The long term goal of the proposed experiments is to understand how animals perceive odors. The experiments in the present proposal are designed to improve our understanding of the function and role of the olfactory bulb in this process. Maps of the input to the bulb are available from optical recordings of calcium and pH signals. Here we propose to use optical recording methods to monitor the activity of postsynaptic cells in the olfactory bulb in an in vivo mouse preparation. First, we plan to use bulk injection of calcium dyes and 2-photon microscopy to simultaneously monitor the activity of many (hundreds) of individual neurons in response to odorant presentations. We plan to make these recordings from both juxtaglomerular neurons that surround the glomeruli and from mitral cells which provide the output of the olfactory bulb. The ability to record from many neurons simultaneously should greatly improve our understanding of olfactory bulb function. Second, we propose to use genetically encoded voltage-sensitive (FP-voltage sensor) or calcium- sensitive proteins expressed in the mitral/tufted cells to monitor the output of the bulb in response to odor presentations. A comparison of the output map with the input map would provide a strong statement about the function of the olfactory bulb in odorant processing. We propose modifications to improve the FP-voltage sensor signal-to-noise ratio and response time constant. These improvements would facilitate their use in any cell type in the mammalian brain and thereby contribute to the understanding of many aspects of brain function.

Public Health Relevance

Olfactory function is compromised in a number of human diseases including Alzheimer's disease and Parkinson's disease (Schiffman, 1992;Doty, 2001). In Parkinson's disease and in the Thy1-aSyn mice mouse model of Parkinson's disease reduced odorant sensitivity is one of the earliest detected symptoms (Fleming and Chesselet, 2006). A hallmark of Parkinson's disease is the premature cell death of dopaminergic neurons;a substantial fraction of periglomerular neurons in the olfactory bulb are dopaminergic. Thus the experiments in the present proposal would not only further our basic understanding of olfactory processing but also allow a characterization of the neuronal substrate of the olfactory symptoms in mouse models. In addition, voltage sensitive dyes are regularly used to follow action potential propagation during cardiac arhythmias (e.g. Matiukas et al, 2006;Mironov et al, 2006). The heart is composed of a variety of cell types. Thus specific targeting of FP-voltage sensors would also be very useful in studying the causes treatment of arhythmias.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Somatosensory and Chemosensory Systems Study Section (SCS)
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Sullivan, Susan L
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Yale University
Schools of Medicine
New Haven
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Sepehri Rad, Masoud; Cohen, Lawrence B; Braubach, Oliver et al. (2018) Monitoring voltage fluctuations of intracellular membranes. Sci Rep 8:6911
Sepehri Rad, Masoud; Choi, Yunsook; Cohen, Lawrence B et al. (2017) Voltage and Calcium Imaging of Brain Activity. Biophys J 113:2160-2167
Byom, Lindsey; Turkstra, Lyn S (2017) Cognitive task demands and discourse performance after traumatic brain injury. Int J Lang Commun Disord 52:501-513
Storace, Douglas A; Cohen, Lawrence B (2017) Measuring the olfactory bulb input-output transformation reveals a contribution to the perception of odorant concentration invariance. Nat Commun 8:81
Storace, Douglas; Sepehri Rad, Masoud; Kang, BokEum et al. (2016) Toward Better Genetically Encoded Sensors of Membrane Potential. Trends Neurosci 39:277-289
Storace, Douglas A; Braubach, Oliver R; Jin, Lei et al. (2015) Monitoring brain activity with protein voltage and calcium sensors. Sci Rep 5:10212
Storace, Douglas; Rad, Masoud Sepehri; Han, Zhou et al. (2015) Genetically Encoded Protein Sensors of Membrane Potential. Adv Exp Med Biol 859:493-509
Kovalchuk, Yury; Homma, Ryota; Liang, Yajie et al. (2015) In vivo odourant response properties of migrating adult-born neurons in the mouse olfactory bulb. Nat Commun 6:6349
Sung, Uhna; Sepehri-Rad, Masoud; Piao, Hong Hua et al. (2015) Developing Fast Fluorescent Protein Voltage Sensors by Optimizing FRET Interactions. PLoS One 10:e0141585
Han, Zhou; Jin, Lei; Chen, Fuyi et al. (2014) Mechanistic studies of the genetically encoded fluorescent protein voltage probe ArcLight. PLoS One 9:e113873

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