Wang Lab Research
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.
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?
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.