Neurosurgery
P.O., Box 208082
New Haven, CT 06520-8082
Tel: 203.785.2805
Fax: 203.785.6916
neurosurgery@yale.edu
Our research group is interested in the earliest stages of axon tract formation and the extracellular cues that help establish axon pathways. Using the olfactory pathway as a model system, we look at early stages of embryonic development using a wide variety of techniques to investigate the molecules and mechanisms that underlie axon guidance and its regulation. We employ a broad range of state-of-the- art technologies including molecular biology, protein biochemistry, confocal imaging and tissue culture to investigate cues in the extracellular matrix, substrate bound guidance cues as well as secreted guidance cues and how they interact to help establish a functioning sensory system. Most recently we have expanded our studies to investigate the regulation of these guidance cues by proteinases as a mechanism controlling axon behavior. These studies will provide important new insights into the complex arrays of molecules that underlying the complexity of targeting and topography in the olfactory system. Importantly, however, these studies are also broadly applicable to other regions of the CNS regions where work continues towards understanding the formation of boundaries and topographic maps. We maintain strong collaborative ties with Dr. Charles Greer and his group which provides an excellent resource, both intellectually as well as practically, in our research for which we are grateful.
Understanding how axons form specific connections during development is critical for understanding CNS formation. Axons often traverse long distances, bypassing many potential targets, before identifying the correct synaptic targets. The mechanisms used to identify synaptic targets fall into four basic classes: guidance cues that can either be attractive or repulsive and either be secreted or substrate bound. Axons use combinations of these cues to navigate to target sites.
Figure 1: Taken from Treloar HB, Bartolomei JC, Lipscomb BW, Greer CA. (2001) Mechanisms of axonal plasticity: lessons from the olfactory pathway. Neuroscientist. 7:55-63. Schematic diagram of the four mechanisms of axon guidance. Attractive (green) or repulsive (red) cues can either be secreted (A, B) or substrate bound (C, D). A, Axons growing toward a secreted attractive cue preferentially grow toward the source, extending up a concentration gradient. B, Axons that encounter a secreted repulsive cue preferentially turn and extend away from the source of the cue. C, Axons that encounter substrate-bound attractive cues preferentially extend along the surface of those cells. D, Axons that encounter substrate-bound repulsive cues retract their growth cones, resample the environment, and preferentially extend on cells expressing different cues.
The olfactory system is an excellent model to study the development of connectivity in the CNS. First, the projection of OSN axons from the olfactory epithelium (OE) to the olfactory bulb (OB) has a complex topography. Axons arising from adjacent neurons in the OE project to disparate glomerular targets in the OB while individual glomeruli receive input from axons arising from disparate sites in the OE. Remarkably, this pattern appears highly specific and is maintained across animals. All axons expressing the same OR terminate in specific glomeruli and the pattern of glomerular activation is believed to encode the identity of specific odors. Second, the olfactory pathway has a unique capacity to continually regenerate throughout life. Newly generated OSNs extend axons to the OB and establish connections with output neurons in appropriate glomeruli, maintaining the topography that underlies olfactory coding. Third, olfaction is an extremely important sensory modality for most animals, underlying key behaviors such as feeding and reproduction. Forth, advances in understanding how this key sensory system develops are expected to be broadly relevant to understanding circuit formation and topographic map development elsewhere in the CNS.
Figure 2: Schematic diagram of the synaptic circuitry of the olfactory system (adapted from Mori, 1995). Mosaic olfactory projection: the diagram shows the convergence of primary sensory olfactory neurons widely distributed in the nasal cavity expressing the same odorant receptor proteins (depicted in the same color) onto a single glomerulus. These primary sensory olfactory neurons synapse with the dendrites of mitral/tufted cells within glomeruli. Color coding of mitral/tufted cells demonstrates the odor specificity of these cells. Mitral/tufted cells project axons back to cortical regions via the lateral olfactory tract (LOT). Inhibitory synapses from neighboring periglomerular cells are demonstrated. The diagram also shows that lateral inhibitory pathways of mitral/tufted cells from neighboring glomeruli via granule cells. Black arrows and white arrows indicate excitatory and inhibitory synapses respectively.
A potential source of guidance cues that could influence OSN axons during development is the extracellular matrix (ECM). There is increasing evidence that ECM-associated factors are critically involved in the formation of neuronal networks during development, and their plasticity in the adult. The ECM accounts for a relatively large volume of nervous tissue: 20% of the adult CNS and approximately 40% of neonatal CNS. In the nervous system, the ECM is crucial in many developmental processes such as neuronal migration, neurite outgrowth, growth cone guidance, and synapse formation and stabilization. The major components of ECM are collagens, non-collagen glycoproteins (which include fibronectin, laminins, vitronectin, thrombospondins, tenascins) and proteoglycans (PGs). The 2 major classes of PGs in the ECM of the CNS are the chondrointin sulfate proteoglycans (CSPGs) and heparan sulfate proteoglycans (HSPGs). ECM does not have a static composition of these molecules either during development or in the adult. Rather it is dynamic, with its composition constantly being modified in response to intrinsic and external factors.
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6/30/08
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