Functional Recovery of Sensory Input to Olfactory Bulb

描述(申请人提供)：拟议的实验使用小鼠嗅觉系统作为模型，以了解神经元如何在大量神经元丢失和随后的再生后恢复与其在中枢神经系统中的目标的功能连接。哺乳动物的嗅觉系统在其初级感觉神经元(嗅觉感觉神经元)完全丧失后具有显著的再生和再生能力。然而，感觉神经元轴突重新长到大脑中合适的目标--嗅球的肾小球--似乎并不完美，许多轴突与不适当的肾小球接触。拟议中的实验将第一次询问这种错误定位如何改变通常代表气味信息的肾小球活动地图。一种遗传编码的嗅觉感觉神经元激活指标将被用来比较正常和上皮病变恢复的小鼠的气味表征。同时，对单个分子识别受体类型的重定向的组织学分析将允许对这一现象进行详细的解剖学分析。实验包括：a)研究肾小球活动图再生的时程和损伤后肾小球活动图恢复的精确度；b)测试感觉神经元重定向的精确度是否依赖于嗅觉诱发神经元的激活；c)研究嗅觉感觉神经元的气味反应特性与它们选择肾小球靶点的关系。这些实验应该会产生第一张关于气味的功能表征在受损和恢复后发生变化的总体图景，并指出嗅觉神经元和它们的目标之间的连接被重塑的机制。肾小球神经再支配的错误可能是由于创伤或感染而导致嗅觉丧失恢复的人的嗅觉功能障碍的机制。这些实验可能为这种临床缺陷提供改进的细胞水平的解释，并可能提出治疗策略。更广泛地说，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的错误连接可能会导致痛觉过敏和其他神经疾病。这项工作可能会为这些和其他与不适当的神经元连接有关的综合征的治疗策略提供潜在的见解。

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.