Ph.D. Massachusetts Institute of Technology
Postdoc. University of California, Berkeley
RESEARCH BACKGROUND
The central nervous system (CNS) is operated by complex and dynamic cellular networks that generate functional outputs in response to sensory cues and physiological changes. Neurotransmission, which mediates the communication and interplay between neurons, is fundamental for CNS function and development. However, decoding neurotransmission in the brain is enormously challenging, as signaling molecules involved in neurotransmission are highly diverse. A neurotransmitter may act through multiple types of receptors which have various assemblies and cellular/subcellular distributions. Moreover, the expression profile of neurotransmitter receptors varies with cell types and/or developmental stages. Studying neurotransmission with conventional approaches (e.g., pharmacology or gene knock-out) has thus encountered critical obstacles. Breakthroughs in neurotransmission decoding await new methods that enable control over signaling mediators with high spatial, temporal, and biochemical precision.
We integrate chemical, biochemical, and genetic approaches to develop these methods, with a special focus on next-generation optogenetics. Optogenetics is a revolutionary technique for precise manipulation/probing of complex biological events such as cellular signaling and neural circuitry. Through the action of a light-sensitive protein, the physiology of a cell or an organism can be optically controlled in defined space and time. Photocontrol can be further confined to a cell type of interest via genetic manipulations, facilitating the dissection of neural circuitry. We aim to optogenetically manipulate neurotransmitter receptors, the therapeutic targets for many neurological, psychiatric and developmental disorders. Knowing why and how the CNS utilizes such a diverse set of signaling mediators will bring an exciting new dimension to our understanding of brain function, dysfunction, and development.
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CURRENT PROJECTS
1. Engineering light-sensitive neurotransmitter receptors for precise manipulation of specific signaling components in the CNS. These tools will facilitate optogenetic decoding of neurotransmission with high biochemical resolution. We have previously developed a series of light-sensitive GABAA receptors for precise control of neuronal inhibition, both in vitro and in vivo (NEURON, 2015) (JACS, 2018). On this basis, we are exploring new strategies to enhance tool performance and to simplify the engineering procedures. We will also confer light sensitivity onto other classes of neurotransmitter receptor. Our ambitious goal is to generalize the approaches, expanding the optogenetic toolkit for a truly comprehensive decoding of neuronal signaling.
2. Developing novel methods to optically control native neurotransmitter receptors in defined neuronal types and/or subcellular compartments. Such methods will allow optogenetic interrogations of neurotransmission with reduced expenses/obstacles of genetic manipulations. We are developing chemical-genetic approaches to recruit photoswitchable drugs to the neuron of interest, thereby site-specifically manipulate the local receptors. We also aim to engineer genetically encoded photoswitchable modulators to bypass the need of drug treatment. Together, these approaches will enable researchers to systematically investigate neurotransmission at the molecular, cellular, and circuit levels.
3. Targeting biomolecular tools to specific subcellular compartments of neurons. Due to the highly polarized morphology and compartmentalized functionality of neurons, precise manipulation or measurement of biological activities in the brain may require targeting of an optogenetic/chemogenetic actuator or probe/reporter to a specific subcellular domain in neurons. Moreover, enrichment at the designated subcellular compartment can enhance the efficiency and/or sensitivity of the tools. We are thus exploring strategies to target genetically encoded tools (e.g., opsins, voltage indicators, and sonogenetic actuators) to soma, dendrites, axons, and synapses. Together with careful evaluations by imaging and electrophysiology, we aim to provide the neuroscience community with more precise and user-friendly resources, promoting the advances of scientific discoveries.
With the new technologies in hand, we will collaborate with experts in neuroscience, biomedicine, and engineering to unlock the mysteries of synaptic plasticity, learning/memory, pain sensation, and motor control.