H, Molday LL, Molday RS, and Yau KW. (2002) The heteromeric cyclic nucleotide-gated channel adopts a 3A:1B stoichiometry. Nature 420:193-198.
Munger SD, Lane AP, Zhong H, Leinders-Zufall T, Yau KW, Zufall F, and Reed RR. (2001) Central role of the CNGA4 channel subunit in Ca2+-calmodulin-dependent odor adaptation. Science 294:2172-2175.
Grunwald ME, Zhong H, Lai J, and Yau KW. (1999) Molecular determinants of the modulation of cyclic nucleotide-activated channels by calmodulin. Proc. Natl. Acad. Sci. USA 96:13444-13449.