Throughout the CNS diversity in the location and laminar organization of subpopulations of neurons and their synaptic circuits underlies functional specificity, as is evident in the visual pathways mediating low versus high resolution images. The degree of circuit specification in the olfactory bulb remains controversial. Functional analyses suggest a topography of odor-induced activity, but this has focused on the glomeruli where sensory neuron axons expressing the same odor receptor converge and terminate;conflicting data has been reported on the odor-specificity of mitral cells and the deeper radial and horizontal circuits in the bulb. Our proposal has two primary goals. First, there is little information on the innervation of individual glomeruli by subsets of mitral cells. Estimates suggest that each glomerulus is innervated by a subset of 25 mitral cells, but given the heterogeneity in the volume of individual glomeruli, this is likely a misleading generalization. Whether the mitral cells innervating single glomeruli share a common birth date, migratory timeframe or molecular phenotype are also not known. Second, while several studies have examined deafferentation in the bulb, we know comparatively little about trophic mechanisms influencing the fine structural organization of dendrites and their synaptic organization. In brief, our overarching goal is a better understanding of the embryonic and perinatal events underlying the primary cellular organization in the olfactory bulb. To achieve this goal our specific aims are summarized as: 1) Determine the principles underlying targeting of glomeruli by subsets of mitral cells;2) Establish the relationship between birth date, apoptotic cell death, and topography of olfactory bulb mitral cells;and 3) Test the hypothesis that trophic mechanisms, in particular BDNF, contribute to the differentiation and maturation of mitral cells. This work provides insight into determinants of early development relevant to diseases such as Kallman's syndrome and autism;the principles derived are also likely relevant to broad categories of anomalous cortical development and syndromes such as Fragile-X.

Public Health Relevance

The mechanisms that regulate the development of organization and functional properties of the nervous system remain largely unknown. Developmental disorders such as Kallmans syndrome, autism and cortical dysplasia all represent likely aberrations in the development and differentiation of the central nervous system. The studies proposed here address questions related to the genesis of new neurons and the mechanisms that may influence their distribution, organization and connections in the brain. As such, these new studies are likely to be important in understanding and developing interventional strategies for syndromes such as those noted above, among others.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC000210-27
Application #
8479133
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Sullivan, Susan L
Project Start
1983-12-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
27
Fiscal Year
2013
Total Cost
$320,180
Indirect Cost
$126,717
Name
Yale University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Imamura, Fumiaki; Greer, Charles A (2015) Segregated labeling of olfactory bulb projection neurons based on their birthdates. Eur J Neurosci 41:147-56
Mobley, Arie S; Rodriguez-Gil, Diego J; Imamura, Fumiaki et al. (2014) Aging in the olfactory system. Trends Neurosci 37:77-84
Rodriguez-Gil, Diego J; Hu, Wilbur; Greer, Charles A (2013) Dishevelled proteins are associated with olfactory sensory neuron presynaptic terminals. PLoS One 8:e56561
Imamura, Fumiaki; Greer, Charles A (2013) Pax6 regulates Tbr1 and Tbr2 expressions in olfactory bulb mitral cells. Mol Cell Neurosci 54:58-70
Kerrisk, Meghan E; Greer, Charles A; Koleske, Anthony J (2013) Integrin *3 is required for late postnatal stability of dendrite arbors, dendritic spines and synapses, and mouse behavior. J Neurosci 33:6742-52
Imamura, Fumiaki; Ayoub, Albert E; Rakic, Pasko et al. (2011) Timing of neurogenesis is a determinant of olfactory circuitry. Nat Neurosci 14:331-7
Rodriguez-Gil, Diego J; Treloar, Helen B; Zhang, Xiaohong et al. (2010) Chromosomal location-dependent nonstochastic onset of odor receptor expression. J Neurosci 30:10067-75
Whitman, Mary C; Greer, Charles A (2009) Adult neurogenesis and the olfactory system. Prog Neurobiol 89:162-75
Lecoq, Jerome; Tiret, Pascale; Najac, Marion et al. (2009) Odor-evoked oxygen consumption by action potential and synaptic transmission in the olfactory bulb. J Neurosci 29:1424-33
Rodriguez-Gil, Diego J; Greer, Charles A (2008) Wnt/Frizzled family members mediate olfactory sensory neuron axon extension. J Comp Neurol 511:301-17

Showing the most recent 10 out of 11 publications