The function of a neural circuit is constrained by the properties of individual neurons and their wiring. In many sensory systems, the responses of the circuit elements vary systematically with physical position, leading to a topographic representation of the stimulus space. Sensory representation in the olfactory system has been harder to decipher, in part due to the difficulty in finding appropriate metrics to characterize the odor space and in sampling this space densely. Progress has also been slowed by technological limitations in probing and controlling individual circuit elements in early olfactory circuits. In this proposal, we aim to develop new methods that will greatly aid the dissection of functional neural circuits in the olfactory system in mice. Mice rely on olfaction to find food, choose mates and avoid predators. In mammals, olfactory sensory neurons send their axons to the olfactory bulb (OB), where there is a characteristic physical layout of inputs in the glomerular layer. Each glomerulus receives convergent afferents from a large number of olfactory sensory neurons expressing the same odorant receptor, so each point on the surface of the OB has a specific chemical response spectrum. The principal neurons in the OB, the mitral and tufted (M/T) cells, typically have a single primary dendrite that projects to a single glomerulus. M/T cells also receive lateral GABAergic inputs from a variety of interneurons in the glomerular and external plexiform layers, thus allowing them to sample information from several functionally diverse glomeruli. Odor processing in the OB is also strongly modulated by feedback from the cortex as well as brainstem neuromodulatory centers. Here, we propose to develop new reagents and methods that will accelerate the pace of research into mammalian olfaction. Our experiments will be guided by three specific aims.
Aim 1 : To generate transgenic mouse lines that express the light-activated ion channel channelrhodopsin specifically in olfactory sensory neurons, rendering the input layer of the olfactory bulb (glomeruli) optically excitable.
Aim 2 : To demonstrate the feasibility of using this mouse model to study functional connectivity in the OB and its downstream target areas using in vitro slice preparation and digital mirror device technology.
Aim 3 : To demonstrate the feasibility of constructing glomerular receptive fields of neurons in the OB and its target brain areas in the intact, freely breathing mouse. Tools developed here will help advance our understanding of odor coding. In addition, since the olfaction is often used as a sensory gateway to study higher brain function such as decision making, our tools will also have broader use. Finally, by crossing these "opto-olfactory" mice with other mouse models of disease, we can catalyze studies of sensory dysfunction in brain disorders such as autism and Alzheimer's disease.

Public Health Relevance

Our studies will produce novel reagents - transgenic mouse lines and optical stimulation devices - that will aid future investigation of how sensory information processing occurs normally in the brain and how it is modulated. More generally, our studies also have direct implications for human health, since olfactory deficits have also been strongly associated with aging and some neurological diseases such as Alzheimer's.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Molecular Neurogenetics Study Section (MNG)
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Sullivan, Susan L
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Harvard University
Schools of Arts and Sciences
United States
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Rokni, Dan; Hemmelder, Vivian; Kapoor, Vikrant et al. (2014) An olfactory cocktail party: figure-ground segregation of odorants in rodents. Nat Neurosci 17:1225-32
Hochbaum, Daniel R; Zhao, Yongxin; Farhi, Samouil L et al. (2014) All-optical electrophysiology in mammalian neurons using engineered microbial rhodopsins. Nat Methods 11:825-33
Haddad, Rafi; Lanjuin, Anne; Madisen, Linda et al. (2013) Olfactory cortical neurons read out a relative time code in the olfactory bulb. Nat Neurosci 16:949-57