Big Picture: Human Mind

My long-term or life-term goal is to answer what is human mind. Maybe this question can never be answered, but I hope to further our understanding of human behavior at the molecular or cellular level, and to improve our health by increasing our knowledge of the nervous system.

Human mind and intelligence are performed by nervous system. And I believe that to understand mind, it is necessary to understand nervous system at two levels: one is the molecular and cellular or intra-cellular level; and the other is the neural network or the inter-cellular level. I also believe that there are some basic problems, solvement of which will lead to answer of a lot of other questions. I need to find such "central" questions and work on them.

Current Research: How Neural Circuits Control Animal Behavior

key words: amygdala, neural circuits, behavior, fear conditioning

A major function of our brain is to regulate our behavior through our experience in environment, during which our brain undergoes learning and memory. malfunction in any step of this process results in neuronal diseases. Amygdala is a good model to understand the brain function for a lot of reasons: the most robust assay so far developed in studying high brain function, fear conditioning, is centered on amygdala; the general pathway of fear conditioning from sensory input to behavior output is relatively clear in the last two decades, which laid the foundation to study its function in depth; anomlies in amygdala function results in neuronal disorders such as anxiety and depression, which affect modern people more and more seriously but were largely neglected as diseases.

Although numerous studies have been carried on amygdala (pubmed returns more than 21,000 publications with the entry "amygdala".) , we still confused about the functions of amygdala and don't know its mechanism. A major problem might be, as proposed by David Anderson, the heterogeneity of the amygdala neurons (this might be true for most brain regions). So the traditional lesion studies, in which part of the brain region is destroyed by electricity or chemicals, results in damages in neurons or fibers with different functions. therefore, it is unlikely to get consistent results from this kind of studies, let alone the mechanism of the neural circuits. Due to the great progress in molecular genetics, we can manipulate specific neurons if we could find molecular markers that specifically expressed in those neurons. As more and more markers are discovered, we could gain much more deeper insight into how brain functions.

Our lab has identified a marker that label a subpopulation of neurons in the lateral part of the central amygdala nucleus (CeL), and silencing these neurons increase fear and anxiety. Now we are mapping the functional circuits of this population of neuron and study how it is involved in behavioral control.

Previous Research: Molecular Mechanism in Synaptic Transmission

key words: complexin, exocytosis, SNARE

Synaptic transmission is a bridge between intra and inter cellular levels, where a central role is performed by regulated vesicle exocytosis. Typically, the vesicles have to dock at their release site, and a fraction of the docked vesicles are primed to be release ready, that is, the vesicle membrane can fuse with the plasma membrane in response to calcium trigger without further maturation steps. It is generally accepted that exocytosis is mediated by SNARE proteins, whose function is fine tuned through interaction with other proteins. But, how exocytosis is regulated by these proteins remains unclear.

[ Click the figure above to view the vesicle cycle animation (Galli, T. and Haucke, V., 2001) ]

My graduate study focuses on a small protein called complexin, which binds to the assembled SNARE core complex. We used adrenal chromaffin cell as the model sytem, combining electrophysiological, electrochemical and morphological methods, to understand how complexin regulates exocytosis. Our study demonstrated that adrenal chromaffin cells express only one complexin isoform, complexin II. We found that chromaffin cells from complexin II knock-out
mice exhibit markedly diminished readily releasable vesicle pools but show no change in kinetics of fusion pore dilation or morphological vesicle docking; overexpression of complexin II in complexin knock-out cells rescues the knock-out phenotype, and in wild-type cells, it markedly enhances the readily releasable pools. So we conclude that complexin is a positive regulator for Ca2+-regulated exocytosis, acting upstream of fusion pore formation by facilitating vesicle priming. Our work further demonstrated that this priming function of complexin requires phosphorylation at serine-93.