[Research Interests] [Representative Publications] [Lab Members] RESEARCH INTERESTSMolecular and cellular mechanisms underlying the function and development of olfactory sensory neurons. Olfactory sensory neurons of mammals offer rich opportunities to study a range of fundamental questions in the areas of signal transduction, regulation of gene expression, and the development and maintenance of neuronal circuits. Unique features of these cells include the signal transduction in cilial microcompartment, the strictly regulated expression of a large repertoire of odorant receptors, stereotyped patterns of axonal projection, and a dynamically maintained neuronal population. The long-term goal of our research is to capitalize on the unique aspects of olfactory sensory neurons to gain insights into neuronal function and development as well as the sense of smell. Olfactory sensory neurons, which are located within the olfactory epithelium inside the nose, generate electrical responses to encode odor stimulation. The signal transduction process, which converts the binding of odorous molecules to odorant receptors into the depolarization of the cell membrane, occurs at the cilia extending from the dendrite of olfactory sensory neurons. Over the past two decades, intense studies have elucidated a G protein-coupled, cyclic AMP second messenger-mediated core signal transduction pathway. However, the molecular identities of a few components in the signal transduction pathway have not been determined. Further, understanding how the olfactory sensory neuron responds to ever changing environmental stimuli requires the knowledge of how the signal transduction pathway is modulated, which allows the sensory neuron to react rapidly to the stimulation, to terminate the response rapidly after the stimulation, and to adjust sensitivity (i.e. to adapt) according to the intensity and duration of odor exposures. Our current research focuses on identifying proteins that partake in or regulate the olfactory signal transduction and on understanding how specific regulatory events targeting specific proteins will influence olfactory signal transduction. Olfactory sensory neurons in the nose form precise connections with neurons in the brain. In olfactory system, olfactory sensory neurons expressing the same odorant receptor, though randomly dispersed in a broad area of the olfactory epithelium, project axons to the same locations in the olfactory bulb of the brain. Further, olfactory sensory neurons have a relatively short life span and are susceptible to damage caused by environmental factors. The neuronal population is continuously renewed throughout life and maintains a conserved connection pattern to the olfactory bulb. We are interested in understanding mechanisms that account for the formation and maintenance of such precise neuronal connections. Our experimental approaches include gene-targeting in mice, molecular and histological characterizations of gene expression, electrophysiological recordings, and behavioral tests.
The above picture shows a histochemical staining (blue color) for expression of a reporter protein b-galactosidase (b-gal) in an olfactory bulb section of a TOPGAL transgenic mouse at the age of postnatal-day 16. In TOPGAL mice (DasGupta and Fuchs, 1999), b-gal expression reports the nuclear b-catenin activity, usually caused by the activation of the canonical Wnt signaling pathway. The staining reveals a layer of b-gal positive cells located at the interface between the olfactory sensory neuron axons and their final target, the glomeruli. In the enlargement is the illustration of olfactory sensory neuron axons (red and green trace) innervating glomeruli (G) and making synaptic connections with the dendrite of the olfactory bulb projection neurons, mitral cells (M). During development, growth cones of OSN axons pass through this layer of cells before reaching glomeruli. We found that the b-gal expression in the olfactory bulb is developmentally regulated with the peak expression occurring at late embryonic and early postnatal stages. The reporter expression diminishes in adulthood, but could be recovered by forcing regeneration of olfactory sensory neurons. The temporal coincidence between the peak of b-gal expression and periods of formation of olfactory sensory neuron connections, together with the spatial location of these cells, suggest a role of these cells in the formation of olfactory sensory neuron connections in the olfactory bulb. REPRESENTATIVE PUBLICATIONSAB Stephan, EY Shum, S Hirsh, KD Cygnar, J Reisert, and H Zhao (2009) ANO2 is the cilial calcium-activated chloride channel that may mediate olfactory amplification. Proc Natl Acad Sci U S A. 106(28):11776-81. KD Cygnar and H Zhao (2009) Phosphodiesterase 1C is dispensable for rapid response termination of olfactory sensory neurons. Nature Neuroscience 12(4):454-62. Y Song, KD. Cygnar, B Sagdullaev, M Valley, S Hirsh, A Stephan, J Reisert, H Zhao (2008). Ca2+/calmodulin-mediated fast desensitization by the B1b subunit of the CNG channel affects response termination but not sensitivity to recurring stimulation in olfactory sensory neurons. Neuron 58(3):374-86. T Booker-Dwyer, S Hirsh, and H Zhao (2008). A Unique Cell Population in the Mouse Olfactory Bulb Displays Nuclear beta-catenin Signaling During Development and Olfactory Sensory Neuron Regeneration. Developmental Neurobiology 68(7):859-69 AD Güler, JL Ecker, GS Lall, S Haq, CM Altimus, HW Liao, AR Barnard, H Cahill, TC Badea, H Zhao, MW Hankins, DM Berson, RJ Lucas, KW Yau, and S Hattar (2008). Melanopsin cells provide the principal conduit for rod/cone contribution to non-image forming vision. Nature 453(7191):102-5. H Zhao and RR Reed (2001). X inactivation of the OCNC1 channel gene reveals a role for activity-dependent competition in the olfactory system. Cell 104, 651-660. H Zhao, L Ivic, JM Otaki, M Hashimoto, K Mikoshoba, and S Firestein (1998). Functional expression of a mammalian odorant receptor. Science 279, 237-242. Lab MembersGraduate Student:
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