Research areas

Neurons convert synaptic inputs arriving onto dendrites into action potentials that propagate outward along axons. Back-propagating action potentials (bAPs) also go from soma into dendrites and interact with synaptic inputs to strengthen or weaken individual synapses. During this process, neuronal dendrites are not a passive cable; rather, dendrites actively generate local Na+ and Ca2+ spikes. These voltage-gated conductances control intrinsic neuronal properties and single-neuron computations, thus affecting synaptic plasticity rules.

Synaptic plasticity is the cellular basis of memory formation that controls the efficacy of communications among neuronal ensembles. Our ability to learn and recall deteriorates over the course of life in both normal and disease states. The root cause has been associated with dysfunction in intrinsic neuronal properties (e.g., membrane excitability), dendritic integration, and synaptic plasticity. However, we currently lack a deep understanding of the critical cellular and molecular mechanisms that generate and maintain memory.

The overarching aim of our lab is to understand the mechanisms of learning and memory at the levels of synaptic plasticity, dendritic biophysics, and neuronal ensembles. We develop molecular, optical, and computational tools for spatiotemporally mapping bioelectric activities to elucidate single-neuron computations and plasticity rules in behaving animals. These measurements will lay the groundwork to understand the molecular mechanisms of memory, with the ultimate goal of delaying or reversing memory dysfunctions. We further aim to extend these insights into the realm of brain-machine interface.

Major interest

Molecular and optical tool development for voltage imaging

1. Developing new voltage sensors with rationalized design and directed evolution

2. Improving membrane trafficking of the voltage sensors and channelrhodopsins

3. Advancing optical instruments for imaging with high resolution in space and time

Mechanisms of learning and memory

1. Exploring fundamental rules of memory formation and maintenance from molecules to systems

2. Understanding the roles of diverse cell types and neuromodulatory circuits in memory

3. Discovering new methods to improve or reverse memory in health and disease

Signal processing in dendrites

1. Exploring single-neuron computations, signal processing, and input-output functions

2. Understanding local circuit engagement and excitation-inhibition (E-I) balance

3. Elucidating the mechanisms of dendritic excitability and neurodegeneration

Methods

We combine molecular tool development, fluorescence imaging, and electrophysiology to advance our understanding of brain physiology. Our team engineers proteins and modifies gene expression to dissect biological processes. While studies in cultured cells and tissue samples provide valuable insights into what can happen, our primary focus is on behaving animals to elucidate what actually happens during learning and memory.

Our primary animal model is the mouse, chosen for its sophisticated neural architecture and relevance to human biology. We are also open to using simpler animal models (e.g., zebrafish, fruit flies, and roundworms) to facilitate a clearer and deeper understanding of specific neural processes.

Genetic manipulation

Robust gene expression is the key to successful fluorescence microscopy. We are using both virological and electrical gene transfer methods. In particular, we are taking advantage of in utero electroporation and in vivo single-cell electroporation to sparsely label and resolve fine details of dendritic information. We are using adeno-associated virus (AAV) and transgenic animal methods for system-level studies.

Fluorescence imaging

We are combining 1-photon and 2-photon microscopy to map sub-millisecond voltage dynamics with fine structural details. In addition, we are extending our imaging toolbox to visualize and trace other biomolecules, such as Ca²⁺ and cAMP. Functional imaging in space and time provides a deeper understanding of the molecular interactions and propagations that underlie signal processing and plasticity.

Electrophysiology

We are using in vitro and in vivo electrophysiology. Our expertise involves patch clamp and extracellular field-potential recordings. For in vivo patch clamp, we are using both 2P-guided and resistance change-based blind patching techniques. We often combine optical and electrophysiological methods coupled with animal behaviors to obtain multi-dimensional information of the brain at play.

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