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
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.