Overview
Neural computation relies highly on two basic types of chemical transmission: synaptic transmission and volume transmission. In synaptic transmission, a presynaptic terminal rapidly and precisely signals to its postsynaptic partner in a point-to-point mode. By contrast, neuromodulators like dopamine and acetylcholine act through volume transmission, where they diffuse to mediate effects over a large area. Our lab is interested in the fundamental principles of neuronal communications in the mammalian brain that give rise to consciousness and behavior. We employ a variety of cutting-edge technologies to dissect the activity dynamics and functional architecture of neurotransmission and neuromodulation in health and disease.
Our current research focuses on three directions:
1) The coding principles of dopaminergic and cholinergic systems in the brain.
2) The biophysics and molecular mechanisms of synaptic transmission.
3) The next-generation drug discovery technologies for central nervous system (CNS) disorders.
These studies will build the foundation for understanding the nature of brain computation and will ultimately power the development of new therapeutic strategies for treating related disorders.
Coding Principles of Dopaminergic and Cholinergic Systems in the Brain
Motor control and adaptive learning are crucial for survival. The striatal circuits play a central role in these functions, with medium spiny neurons (MSNs), dopamine (DA), and acetylcholine (ACh) as the three most important players. Dysfunctions of the striatum are highly related to several types of brain disorders ranging from addiction and schizophrenia to Parkinson’s disease and Huntington’s disease. We study how the striatum functions in health and malfunctions in disease. Our long-term goal is to uncover the fundamental principles underlying striatal DA and ACh signaling, how they contribute to striatal computation, and their functional alterations under pathological conditions.
Biophysics and Molecular Mechanisms of Synaptic Transmission
Synaptic transmission is the primary form of neuronal communication, which highly relies on a molecular complex called the active zone residing in the presynaptic terminal (bouton). The active zone is essentially doing two things: First, it directs vesicles to presynaptic release sites exactly opposed to postsynaptic receptors and generates the readily releasable pool (RRP). Second, it couples with the voltage-gated calcium channels (VGCCs) and controls the release probability of the vesicles (Pv). The RRP and Pv are two key parameters that largely determine the information flow between neurons and control the computations at individual synapses. We dissect the active zone functionally to understand the physical and molecular basis behind the RRP and Pv.
Next-Generation Drug Discovery Technologies for Central Nervous System (CNS) Disorders
The CNS disorders account for 28% of the global burden of disease. Although the social, clinical, and economic need for improved treatment of CNS disorders is paramount, the efforts to discover and develop new drugs for tackling these problems have been relatively unsuccessful due to our limited understanding of brain functions and brain diseases. The human brain is a complex interconnected network composed of 80 billion neurons and even more numbers of glia, and most CNS disorders are functional deficits without a clear biomarker. These features make it extremely challenging to evaluate drug effects using target-based theories or traditional bioassays. We develop new high-throughput methods for phenotypic characterization of the brain function to boost the speed and efficiency of CNS drug discovery and development.