权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Functional integration of newborn olfactory sensory neurons in the healthy and regenerating olfactory system

新生嗅觉感觉神经元在健康和再生嗅觉系统中的功能整合

基本信息

批准号：
10310501
负责人：
Claire Elizabeth Jane Cheetham
金额：
$ 32.99万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10310501
关键词：
Ablation Adult Affect Area Axon Behavior Biological Assay Brain Brain Injuries Calcium Cell Therapy Chemicals Data Detection Development Effectiveness Electron Microscopy Exhibits Functional Imaging Functional Regeneration Goals Image Immunohistochemistry Life Location Mammals Maps Mediating Modeling Mus Natural regeneration Neurodegenerative Disorders Neurons Newborn Infant Odorant Receptors Odors Olfactory Epithelium Olfactory Pathways Phase Play Population Presynaptic Terminals Publishing Research Role Sensory Signal Transduction Stem Cell Development Stem cell transplant Synapses Testing Time Transcript Work epithelial stem cell in vivo innovation insight nervous system disorder neural circuit neurogenesis neuron development newborn neuron olfactory bulb olfactory marker protein olfactory sensory neurons optogenetics protein expression receptor expression repaired sensory input stem stem cell population stem cells synaptogenesis two-photon

项目摘要

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.