The perception of odors begins in the olfactory epithelium when odorant ligands bind to molecular receptors expressed on the cilia of the olfactory sensory neurons, each of which expresses only 1 of 1200 candidate receptors. As the sensory neuron axons exit the epithelium they progress over the surface of the olfactory bulb and all of the axons coming from neurons expressing the same odorant receptor converge into only 2-3 glomeruli in the olfactory bulb. However, the convergence and discrete circuitry of the olfactory bulb is not apparent in piriform cortex (PCX), at least grossly. Afferent projections to piriform appear divergent and broadly distributed. Moreover, in contrast to the more widely studied neocortex, the 3 layer piriform paleocortex does not exhibit a definitive columnar structure, leaving open the question of whether principles learned from neocortex can be applied to understanding piriform. Most of what we know of the neuronal and synaptic organization of piriform has come from early studies of rat and opossum that while important did not benefit from contemporary genetic and molecular tools. The mouse, which has emerged as the dominant mammalian model for studies of the olfactory epithelium and bulb, has benefited immeasurably from these new tools. However, there are few examples of the application of contemporary genetic and molecular methods to studies of mouse piriform cortex. We remain woefully ignorant of the most fundamental features of mouse piriform cortex: When are the PCX neurons born and what is the timeline for the laminar organization? When do synapses first appear in mouse PCX and when do they achieve laminar segregation? What is the role of functional activity in the dynamics of PCX development and final organization? What are the molecular mechanisms/transcription factors underlying the fate and specificity of PCX neurons/structure? To begin addressing these significant gaps in our knowledge we are proposing 3 specific aims:
Aim 1 - Test the hypothesis that the subpopulations of neurons in PCX have distinct developmental lineages and that the emergence of laminar specificity occurs along a coordinated timeline;
Aim 2 - Test the hypothesis that odor experience, afferent activity, influences PCX neuron fate and synaptic circuitry;
and Aim 3 - Test the hypothesis that candidate transcription factor expression occurs in a sequentially defined manner and is an essential determinant of PCX neuronal fate.

Public Health Relevance

Early developmental events shape the structural and functional organization of sensory systems in neocortex. Perturbing neocortical sensory input can have profound and enduring effects on both cellular and functional properties and can persist throughout life. In contrast to most neocortical structures, the olfactory system is one of the few sites in the brain that has sustained neurogenesis in the adult, leading to complete and ongoing remodeling of synaptic circuits in the olfactory bulb. How this level of plasticity may influence organization in higher order cortical sites of odor coding is not well understood. This proposal will pursue a comprehensive understanding of the development of structural and molecular organization of olfactory cortex and the role of activity in sculpting these events. These data will provide better insight into the mechanisms regulating development in the brain and will lead to improvements in strategies for treating traumatic and genetic perturbations of neuronal circuits.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC013791-04
Application #
9380332
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Sullivan, Susan L
Project Start
2014-12-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Yale University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Kawasawa, Yuka Imamura; Salzberg, Anna C; Li, Mingfeng et al. (2016) RNA-seq analysis of developing olfactory bulb projection neurons. Mol Cell Neurosci 74:78-86
Bartel, Dianna L; Rela, Lorena; Hsieh, Lawrence et al. (2015) Dendrodendritic synapses in the mouse olfactory bulb external plexiform layer. J Comp Neurol 523:1145-61
Dubacq, Caroline; Fouquet, Coralie; Trembleau, Alain (2014) Making scent of the presence and local translation of odorant receptor mRNAs in olfactory axons. Dev Neurobiol 74:259-68