Research: Function of the cerebellum and other brain circuits
Areas of Research: Biophysics, Chemical Biology, Computation & Modeling, Development, Evolution, Genetics, Neuroscience, Policy, Structural Biology
Information processing and learning in mammalian brains
The Wang laboratory does basic research in several areas: (1) information processing in the cerebellum, including its contributions to motor learning; (2) cerebellar roles in cognitive and affective function and autism spectrum disorder; (3) the improvement of tools for awake, in vivo optical imaging; and (4) synaptic learning rules throughout the brain.
We rely on advanced methods for the optical control and imaging of brain activity. Research interests are represented both by published papers and by more recent work. (For Sam Wang's public writings, see WelcomeToYourBrain.com. For Presidential polling meta-analysis see the Princeton Election Consortium.)
Optical imaging of the learning cerebellum in awake mice. Recent research has revealed a broad role for cerebellum as a general processor of unexpected events. We are among the first in the world to make extensive use of multiphoton fluorescence microscopy to probe what cerebellar circuits do during awake behavior. In a central recent finding, external and internal events are encoded by overlapping populations of Purkinje cells in a behavioral state-dependent manner, in the form of synchronous complex spiking. We have also made an analogous observation in granule cells and molecular layer interneurons. Recently, in collaboration with Javier Medina at the University of Pennsylvania, our laboratory implemented head-fixed recording methods for classical eyeblink conditioning in mice, achieving well-timed responses, learning over a time course of days, and consistency from animal to animal. Head-fixed recording is applicable to eyeblink conditioning and a variety of other behavioral and learning tasks.
Autism spectrum disorder. One of the most important unanswered questions in autism research today is the identity of the neural circuit(s) responsible for autistic behavior. We are interested in identifying brain dysfunction that is developmentally “upstream” of the many problems found in autistic brains. The cerebellum is not just a motor structure, but also has cognitive and affective roles. Accumulating evidence suggests that cerebellar abnormalities may play an ongoing role in, or even act as a developmental cause of the core social and cognitive deficits experienced by autistic persons. We are using mouse models to test two questions: (a) In mice with the same genetic disruptions as those found in autistic persons, is cerebellar function also disrupted? (b) Does disruption of cerebellar function during key periods of brain development lead to autistic-like behaviors?
Optical methods and genetically encodable calcium indicator proteins. Central tools in our laboratory include multiphoton in vivo imaging of neural activity, head-fixed awake recording, and the use of fluorescent calcium indicators. In a current project, we are at work on improving GECIs while avoiding the de-optimization of existing beneficial features. In the case of Green fluorescent protein / Calmodulin protein sensor (GCaMP), such features include low degradation, high per-molecule brightness, and large fluorescence changes. We making two improvements. First, we seek to engineer KD by making targeted changes that vary the affinity but preserve probe performance thus allowing a larger range of activity levels (i.e. firing rates) to be monitored accurately. Second, we are engineering faster kinetics to better track variations in calcium. Dendritic calcium signals can rise in 1 ms and fall in 10-100 ms. Faster variants of GCaMP will allow many laboratories, including our own, to track neuronal signaling events with unprecedented precision.
Synaptic learning rules. In addition, in past years the laboratory has identified fundamental principles by which molecular signaling mechanisms shape learning rules. For example, we have found that calcium signaling mechanisms drive the switchlike strengthening and weakening of single synapses. The likelihood and direction of this change is closely dependent on the precise occurrence of certain presynaptic and postsynaptic spike patterns. In the case of cerebellum, we have identified a learning rule that favors parallel fiber activity that leads the complex spike by tens to hundreds of milliseconds, consistent with order-dependent learning seen in vivo.
Other projects. In vitro, the laboratory studies how single-neuron function is modified by dynamic changes in neural activity such as complex input patterns of neurotransmitters and neuromodulators. Rapid barrages of dendritic input activation may alter function in a fraction of a second, thus altering circuit function and driving synaptic plasticity. These questions are being pursued using uncaging methods, which allow neurotransmitters such as glutamate to be generated in femtoliter (1 cubic micron) volumes within a millisecond. With rapid beamsteering technology we can uncage at tens of thousands of locations per second. Projects focus on large neurons such as cerebellar Purkinje neurons and pyramidal neurons of the neocortex and hippocampus, all of which receive a large convergence of synaptic input.
Brain scaling and evolution. We use comparative biophysical principles to infer functional principles of brain architecture. For example, the mammalian neocortex (also known as cerebral cortex) shows regularities of structure that suggest that brain structure may be subject to universal design constraints. From shrews to whales, mammalian brains vary over 100,000-fold in volume. Over this range large brains are more folded than small brains: the surface area of the cerebral cortex follows a power law relative to cortical volume greater than simple geometry would predict. We want to understand how these power laws are 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 space demanded by these axons is sufficient to account for the increased folding seen in large brains. This widening of axons may be driven by an evolutionary need to preserve the time it takes for a nerve impulse to cross the brain.
- Najafi F, Giovannucci A, Wang SS, Medina JF. (2014) Sensory-driven enhancement of calcium signals in individual Purkinje cell dendrites of awake mice. Cell Rep. 6: 792-98. Pubmed
- Shi DD, Trigo FF, Semmelhack MF, Wang SS. (2014) Synthesis and biological evaluation of Bis-CNB-GABA, a photoactivatable neurotransmitter with low receptor interference and chemical two-photon uncaging properties. J Am Chem Soc. 136: 1976-81. Pubmed
- *Sun XR, *Badura A, Pacheco DA, Wang SS-H. (2013) Fast GCaMPs for improved tracking of neuronal activity. Nat Commun. 42167: 1-10. Pubmed
- Schneider ER, Civillico EF, Wang SS. (2013) Calcium-based dendritic excitability and its regulation in the deep cerebellar nuclei. J Neurophysiol. 109: 2282-92. Pubmed
- Akerboom J, Chen TW, Wardill TJ, Wang SS, Looger LL. (2012) Optimization of a GCaMP calcium indicator for neural activity imaging. J Neurosci. 32: 13819-40. Pubmed
- Ozden I, Dombeck DA, Hoogland TM, Tank DW, Wang SS. (2012) Widespread state-dependent shifts in cerebellar activity in locomoting mice. PLoS One. 7: e42650. Pubmed
- Kuhn B, Ozden I, Lampi Y, Hasan MT, Wang SS. (2012) An amplified promoter system for targeted expression of calcium indicator proteins in the cerebellar cortex. Front Neural Circuits. 6: 49. Pubmed
- Richard Sun X, Giovannucci A, Sgro AE, Wang SS. (2012) SnapShot: Optical control and imaging of brain activity. Cell. 149: 1650-50. PubMed
- Wang SSH, Campbell BC. (2012) Mr. Bayes Goes to Washington. Science 339: 758-59.
- Campbell BC, Wang SS. (2012) Familial linkage between neuropsychiatric disorders and intellectual interests. PLoS One. 7: e30405. PubMed
- 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: 10463-73. PubMed
- Hoogland TM, Kuhn B, Göbel W,...Wang SS. (2009) Radially expanding transglial calcium waves in the intact cerebellum. Proc Natl Acad Sci. 106: 3496-501. PubMed
- Wang SS. (2008) Functional tradeoffs in axonal scaling: implications for brain function. Brain Behav Evol. 72: 159-67. 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,...Wyatt KD. (2008) Functional trade-offs in white matter axonal scaling. J Neurosci. 28: 4047-56. PubMed
- Sarkisov DV, Wang SS. (2008) Order-dependent coincidence detection in cerebellar Purkinje neurons at the inositol trisphosphate receptor. J Neurosci. 28: 133-42. 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: 25517-26. 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: 664-78. PubMed
- Sarkisov DV, Wang SS (2006). Alignment and calibration of a focal neurotransmitter uncaging system. Nat Protoc. 1: 828-32. PubMed
- Wittenberg GM, Wang SS. (2006) Malleability of spike-timing-dependent plasticity at the CA3-CA1 synapse. J Neurosci. 26: 6610-07. PubMed
- Shoham S, O'Connor DH, Sarkisov DV, Wang SS. (2005) Rapid neurotransmitter uncaging in spatially defined patterns. Nat Methods. 2: 837-43. PubMed
- O'Connor DH, Wittenberg GM, Wang SS. (2005) Graded bidirectional synaptic plasticity is composed of switch-like unitary events. Proc Natl Acad Sci. 102: 9679-84. PubMed
- Sullivan MR, Nimmerjahn A, Sarkisov DV, Helmchen F, Wang SS. (2005) In vivo calcium imaging of circuit activity in cerebellar cortex. J Neurophysiol. 94: 1636-44. PubMed
- O'Connor DH, Wittenberg GM, Wang SS. (2005) Dissection of bidirectional synaptic plasticity into saturable unidirectional processes. J Neurophysiol. 94: 1565-73. PubMed
- Wyatt KD, Tanapat P, Wang SS. (2005) Speed limits in the cerebellum: constraints from myelinated and unmyelinated parallel fibers. Eur J Neurosci. 21: 2285-90. PubMed
- Burish MJ, Kueh HY, Wang SS. (2004) Brain architecture and social complexity in modern and ancient birds. Brain Behav Evol. 63: 107-24. PubMed
- Wang SS, Major G. (2003) Integrating over time with dendritic wave-fronts. Nat Neurosci. 6: 906-08. PubMed
- Harrison KH, Hof PR, Wang SS. (2002) Scaling laws in the mammalian neocortex: does form provide clues to function? J Neurocytol. 31: 289-98. PubMed
- Wang SS-H, Mitra PP, Clark DA. (2002) Brain evolution (Communications arising): How did brains evolve? Nature. 415: 135.
- Clark DA, Mitra PP, Wang SS. (2001) Scalable architecture in mammalian brains. Nature. 411: 189-93. PubMed
- Wang SS, Denk W, Hausser M. (2000) Coincidence detection in single dendritic spines mediated by calcium release. Nat Neurosci. 3: 1266-73. 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. 97: 8635-40. PubMed
- Furuta T, Wang SS, Dantzker JL,...Tsien RY. (1999) Brominated 7-hydroxycoumarin-4-ylmethyls: photolabile protecting groups with biologically useful cross-sections for two photon photolysis. Proc Natl Acad Sci. 96: 1193-200. PubMed
- Pettit DL, Wang SS, Gee KR, Augustine GJ. (1997) Chemical two-photon uncaging: a novel approach to mapping glutamate receptors. Neuron. 19: 465-71. PubMed
- Kupferman R, Mitra PP, Hohenberg PC, Wang SS. (1997) Analytical calculation of intracellular calcium wave characteristics. Biophys J. 72: 2430-44. PubMed
- Wang SS, Augustine GJ. (1995) Confocal imaging and local photolysis of caged compounds: dual probes of synaptic function. Neuron. 15: 755-60. PubMed
- DeBello WM, O'Connor V, Dresbach T,...Wang SS,...Augustine GJ (1995). SNAP-mediated protein-protein interactions essential for neurotransmitter release. Nature. 373: 626-30. PubMed
- Wang SS, Thompson SH. (1995) Local positive feedback by calcium in the propagation of intracellular calcium waves. Biophys J. 69: 1683-97. PubMed
- Wang SS, Alousi AA, Thompson SH. (1995) The lifetime of inositol 1,4,5-trisphosphate in single cells. J Gen Physiol. 105: 149-71. 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: 483-96. 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: 307-10. PubMed
- Peroutka SJ, Hamik A, Harrington MA,...Wang SS. (1998) (R)-(-)-[77Br]4-bromo-2,5-dimethoxyamphetamine labels a novel 5-hydroxytryptamine binding site in brain membranes. Mol Pharmacol. 34: 537-42. 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: 431-32. PubMed
- 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: 439-43. PubMed