Functional Recovery of Sensory Input to Olfactory Bulb

描述（由申请人提供）：拟议的实验使用小鼠嗅觉系统作为模型，以了解神经元在大量神经元丢失和随后的再生后如何恢复与中枢神经系统目标的功能连接。哺乳动物嗅觉系统即使完全丧失，其初级感觉神经元（嗅觉感觉神经元）也具有显著的再生和再生能力。然而，感觉神经元轴突再生到大脑中适当的目标-嗅球肾小球-似乎是不完善的，许多轴突接触不适当的肾小球。该实验将首次探讨这种错误定位如何改变通常代表气味信息的肾小球活动图。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，对单个分子识别的受体类型的重靶向进行组织学分析将允许对这一现象进行详细的解剖分析。本文提出了一种实验方法：a)研究肾小球活动图再生的时间过程及其损伤后恢复的精度；B)测试感觉神经元重定向的精度是否依赖于气味诱发的神经元激活；c)研究嗅感觉神经元的气味反应特性与其肾小球靶点选择的关系。这些实验应该会产生气味的功能表征在损伤和恢复后改变的程度的第一个总体图像，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。肾小球再神经支配的错误可能是创伤或感染导致嗅觉丧失后恢复的人类嗅觉功能障碍的机制。这些实验可能为这些临床缺陷提供更好的细胞水平解释，并可能提出治疗策略。更一般地说，重建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的连接不正确会引起痛觉过敏和其他神经病变。这项工作可能会对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产生潜在的见解。

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.