The encoding of smell by the olfactory system is critical to mammalian communication and survival. Under- standing olfaction has proven extremely difficult, however, due to the vast diversity of odors, the large number of odor receptors, and the lack of any clear mapping of odor qualities. Fundamental research identifying the neural circuitry and basic computations performed in the olfactory system has thus been pivotal in elucidating principles of olfaction. In the olfactory bulb, sensory information is contained in precise spatiotemporal patterns of activity in mitral cells, the olfactory bulb princial neurons. These odor-specific patterns are generated in two stages. First, each mitral cell receives sensory input at a single input structure called a glomerulus. Odors activate specific but overlapping glomeruli, yielding poorly discriminable patterns of mitral cell input. Second, local inhibitory granule cells mediate lateral inhibition between mitral cells and decorrelate mitrl cell activity across time. Mitral cell-granule cell interactions thereby increase the discriminabilty of mitral cell activity patterns between different odors. Functional recruitment of granule cells i thus a critical step in olfaction, yet multiple fundamental questions remain concerning granule cell recruitment. First, what is the role of glomerular organization in granule cell recruitment? Anatomical data suggests that granule cells preferentially link mitral cells connected to the same glomerulus, but this spatial preference remains to be functionally confirmed. Second, how does the temporal sequence of mitral cell activity influence granule cell recruitment? The slow but input- specific kinetics of granule cell recruitment suggest that synchronous mitral cell activity may not be optimal for functionally recruiting granule cells. Thus, the primary objective of the proposed research is to investigate the spatial and temporal properties governing granule cell recruitment.
Aim 1 of the proposed research is to test whether spatial glomerular organization controls granule cell recruitment. Feedforward input to granule cells will be compared across glomeruli using voltage-clamp recordings and extracellular and optogenetic glomerular stimulation, with the hypothesis that input will be strongest when stimulating a specific glomerulus. To test if granule cells preferentially link mitral cells connected to the same glomerulus, granule cell-mediated lateral inhibition will be compared between mitral cells connected to the same glomerulus and mitral cells connected to different glomeruli using paired voltage-clamp recordings.
Aim 2 of the proposed research is to determine how the temporal sequence of mitral cell activity regulates granule cell recruitment. The temporal tuning of granule cell recruitment will first be measured using calcium imaging to monitor recruitment across large granule cell populations while stimulating neighboring glomeruli at varying temporal offsets. The influence of mitral cell syn- chrony on granule cell recruitment will then be directly examined using paired mitral cell recordings coupled with calcium imaging. Collectively, the proposed research will thus provide novel insight into a critical aspect of olfactory bulb circuitry: the sptial and temporal properties governing granule cell recruitment.

Public Health Relevance

Functional recruitment of granule cell neurons in the olfactory bulb is a critical step in encoding sensory experience in the olfactory system, yet the fundamental spatial and temporal properties governing granule cell recruitment remain poorly understood. Experiments described in this proposal investigate the dependence of granule cell recruitment on both the spatial organization and temporal sequence of afferent input and principal neuron activity in the olfactory bulb. Resolving the spatial and temporal properties of granule cell recruitment will provide novel insight into how dynamic interactions between interneurons and principal neurons shape sensory experience.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZDC1)
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Sklare, Dan
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Carnegie-Mellon University
Schools of Arts and Sciences
United States
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Burton, Shawn D; LaRocca, Greg; Liu, Annie et al. (2017) Olfactory Bulb Deep Short-Axon Cells Mediate Widespread Inhibition of Tufted Cell Apical Dendrites. J Neurosci 37:1117-1138
Case, Daniel T; Burton, Shawn D; Gedeon, Jeremy Y et al. (2017) Layer- and cell type-selective co-transmission by a basal forebrain cholinergic projection to the olfactory bulb. Nat Commun 8:652
Burton, Shawn D (2017) Inhibitory circuits of the mammalian main olfactory bulb. J Neurophysiol 118:2034-2051
Geramita, Matthew A; Burton, Shawn D; Urban, Nathan N (2016) Distinct lateral inhibitory circuits drive parallel processing of sensory information in the mammalian olfactory bulb. Elife 5:
Zhou, Pengcheng; Burton, Shawn D; Snyder, Adam C et al. (2015) Establishing a Statistical Link between Network Oscillations and Neural Synchrony. PLoS Comput Biol 11:e1004549
Tripathy, Shreejoy J; Burton, Shawn D; Geramita, Matthew et al. (2015) Brain-wide analysis of electrophysiological diversity yields novel categorization of mammalian neuron types. J Neurophysiol 113:3474-89
Burton, Shawn D; Urban, Nathaniel N (2015) Rapid Feedforward Inhibition and Asynchronous Excitation Regulate Granule Cell Activity in the Mammalian Main Olfactory Bulb. J Neurosci 35:14103-22
Yu, Yiyi; Burton, Shawn D; Tripathy, Shreejoy J et al. (2015) Postnatal development attunes olfactory bulb mitral cells to high-frequency signaling. J Neurophysiol 114:2830-42
Burton, Shawn D; Urban, Nathaniel N (2014) Greater excitability and firing irregularity of tufted cells underlies distinct afferent-evoked activity of olfactory bulb mitral and tufted cells. J Physiol 592:2097-118
Tripathy, Shreejoy J; Savitskaya, Judith; Burton, Shawn D et al. (2014) NeuroElectro: a window to the world's neuron electrophysiology data. Front Neuroinform 8:40