Ongoing Research in Liu Lab
Comprehensive biophysical mapping and modeling of the C. elegans nervous system
One of the ultimate goals of neuroscience is to model a nervous system from sensory input to behavioral output in a predictive manner. C. elegans, with a small nervous system of only 302 neurons and the fully reconstructed wiring diagram (“connectome”), is probably our best hope to achieve this goal. A decisive reason why theorists have not been able to model this simplest brain is that a critical link between the physical connectivity and behavior is missing: how individual neurons and circuits compute information.
At the neuronal level, computations are determined by biophysical properties, which are in turn derived from the composition of ion channels functioning in each individual neuron. Such information is largely unknown in C. elegans due to the scarcity of electrophysiological studies. This knowledge gap one of the most pressing issues in the field and would like to address it by establishing a complete biophysical map – electrophysiomics – of the entire C. elegans nervous system. With the technical advantage we have developed in worm electrophysiology in our lab, we have already preliminarily characterized more than 25% of neuronal cell types and identified novel properties that will be followed up with in-depth investigations as separate but convergent projects. The long-term goal of our research is to achieve a comprehensive biophysical characterization of a complete nervous system, and work with theorists to combine this bottom-up information with top-down theoretical framework to construct a predictive model from sensory input to neuronal activity and ultimately behavior.
Dissecting the mechanism of gut-brain oscillations underlying the C. elegans enteric rhythm
Central pattern generators (CPGs) are networks that produce intrinsic oscillatory activities underlying most rhythmic motor behaviors such as breathing, heartbeat and locomotion in almost all animals studied to date, including humans. However, the inner workings and modulations of CPGs are diverse and poorly understood across different systems. The C. elegans defecation cycle, also called defecation motor program (DMP), consisting of a series of stereotyped motor sequences activated every 45 sec, is a particularly well-studied behavior regulated by the gut and the enteric nervous system. Previous work has established that internal clock underlying the C. elegans DMP relies on inositol triphosphate receptor (IP3R) oscillations of intestinal calcium. However, how the intestinal clock is self-generated and modulated by neural inputs and linked to rhythmic activities within the central nervous system are fundamental questions yet to be addressed. We aim to determine the mechanisms of gut-brain communications that generate and regulate the rhythmic defecation behavior in C.
elegans. We plan to attain our research goal by determining the ionic mechanisms underlying the intestinal membrane potential dynamics using electrophysiological, calcium and voltage fluorescent imaging approach. We will also develop quantitative models to reconstruct the intestinal oscillation to simulate the enteric clock underlying the defecation motor behavior. This work is expected to contribute in-depth understanding of how the C. elegans gut-brain axis modulates a well-defined rhythmic behavior from molecular mechanisms to cellular physiology and circuit property. This contribution will be significant because it is expected to develop and test novel models to connect two key aspects of neuroscience with mounting interests - central pattern generation and gut-brain communication - within a simple physiological circuit that can be mapped to quantifiable behaviors at single-cell resolution.
Synthetic biology – reengineering the C. elegans nervous system
“What I cannot create, I cannot understand,” one of Richard Feynman’s famous dictums, nicely highlights the need to build systems to drive their understanding. Building a working in silico model of the C. elegans nervous system could allow us to test hypotheses and principles, develop new therapeutic approaches inexpensively and rapidly, and catalyze the design of new information processing systems in developing artificial intelligence and brain-inspired Intelligence. In parallel to our worm brain modeling effort, we will also use the approach of synthetic biology to re-engineer the C. elegans nervous system to get insight of its function. Both electrophysiological studies and single-cell RNA sequencing data suggest that each C. elegans neuronal class may express a unique set of ion channels to implement its distinct sensitivity and computational function. Therefore, we could take advantage of powerful worm genetics to alter the biophysical properties of specific neuronal cell types by rearranging their ion channel compositions. This approach is more informative than simply killing or silencing neurons because it probes the coding functions of specific biophysical properties and the related behavioral consequences. For example, we could remodel non-spiking neurons into spiking neurons and vice versa by knocking out their native channels and expressing spike-generating channels in appropriate combinations. We predict that animals with re-engineered neurons or neural circuits would generate aberrant behaviors, such as ascending or descending stimulus gradients not seen in wild-type animals.
