Functional Organization of the Olfactory Cortex

描述（由申请人提供）：嗅觉丧失是许多神经退行性疾病和衰老障碍的最初迹象之一。了解大脑中的神经元结构和信息流途径对于确定患病大脑嗅觉丧失的原因非常重要，这可能导致早期诊断和更好地治疗潜在疾病。过去的研究已经揭示了小鼠嗅上皮和嗅球中气味检测的机制，但对感觉信息如何在皮层中编码知之甚少。我们之前的研究表明，来自不同类型气味受体（ORs）的输入是针对不同但空间重叠的皮层神经元簇的，每个皮层神经元似乎接收来自多个ORs的输入。鉴于每个气味分子都是通过不同的嗅觉反应的组合在鼻子中检测到的，本提案将开发和应用遗传和功能方法来测试来自相同气味激活的不同嗅觉反应的输入是否会聚到皮层神经元上，以确定它们的反应特异性。在Aim 1中，我们将开发重组腺相关病毒（rAAV）来表达不同的跨神经元示踪剂。由于每个球肾小球代表一种单一类型的OR，我们将在不同的肾小球中注射不同的raav，以在与注射肾小球相连的球二尖瓣细胞和簇状细胞中表达不同的示踪剂。示踪剂将从球茎转移到皮层，以显示相应ORs的皮层组织。这些研究将测试来自相同气味激活的ORs的输入是否会聚到皮质神经元上。在目标2中，我们将检查被气味激活的神经元是否接收来自其ORs的收敛输入。此外，我们将比较单独或组合输入激活的皮质神经元，以测试组合或输入是否塑造皮质神经元的反应特异性。总之，这些研究将表明，不同的ORs检测到的不同化学特征如何在皮层中整合，从而产生不同的感知。在这个提议中开发的新的追踪方法也将有助于系统地分析定型球图在皮层中的地形表征，以及不同的气味质量是否由不同的皮层模式表征。拟议的研究非常适合R21机制。

DESCRIPTION (provided by applicant): Loss of smell is one of the first signs of many neurodegenerative diseases and aging disorders. Knowledge of neuronal structure and the pathways of information flow in the brain is important for identifying the cause of smell loss in diseased brains which may lead to early diagnosis and better treatment of the underlying conditions. Studies in the past have uncovered much about the mechanisms of odor detection in the mouse olfactory epithelium and bulb, but little is known about how sensory information is encoded in the cortex. We previously showed that inputs derived from different types of odorant receptors (ORs) are targeted to different but spatially overlapping clusters of cortical neurons and each cortical neuron appears to receive inputs from multiple ORs. Given that each odor molecule is detected in the nose by a combination of different ORs, this proposal will develop and apply genetic and functional approaches to test if inputs from the different ORs activated by the same odorant converge on cortical neurons to determine their response specificity. In Aim 1, we will develop recombinant adeno-associated virus (rAAV) to express different transneuronal tracers. As each bulb glomerulus represents a single type of OR, we will inject different rAAVs into different glomeruli to express a distinct tracer in bulb mitral and tufted cells connected to the injected glomeruli. The tracer will migrate from bulb to cortex to reveal the cortical organization of the corresponding ORs. These studies will test if inputs from the ORs activated by the same odorant converge on cortical neurons. In Aim 2, we will examine if the neurons activated by an odorant are those that receive convergent inputs from its ORs. In addition, we will compare the cortical neurons activated by separate versus combined OR inputs to test if combinations of OR inputs shape the response specificity of cortical neurons. Together, these studies will show how different chemical features detected by different ORs are integrated in the cortex to yield distinct perceptions. The new tracing method developed in this proposal will also be useful to systematically analyze how the stereotyped bulb map is topographically represented in the cortex and if different odor qualities are represented by distinct cortical patterns. The proposed studies are ideally suited for the R21 mechanism.