Molecular Neurobiology

All of our behaviors, both simple and complex, are determined by the function of synapses between neurons in our central nervous system. Thus, an understanding of behavior requires knowledge of how synapses are made and how synapses function. Research conducted in the Molecular Neurobiology Program is aimed at understanding the mechanisms that lead to the generation of neural cells and their targets as well as the mechanisms that allow axons to project to their targets, form synapses and signal to one another.

These studies take advantage of invertebrates, such as Drosophila and C. elegans, that are amenable to genetic analysis and that facilitate the identification of genes required for cell fate determination and for axon guidance. Several groups use mice and mammalian cells grown in cell culture to study the complex inductive interactions between presynaptic and postsynaptic cells required for neural differentiation and synapse formation.

Administrative Assistants: Derek Hood, Elisabeth Gulotta

Burden Lab

Motor neurons extend axons into target muscles that are already regionally specialized, as acetylcholine receptors (AChRs) are preferentially expressed in the central region of muscle prior to and independent from innervation. Importantly, this pre-patterned region of the muscle pre-configures the region where synapses will ultimately form. We are studying how muscle is patterned in the absence of innervation, how innervation refines muscle pre-patterning, how MuSK, a synapse-specific muscle receptor tyrosine kinase, establishes muscle pre-patterning and whether the pattern of MuSK expression regulates where synapses will form.

Following contact with the growth cone of a developing motor neuron, these developing muscle fibers undergo a still further complex differentiation program in the synaptic region, which is dependent upon motor neuron-derived signals. In addition, signals from the muscle further regulate differentiation of presynaptic nerve terminals. This reciprocal exchange of signals between motor neurons and muscle is necessary to stabilize and modify the structure and function of nascent synapses.

Three different innervation-dependent signaling pathways regulate these latter aspects of synapse formation. The signal for one pathway is Agrin, a synaptic basal lamina protein that refines the organization of AChRs at synaptic sites. The mechanisms of Agrin-mediated signaling are poorly defined, but MuSK is a critical component of the Agrin-receptor complex. The second synaptic signaling pathway stimulates the expression of AChR subunit genes in myofiber nuclei that are positioned near the synaptic site. The signals that regulate synapse-specific transcription remain elusive. The third signaling pathway is mediated by propagated electrical activity in muscle fibers, and this innervation-dependent signaling pathway represses AChR expression and regulates expression of other muscle genes in all nuclei of the myofiber. Our laboratory uses mouse molecular genetics as well as molecular biological approaches to study how these signaling mechanisms regulate synapse formation and muscle structure.

Chao Lab

Our laboratory is interested in defining mechanisms of neurotrophin signal transduction responsible for cell survival, apoptosis, and changes in synaptic plasticity. The actions of neurotrophins, such as NGF, are dictated by an unusual transduction system with two different receptors, the Trk tyrosine kinase and the p75 neurotrophin receptor. We have found that the two receptors collaborate to send a survival signal under limiting concentrations of NGF. However, neurotrophins can also induce a cell death signal. This presents a biological paradox, in which life-death decisions in the nervous system are dependent upon the expression and action of two receptors with distinctive signaling mechanisms.

We are also studying the mechanisms that promote differentiation of oligodendrocytes and Schwann cells. We have found that dramatic changes in the levels of CDK2 kinase and the cell cycle inhibitor, p27, accompany the growth arrest of oligodendrocyte precursor cells. We also want to define neuronal signals responsible for glial cell differentiation. The axonal signals that trigger myelination by oligodendrocyte and Schwann cells will be approached by a combination of molecular and cellular approaches. These lines of research are directly applicable to a number of neurodegenerative diseases, including Alzheimer's and Lou Gehrig's disease, and disabling disorders, such as spinal cord injury and multiple sclerosis.

Clark Lab

Neurons extend axons along stereotypic pathways to their appropriate targets during the formation of the nervous system. Axons can also be eliminated during normal development as well as in response to injury or neurodegenerative processes. We are using genetic and molecular approaches in the nematode C. elegans to investigate the molecular mechanisms involved in axonal development and degeneration. C. elegans is well suited for our studies because it has a simple nervous system containing only 302 neurons, its genetics is well understood and the sequence of its genome is complete.

We are investigating the role of microtubule dynamics in axon growth; in particular, we found that a microtubule-destabilizing protein can regulate axon formation and extension. We are using several approaches to identify genes regulated by ZAG-1, a transcriptional repressor that controls multiple, discrete aspects of neuronal differentiation, including axonal pathfinding and branching. We are studying axonal degeneration through the analysis of the gene wly-1, which causes the inappropriate degeneration of specific axons when mutated.

Gan Lab

One of the most important features of the nervous system is its remarkable plasticity of synaptic connections throughout life. While synaptic rearrangement is critical for memory formation and functional recovery after nerve injury, synaptic loss correlates with cognitive decline in the elderly and plays pivotal roles in the pathogenesis of many neurodegenerative diseases. At present, very little is known about how synaptic changes take place in living animals.

Using Green Fluorescent Protein (GFP) expressing transgenic mice and in vivo transcranial two-photon microscopy, we have been able to image the same GFP-labled synapses over extended periods of time in both the central and peripheral nervous system. This ability to follow individual neuronal synapses in vivo opens a direct window to study structural plasticity of synapses under normal and pathological conditions. We are currently investigating experience-dependent synaptic change as well as synapse loss in the pathogenesis of Alzheimer's disease.

Salzer Lab

Axons and myelinating glia exhibit a series of striking cell interactions during development. Axons promote gliogenesis and glial differentiation, most dramatically formation of the myelin sheath that spirals around axons. Glial cells promote the survival of neurons and direct the reorganization of the entire length of the axon into a series of specialized domains. These domains are centered around nodes of Ranvier and consist of distinct multiprotein complexes of cell adhesion molecules, ion channels, and scaffolding molecules. This organization promotes saltatory conduction, synchronizes presynaptic inputs, and is crucial for axon function and integrity. Elucidation of the signaling between axons and glia is providing important insights into formation of myelinated nerves and the pathogenesis of neurologic disorders such as Multiple Sclerosis in which axo-glial interactions are disrupted.

Our current studies focus on three aspects of axo-glial interactions. We are characterizing growth factors on axons, and the signaling pathways they activate in glia, that promote glial differentiation and myelination. We are investigating the morphogenetic events mediated by the cytoskeleton that drive spiral formation of the myelin sheath. Lastly, we have identified novel components of the domains of myelinated axons and are studying how they are targeted to and assemble at their precise locations along the axon. As experimental approaches, we utilize tissue culture models of myelination, molecular genetic approaches and mouse mutants deficient in specific domain components.

Suh Lab

We like the smell of french fries sizzling in a deep fryer when we are hungry, but the smell is not appealing when we are completely sated. This phenomenon, that the valence of food odor is determined by the satiety state is observed in other organisms including fruit flies. Our laboratory uses molecular genetic tools, behavioral assays, and calcium imaging and electrophysiology techniques to study how valence is coded in the fly brain. This study would provide insight not only into the basic neurobiological mechanism, but it could also help to develop new treatments for obesity.