Le Ma, PhD

How to Build & Rebuild Neural Networks from Axons & Dendrites?

One remarkable feature of the nervous system is the web-like networks linking axons and dendrites, the long and thin extensions form nerve cell bodies.  These intricate networks are responsible for sophisticated behaviors, such as walking and talking.  They are built by a series of developmental processes, including the formation of nerve branches that allow dendrites to maximize synaptic inputs and axons to relay outputs to multiple targets.  Although elaborate nerve branches are known for more than a century and often associated with specific cell types and functions, the mechanisms underlying their development and regulation are not well understood.   How do they form at the right time and in the right place?  How do they attain specific pattern and size?   How do they remodel in response to experience or injury?  And, how do they contribute to brain disorders and nerve regeneration?  To address these fundamental questions, three major research directions are currently being pursued in the laboratory.

1. Identify molecular pathways involved in branching. Using mammalian neuronal cell models, we investigate known factors in controlling stereotypic branched patterns and search new genes that are critical to regulating different aspects of branching.  A variety of modern molecular techniques, such as RNAseq and CRISPR, are combined with primary cell culture and in vivo analysis in these studies.  For examples, a) following sensory neurons in the dorsal root ganglion, we have identified two signaling mechanisms required for proper bifurcation during early spinal cord development; and b) using a viral delivery technique to inactivate gene function while simultaneously visualizing single cell morphology, we have identified a cell surface signaling system required for dendrite self-avoidance, a patterning mechanism generating elaborated branches that rarely overlap, in cerebellar Purkinje cells.
2. Explore cell biological regulation of branching.  Although branched morphologies come in different shape and size, only a limited number of factors are encoded by the genome.  To understand how branching patterns are defined by a combination of environmental cues and intrinsic programs, we investigate the cooperation of molecules that regulates different steps of branching, including initiation, growth, guidance, stabilization, and patterning.  Cutting-edge cell biological tools, including live cell imaging, micro-patterning, and computer vision, are employed here to examine the regulation of cellular machineries during branch development.
3. Define the contribution of branching to circuit function and repair. Branching morphogenesis is essential to generating complex neural networks, but what is the physiological consequence when branching regulation is perturbed?  How are they affected in neurological and psychiatric disorders?  Knowledge of molecular pathways coupled to the anatomically robust phenotypes offers us a unique opportunity to: a) investigate the contribution of nerve branching to normal circuit functions using a battery of behavioral assays, and b) identify potential animal models that mirror commonly seen disease phenotypes.  In addition, we are interested in the response of nerve branches to degeneration associated with many diseases as well as the potential to translate our newly acquired knowledge from developmental studies of branching to nerve regeneration in adults.

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