Central Nervous System; Neuroglia; Neurons; Nose; Gene Expression Profiling
Stem Cell Center, Yale: Transcriptional Regulation of Stem and Progenitor Cells
We study mechanisms mediating the complex pathfinding and
synaptogenesis of axons and dendrites during early development and how
those mechanisms may degrade during aging. In the olfactory system,
~1,000 subpopulations of sensory neurons express different odor
receptors. The sensory neuron axons segregate in the olfactory bulb
based on odor receptor expression, producing a highly specific molecular
map. Understanding the molecular basis of this segregation of axons is
one of our primary goals.
In parallel, we study the targeting and differentiation of dendrites to understand the mechanisms that regulate their highly specific interactions with small subsets of the sensory neuron axons. Unique to the olfactory system, ongoing adult neurogenesis generates new populations of sensory neurons in the olfactory epithelium and interneurons centrally. The molecular differentiation and integration of these adult generated neurons into synaptic circuits is an ongoing interest in the lab.
Extensive Research Description
Current Research Program
A major goal of my laboratory is understanding the basic mechanisms that contribute to the establishment of orderly topographic maps within the CNS, during both normal development and during regenerative events following injury or disease. We have been focusing our efforts on the olfactory system, in part because of the complexity of the map between the olfactory epithelium and the olfactory bulb. Axons sort into 1,000 functional subsets that are targeted with high specificity to olfactory bulb glomeruli.
Using both in vivo and in vitro models, we are currently isolating several mechanisms that may contribute to this complex reorganization including laminin, tenascin and the expression of putative odor receptors in growth cones. In related studies we continue to characterize a unique population of glial cells, ensheathing cells, found in the olfactory nerve. While elsewhere in the mature CNS glia are an impediment to axon growth, the ensheathing cell glia support axon extension and targeting throughout life.
We recently demonstrated that the growth promoting effects of ensheathing cells are not limited to olfactory receptor neurons but are also seen in other populations of neurons. Particularly exciting, our recent studies demonstrate that the ensheathing cells remain pluri-potential and that when implanted into demyelinated spinal cord can adopt a myelinating phenotype which remyelinates the axons and contributes to a restoration of normal conduction velocities.
In parallel studies we are examining the molecular and synaptic organization of the olfactory bulb glomeruli. Using RT-PCR we are mapping the distribution of subsets of olfactory receptor cell axons in glomeruli to gain insights into the topography of odor-ligand maps in the olfactory bulb. In addition, working with colleagues, we are using a GFP tag to test hypotheses regarding the specificity of synaptic organization within glomeruli. Second, using antibodies synaptic vesicle related proteins and confocal microscopy we have begun to describe a hitherto unrecognized segregation of local and projection synaptic circuits in the glomeruli.
It may be that this segregation underlies the lateral inhibitory systems that are believed to be operative in the olfactory system. Beyond my colleagues in Neurosurgery, I maintain active collaborations with the following Departments at Yale: Neurology, Neurobiology, Anesthesiology and Ophthamology. In addition, I have collaborative studies with members of the faculty at Columbia University, Emory University, The Rockefeller, University of Maryland and University of Colorado.
Increasingly, the neurological sciences are focusing on intervention strategies that will both limit the debilitating consequences of injury/disease as well as increase the probability of successful regeneration of pathways and connections in the CNS. In order to facilitate these processes it is necessary for us to understand the molecular and cellular events operative during axon extension, target selection and synapse formation. The studies described above directly assess those questions and, particularly in the case of the ensheathing cells, offer the possibility of clinical application in the near future.
Fate mapping of olfactory bulb projection neurons
The role of axon:axon adhesion in establishing sensory maps
Cell surface and diffusible molecules influencing the extension and convergence of axons
The timing and molecular mechanisms mediating the development of 3-layer piriform cortex
- Imamura F and Greer CA (2015). Segregated labeling of olfactory bulb projection neurons based on their birthdates. European Journal of Neuroscience 41: 147-156.
- Bartel, D, Rela L, Hsieh L and Greer CA (2015). Dendrodendritic synapses in the mouse olfactory bulb external plexiform layer. Journal of Comparative Neurology. Available online on 07 February 2015.
- Chen C, Zou D, Altomare C, Xu L, Greer CA and Firestein S (2014). Nonsensory target-dependent of piriform cortex. Proceedings of the National Academy of Sciences (USA) 111: 16931-16936.
- Lepousez G, Nissant A, Bryant A, Gheusi G, Greer CA and Lledo P (2014). Olfactory learning promotes input-specific synaptic plasticity in adult-born neurons. Proceedings of the National Academy of Sciences (USA) 111: 13984-13989.
- Imamura, F. and Greer CA (2013). Pax6 regulates Tbr1 and Tbr2 expression in olfactory bulb mitral cells. Molecular and Cellular Neuroscience 54: 58-70.
- Imamura, F, Ayoub, AE, Rakic, P and Greer, CA (2011). Timing of neurogenesis is a determinant of olfactory circuitry. Nature Neuroscience 14: 331-337.
- Sarma, AA, Richard, MB and Greer, CA (2011). Developmental dynamics of piriform cortex. Cerebral Cortex 21: 1231-1245.
- Richard, M., Taylor, S. and Greer, C.A. (2010). Age-induced disruption of selective olfactory bulb synaptic circuits. Proceedings of the National Academy of Sciences (USA) 107: 15613-15618
- Imamura F, Greer CA. (2009) Dendritic branching of olfactory bulb mitral and tufted cells: regulation by TrkB. PLoS One 4(8):e6729
- Whitman MC, Greer CA (2007). Synaptic integration of adult-generated olfactory bulb granule cells: basal axodendritic centrifugal input precedes apical dendrodendritic local circuits. J Neurosci. 27(37):9951-61.