Functional Recovery of Sensory Input to Olfactory Bulb

描述（由申请人提供）：所提出的实验使用小鼠嗅觉系统作为模型，以了解在大量神经元损失和随后的再生后，神经元如何恢复与中枢神经系统中其靶点的功能连接。哺乳动物的嗅觉系统具有显著的再生能力，即使在完全丧失后，其初级感觉神经元（嗅觉感觉神经元）也能再生。然而，感觉神经元轴突向其在大脑中的适当目标-嗅球的肾小球-的再生长似乎是不完美的，许多轴突接触不适当的肾小球。拟议中的实验将首次询问这种错误的定位如何改变通常代表气味信息的肾小球活动地图。嗅觉感觉神经元激活的遗传编码指标将用于比较正常和上皮病变恢复小鼠的气味表征。与此同时，对单一分子鉴定受体类型的重靶向的组织学分析将允许对这种现象进行详细的解剖学分析。实验提出，a）调查肾小球活动图的再生的时间过程和它们在损伤后恢复的精确度; B）测试感觉神经元重定向的精确度是否取决于气味诱发的神经元激活;和c）调查嗅觉感觉神经元的气味反应特性和它们选择的肾小球目标之间的关系。这些实验应该产生的第一个一般性的图片在损伤和恢复后的气味的功能表征改变的程度，并指出嗅觉神经元和它们的目标之间的连接被改造的机制。肾小球神经再支配的错误可能是人类从创伤或感染引起的嗅觉丧失中恢复的嗅觉功能障碍的潜在机制。这些实验可能为这种临床缺陷提供改进的细胞水平解释，并可能提出治疗策略。更一般地说，重新建立适当的神经连接是任何感觉或运动系统功能完全恢复的先决条件。例如，周围神经纤维恢复后与CMS的不正确连接可引起痛觉过敏和其他神经病。这项工作可能会深入了解这些和其他与不适当的神经元连接相关的综合征的治疗策略。

DESCRIPTION (provided by applicant): The proposed experiments use the mouse olfactory system as a model to understand how neurons restore functional connections to their targets in the central nervous system after massive neuronal loss and subsequent regeneration. The mammalian olfactory system has the remarkable capacity for regeneration and regrowth of its primary sensory neurons (olfactory sensory neurons) after even a complete loss. However, the regrowth of sensory neuron axons to their appropriate targets in the brain - the glomeruli of the olfactory bulb - appears to be imperfect, with many axons contacting inappropriate glomeruli. The proposed experiments will, for the first time, ask how this mistargeting alters the glomerular maps of activity that normally represent odor information. A genetically-encoded indicator of olfactory sensory neuron activation will be used to compare odorant representations in normal and epithelial lesion-recovered mice. In parallel, histological analysis of the retargeting of a single, molecularly-identified receptor type will permit a detailed anatomical analysis of this phenomenon. Experiments are proposed which a) investigate the time-course of regeneration of glomerular activity maps and the precision with which they recover after lesion; b) test whether the precision of sensory neuron retargeting depends on odorant-evoked activation of the neurons; and c) investigate the relationship between the odorant response properties of olfactory sensory neurons and their choice of glomerular target. The experiments should generate the first general picture of the extent to which functional representations of odors are altered after lesion and recovery, and point to mechanisms by which connections between olfactory neurons and their targets are reformed. Errors in the reinnervation of glomeruli are likely mechanisms underlying olfactory dysfunction in humans recovering from olfactory loss due to trauma or infection. These experiments may provide improved cellular-level explanations for such clinical deficits and could suggest therapeutic strategies. More generally, reestablishing appropriate neural connectivity is a prerequisite for the full recovery of function of any sensory or motor system. For example, incorrect connections to the CMS after recovery of peripheral nerve fibers can cause hyperalgesia and other neuropathies. This work could potentially yield insight into treatment strategies for these and other syndromes related to inappropriate neuronal connections.