Molecular Biology Faculty

Samuel S. Wang

sswang	Wang Research Lab
(609) 258-0388	Guyot Hall, 7
	Lab (609) 258-0374
Faculty Assistant	Rebecca I. Khaitman
This email address is being protected from spambots. You need JavaScript enabled to view it.	(609) 258-2683

Research Focus

Learning and design principles in neural circuits

As an animal interacts with the world, its brain must not only perform many tasks, but also adapt and react to changes in its environment. Our research focuses on the synaptic organization of the nervous system and centers on two issues: (1) What design principles contribute to the function of neural circuits? (2) What principles of plasticity guide synapses in adapting and learning?

Two-photon microscopy and uncaging

We use two-photon methods and traditional electrophysiological techniques to probe network activity in functioning neural tissue. Two-photon fluorescence microscopy allows us to observe activity at a single-synapse level, either in brain slices or in the whole animal. This is made possible by the two-photon excitation principle, in which a converging beam of femtosecond laser pulses causes excitation at the focal point, but not above or below it. We also perform uncaging (including two-photon uncaging) to generate neurotransmitters such as glutamate in femtoliter (1 µm3) volumes within a millisecond. With more widespread activation we can evoke action potentials in the target neuron, and by scanning the light beam through tissue we can locate single synaptic connections and map whole circuits.

Architecture and wiring principles of brains

From shrews to whales, mammalian brains vary over 10,000-fold in volume. Over this wide range are found regularities that suggest that brain structure may be subject to universal design constraints. For example, large brains have a higher proportion of white matter than small brains. The white matter volume in the cerebral cortex follows a power law (see also A universal scaling law between gray matter and white matter of cerebral cortex and Size and shape of the cerebral cortex in mammals. II. The cortical volume.) law relative to gray matter volume that is greater than simple geometry would predict. How is this power law constructed from the cellular architecture of the cortex? Using electron microscopy, we find that on average, axons are wider in large brains than in small brains. The largest axons contribute considerable amounts of volume and are sufficient to account for the increased amount of white matter seen in large brains. This widening of axons may be driven by an evolutionary need to conserve the time it takes for a nerve impulse to cross the brain. We are now investigating what other principles of brain operation might also be conserved.

Computational rules at synapses

Synapses may store information by changing their strength. Synaptic plasticity can depend on the exact relative timing of presynaptic and postsynaptic action potentials (“spikes”); the relationship between activity patterns and plasticity outcomes is termed a learning rule. Learning rules are of functional consequence because spike timing can carry more information than spike rate alone. We think that understanding the general principles that shape learning rules will give insights into what rules are possible, and how these rules might be tailored to in vivo activity patterns. We are now examining learning rules in the cerebellum and hippocampus.

In the cerebellum, one proposed site for motor learning is long-term depression (LTD) of the parallel fiber-Purkinje cell synapse. We find that a burst of activity in a small number of parallel fibers is likely to induce LTD if it occurs approximately 100 milliseconds before a spike in the postsynaptic Purkinje cell. These conditions are also optimal for generating large calcium signals confined to single spines. Because LTD is triggered by an increase in postsynaptic calcium, this suggests a timing-dependent learning rule with high synapse-specificity. We are now using optical methods on single synapses to understand what cellular mechanisms generate this rule.

The CA3-CA1 synapse of the hippocampus is extremely well-studied and is a candidate for understanding, at a detailed biophysical level, a learning rule that includes both LTD and long-term potentiation (LTP). We find that LTP at this synapse is preferentially induced by activity patterns that occur during active exploration, but not under other activity conditions. LTD can be induced under a wider range of conditions, and we are now exploring the possibility that these two forms of synaptic plasticity can be functionally separated, in analogy to the way that Hodgkin and Huxley successfully separated sodium and potassium currents.

Selected Publications

Granstedt AE, Kuhn B, Wang SS, Enquist LW. (2010) Calcium imaging of neuronal circuits in vivo using a circuit-tracing pseudorabies virus. Cold Spring Harb Protoc. pdb.prot5410. PubMed

Granstedt AE, Szpara ML, Kuhn B, Wang SS, Enquist LW. (2009) Fluorescence-based monitoring of in vivo neural activity using a circuit-tracing pseudorabies virus. PLoS One. 4: e6923. PubMed

Ozden I, Sullivan MR, Lee HM, Wang SS. (2009) Reliable coding emerges from coactivation of climbing fibers in microbands of cerebellar Purkinje neurons. J Neurosci. 29: 10463-10473. PubMed

Hoogland TM, Kuhn B, Göbel W, Huang W, Nakai J, Helmchen F, Flint J, Wang SS. (2009) Radially expanding transglial calcium waves in the intact cerebellum. Proc Natl Acad Sci 106: 3496-3501. PubMed

Wang SS. (2008) Functional tradeoffs in axonal scaling: implications for brain function. Brain Behav Evol. 72: 159-167. PubMed

Ozden I, Lee HM, Sullivan MR, Wang SS. (2008) Identification and clustering of event patterns from in vivo multiphoton optical recordings of neuronal ensembles. J Neurophysiol. 100: 495-503. PubMed

Wang SS, Shultz JR, Burish MJ, Harrison KH, Hof PR, Towns LC, Wagers MW, Wyatt KD. (2008) Functional trade-offs in white matter axonal scaling. J Neurosci. 28: 4047-4056. PubMed

Sarkisov DV, Wang SS. (2008) Order-dependent coincidence detection in cerebellar Purkinje neurons at the inositol trisphosphate receptor. J Neurosci. 28: 133-142. PubMed

Sarkisov DV, Gelber SE, Walker JW, Wang SS (2007). Synapse-specificity of calcium release probed by chemical two-photon uncaging of IP3. J Biol Chem 282: 25517-25526. PubMed

O'Connor DH, Wittenberg GM, Wang SS (2007). Timing and contributions of pre-synaptic and post-synaptic parameter changes during unitary plasticity events at CA3-CA1 synapses. Synapse 61: 664-678. PubMed

Sarkisov DV, Wang SS (2006). Alignment and calibration of a focal neurotransmitter uncaging system. Nat Protoc 1: 828-832. PubMed

Wittenberg GM, Wang SS (2006). Malleability of spike-timing-dependent plasticity at the CA3-CA1 synapse. J Neurosci 26: 6610-6607. PubMed

Shoham S, O'Connor DH, Sarkisov DV and Wang SS (2005). Rapid neurotransmitter uncaging in spatially defined patterns. Nat Methods 2: 837-843. PubMed

O'Connor DH, Wittenberg GM and Wang SS (2005). Graded bidirectional synaptic plasticity is composed of switch-like unitary events. Proc Natl Acad Sci USA 102: 9679-9684. PubMed

Sullivan MR, Nimmerjahn A, Sarkisov DV, Helmchen F and Wang SS (2005). In vivo calcium imaging of circuit activity in cerebellar cortex. J Neurophysiol 94: 1636-1644. PubMed

O'Connor DH, Wittenberg GM, Wang SS (2005). Dissection of bidirectional synaptic plasticity into saturable unidirectional processes. J Neurophysiol 94: 1565-1573. PubMed

Wyatt KD, Tanapat P, Wang SS (2005). Speed limits in the cerebellum: constraints from myelinated and unmyelinated parallel fibers. Eur J Neurosci 21: 2285-2290. PubMed

Burish MJ, Kueh HY and Wang SS (2004). Brain architecture and social complexity in modern and ancient birds. Brain Behav Evol 63: 107-124. PubMed

Wang SS, Major G (2003). Integrating over time with dendritic wave-fronts. Nat Neurosci 6: 906-908. PubMed

Harrison KH, Hof PR, Wang SS (2002). Scaling laws in the mammalian neocortex: does form provide clues to function? J Neurocytol 31: 289-298. PubMed

Wang SS-H, Mitra PP and Clark DA (2002). Brain evolution (Communications arising): How did brains evolve? Nature 415: 135.

Clark DA, Mitra PP and Wang SS (2001). Scalable architecture in mammalian brains. Nature 411: 189-193. PubMed

Wang SS, Denk W and Hausser M (2000). Coincidence detection in single dendritic spines mediated by calcium release. Nat Neurosci 3: 1266-1273 PubMed

Wang SS, Khiroug L, Augustine GJ (2000). Quantification of spread of cerebellar long-term depression with chemical two-photon uncaging of glutamate. Proc Natl Acad Sci USA 97: 8635-8640. PubMed

Furuta T, Wang SS, Dantzker JL, Dore TM, Bybee WJ, Callaway EM, Denk W, Tsien RY (1999). Brominated 7-hydroxycoumarin-4-ylmethyls: photolabile protecting groups with biologically useful cross-sections for two photon photolysis. Proc Natl Acad Sci USA 96: 1193-1200. PubMed

Augustine GJ, Pettit DL, and Wang SS-H (1999). Spatially resolved flash photolysis via chemical two-photon uncaging. In: Imaging: a laboratory manual. Yuste R, Lanni F, Konnerth A, eds. Cold Spring Harbor Press.

Wang SS-H and Augustine GJ (1999). Calcium signaling in neurons: a case study in cellular compartmentalization. In: Calcium as a cellular regulator. Carafoli E and Klee CB, eds. Oxford University Press, pp 545-566.

Augustine GJ, Finch EA and Wang SS-H (1998). The spatial range of dendritic signals for cerebellar long-term depression: studies with local photolysis of caged compounds. In: Integrative aspects of Ca2+ signalling. Verkhratsky A and Toescu EC, eds. Plenum Press.

Pettit DL, Wang SS, Gee KR, Augustine GJ (1997). Chemical two-photon uncaging: a novel approach to mapping glutamate receptors. Neuron 19: 465-471. PubMed

Kupferman R, Mitra PP, Hohenberg PC, Wang SS (1997). Analytical calculation of intracellular calcium wave characteristics. Biophys J 72: 2430-2444. PubMed

Augustine GJ, Betz H, Bommert K, Charlton MP, DeBello WM, Dresbach T, Hunt JM, O’Connor V, Schweizer FE, Wang SS-H and Whiteheart SW (1996). Molecular mechanisms of neurotransmitter secretion: functional studies at the squid giant synapse. In: Basic neuroscience in invertebrates. Koike H, Kidokoro Y, Takahashi K, Kanaseki T, eds. Japan Scientific Societies Press.

Wang SS, Augustine GJ (1995). Confocal imaging and local photolysis of caged compounds: dual probes of synaptic function. Neuron 15: 755-760. PubMed

DeBello WM, O'Connor V, Dresbach T, Whiteheart SW, Wang SS, Schweizer FE, Betz H, Rothman JE, Augustine GJ (1995). SNAP-mediated protein-protein interactions essential for neurotransmitter release. Nature 373: 626-630. PubMed

Wang SS, Thompson SH (1995). Local positive feedback by calcium in the propagation of intracellular calcium waves. Biophys J 69: 1683-1697. PubMed

Wang SS, Alousi AA, Thompson SH (1995). The lifetime of inositol 1,4,5-trisphosphate in single cells. J Gen Physiol 105: 149-171. PubMed

Wang SS, Thompson SH (1994). Measurement of changes in functional muscarinic acetylcholine receptor density in single neuroblastoma cells using calcium release kinetics. Cell Calcium 15: 483-496. PubMed

Wang SS, Mathes C, Thompson SH (1993). Membrane toxicity of the protein kinase C inhibitor calphostin A by a free-radical mechanism. Neurosci Lett 157: 25-28. PubMed

Mathes C, Wang SS, Vargas HM, Thompson SH (1992). Intracellular calcium release in N1E-115 neuroblastoma cells is mediated by the M1 muscarinic receptor subtype and is antagonized by McN-A-343. Brain Res 585: 307-310. PubMed

Peroutka SJ, Hamik A, Harrington MA, Hoffman AJ, Mathis CA, Pierce PA, Wang SS (1998). (R)-(-)-[77Br]4-bromo-2,5-dimethoxyamphetamine labels a novel 5-hydroxytryptamine binding site in brain membranes. Mol Pharmacol 34: 537-542. PubMed

Wang SS, Mathis CA, Peroutka SJ (1998). R(-)-2,5-dimethoxy-4-77 bromoamphetamine [77Br-R(-)DOB]: a novel radioligand which labels a 5-HT binding site subtype. Psychopharmacology (Berl) 94: 431-432. PubMed

Wang SS and Peroutka SJ (1989). Historical perspectives. In: The Serotonin Receptors. Sanders-Bush E, ed. Humana Press, pp. 3-20.

Wang SS, Ricaurte GA, Peroutka SJ (1987). [3H]3,4-methylenedioxymethamphetamine (MDMA) interactions with brain membranes and glass fiber filter paper. Eur J Pharmacol 138: 439-443. PubMed