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Principal Investigator: Claire Elizabeth Jane Cheetham
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $332,860
Funding agency: National Institute on Deafness and Other Communication Disorders
Project Summary/Abstract
Understanding how endogenously-generated adult-born neurons functionally integrate into neural circuits may
inform strategies employing stem cell-derived neurons to repair damaged brain areas. Olfactory sensory neurons
(OSNs), which are generated throughout life in all mammals, provide an ideal model to study functional
integration in both the healthy and the regenerating olfactory system. Our long-term goal is to determine how
circuit function and regeneration can be enhanced by functional integration of newborn neurons. The overall
objective of this application is to determine how evoked activity during an immature developmental window
influences OSN survival and integration in the healthy and the regenerating olfactory system. Our central
hypothesis is that odor selective input to immature OSNs is required for their survival and functional integration
in both the healthy and the regenerating olfactory system. To test this hypothesis, we propose three specific
aims. First, we will define the odor selectivity of immature OSN sensory input to the OB, using in vivo 2-photon
calcium imaging. Second, we will determine the role of evoked activity in immature adult-born OSNs in their
survival and functional integration. We will up- and down-regulate evoked activity in OSNs during the immature
developmental stage, and use immunohistochemistry, electron microscopy, optogenetics and in vivo 2-photon
structural and functional imaging to assay their survival, synaptogenesis and functional integration. Finally, we
will determine the role of immature OSN activity in regeneration of OSN input to the OB. For this aim, we will
chemically ablate OSNs, which regenerate from olfactory epithelium stem cells, manipulate activity using naris
occlusion and chemogenetic silencing during regeneration, and use in vivo 2-photon time-lapse imaging to track
structural and functional regeneration of OSN input to glomeruli. We expect to find that evoked activity during
immaturity plays a key role in the survival and integration of that OSN. Hence, our proposed work will have an
important impact by defining how functional integration of an endogenous population of stem cell-derived
neurons is regulated to maintain and regenerate brain function. This study will be highly significant in elucidating
the role of activity in an endogenously-generated population of newborn neurons in regulating their functional
integration, thereby providing important insight relevant to the development of stem cell-based therapeutic
strategies to repair damaged neural circuits. Our proposed research is conceptually innovative in proposing that
sensory input during the immature phase of development is crucial to successful functional integration of OSNs
in the healthy and regenerating OB and will employ a technically innovative array of experimental approaches.
Terms: <0-4 weeks old><2-photon><21+ years old><Ablation><Acquired brain injury><Adult><Adult Human><Affect><Area><Assay><Axon><Axon Terminals><Behavior><Bioassay><Biological Assay><Brain><Brain Injuries><Brain Nervous System><Calcium><Cell Communication and Signaling><Cell Signaling><Chemicals><Data><Degenerative Neurologic Disorders><Detection><Development><Effectiveness><Electron Microscopy><Encephalon><Exhibits><Functional Imaging><Functional Regeneration><Genetic><Goals><Image><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Intracellular Communication and Signaling><Life><Location><Mammalia><Mammals><Maps><Mediating><Mice><Mice Mammals><Modeling><Murine><Mus><Natural regeneration><Nerve Cells><Nerve Unit><Nervous System Degenerative Diseases><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neurologic Disorders><Neurological Disorders><Neurons><Newborn Infant><Newborns><Odor Receptor Protein><Odorant Receptor Proteins><Odorant Receptors><Odors><Olfactory Epithelium><Olfactory Pathways><Olfactory Receptor Proteins><Olfactory system><Phase><Physiologic Imaging><Play><Population><Presynaptic Nerve Endings><Presynaptic Terminals><Progenitor Cell Transplantation><Progenitor Cells><Publishing><Regeneration><Research><Role><Sensory><Signal Transduction><Signal Transduction Systems><Signaling><Stem Cell Development><Stem Cell Transplantation><Stem cell transplant><Synapses><Synaptic><Synaptic Boutons><Synaptic Terminals><Testing><Time><Transcript><Work><adulthood><biological signal transduction><brain damage><brain-injured><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><developmental><epithelial progenitor><epithelial progenitor cell><epithelial stem cell><imaging><in vivo><innovate><innovation><innovative><insight><neural circuit><neural circuitry><neurocircuitry><neurodegenerative illness><neurogenesis><neurological disease><neuron development><neuronal><neuronal development><neuronal survival><newborn child><newborn children><newborn neuron><olfactory bulb><olfactory circuitry><olfactory circuits><olfactory marker protein><olfactory sensory neurons><optogenetics><physiological imaging><progenitor cell based therapy><progenitor cell development><progenitor cell population><progenitor cell therapy><progenitor cell treatment><progenitor development><progenitor population><progenitor therapy><progenitor transplantation><progenitor treatment><protein expression><receptor expression><regenerate><repair><repaired><sensory input><social role><stem and progenitor cell development><stem and progenitor cell population><stem and progenitor cell therapy><stem and progenitor cell transplantations><stem cell based therapy><stem cell mediated therapy><stem cell population><stem cell therapeutics><stem cell therapy><stem cell treatment><stem cell-based therapeutic><stem cell-based treatment><stem cells><structural imaging><synapse><synapse formation><synaptic circuit><synaptic circuitry><synaptogenesis><two-photon>