The cascade of mechanisms that regulate the outgrowth of axons from olfactory sensory neurons (OSNs) and their precise targeting to specific glomeruli in the olfactory bulb remain controversial. While the odor receptors expressed by the OSNs are strongly implicated, there are conflicting reports pertaining to the functional transduction cascade downstream from the odor receptors. An absence of functional activity induced by naris closure, or deletion of a member of the transduction cascade, adenylyl cyclase 111, can have significant effects on the organization of OSN axons and their target glomeruli. However, perturbation of the cyclic nucleotide gated (CNG) channel that is the target of cAMP within the cascade results in little perturbation of axon outgrowth/targeting. Recent findings suggested that cAMP may contribute to OSN axon outgrowth, independent of CNG channel opening, by entering the nucleus and regulating gene expression. My goal is to explore an alternative hypothesis: that 1(h), the current generated by), contributes to OSN depolarization/ excitation and in the absence of the CNG channel can underlie axon outgrowth, coalescence, and formation of glomeruli. I propose a series of studies that will establish the spatio-temporal framework of HCN subunit expression, quantify developmental transients in subunit expression, directly test the effect of HCN on axon outgrowth and branching, and finally, explore how the absence of the HCN1 subunit affects OSN convergence and targeting. The data will have significant implications for developmental disorders such as Kallman's syndrome, and more generally for understanding developmental dynamics and cell-cell interactions during the initial development of sensory systems.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DC010098-02
Application #
7933956
Study Section
Special Emphasis Panel (ZDC1-SRB-L (44))
Program Officer
Cyr, Janet
Project Start
2009-09-01
Project End
2011-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
2
Fiscal Year
2010
Total Cost
$52,154
Indirect Cost
Name
Yale University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Mobley, Arie S; Bryant, Alex K; Richard, Marion B et al. (2013) Age-dependent regional changes in the rostral migratory stream. Neurobiol Aging 34:1873-81
Mobley, Arie S; Miller, Alexandra M; Araneda, Ricardo C et al. (2010) Hyperpolarization-activated cyclic nucleotide-gated channels in olfactory sensory neurons regulate axon extension and glomerular formation. J Neurosci 30:16498-508