Shawn D. Burton, Ph.D. - US grants

DESCRIPTION (provided by applicant): 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.

DESCRIPTION (provided by applicant): 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.

PROJECT SUMMARY How information is transformed as it propagates through a neural circuit remains an outstanding question of modern neuroscience. Answering this question for a given circuit requires knowledge of: 1) the information being transformed, 2) activity in pre- and postsynaptic populations, and 3) connectivity between pre- and postsynaptic populations. The tremendous complexity of neural circuits has made such investigation exceedingly difficult, with success limited to small local circuits or across gross brain regions. The overall goal of this project is to bridge these scales to map the transformation of information across a large neural circuit through technological advances in large-scale monitoring of neural activity and quantitative analyses of high-dimensional neural representations. A secondary goal of this project is to develop a platform for monitoring the transformation of information in a well-defined circuit amenable to the application of interventional tools capable of causally linking circuit elements to aspects of neural coding. To accomplish these goals, this project will capitalize on recent advances in spectrally separated calcium indicators of neural activity and the unique circuitry of the mammalian olfactory system to simultaneously image sensory-evoked activity in large pre- and postsynaptic neural populations while selectively manipulating specific interneuron classes. The resulting dataset will enable multiple exploratory analyses of high-dimensional neural representations as well as hypothesis-driven analyses of how the olfactory system transforms information, including investigating the organization and neural coding roles of interneuronal networks. This project will thus provide fundamental new insight into brain function by exploring how information is transformed across a large neural circuit, and will further generate key advances in the fields of systems neuroscience and olfaction.