Odor Memory Traces in the Mouse Olfactory Cortex

项目摘要/摘要 学习和记忆是大脑的基本功能，但它们的基本细胞和神经回路 机制仍然知之甚少。气味记忆在人类和动物中异常强大， 对生存和繁殖具有突出的重要性，并且极易患上神经退行性疾病 包括阿尔茨海默病。嗅觉(梨状)皮质被认为是气味感觉最先出现的地方， 一直被认为是用来编码气味记忆的。然而，细胞衬底和电路机制 对于嗅觉学习的影响是未知的。我们的长期目标是了解细胞和神经回路 气味感知和记忆的机制。这项提议的目的是提供一种机械性的 对气味记忆如何编码和表达的细胞/分子理解。为实现这一目标 我们已经在老鼠身上开发了基于活动的交叉遗传方法，使我们能够识别和 操纵在嗅觉学习过程中被激活的梨状神经元的活动。我们的总体假设 气味激活稀疏的、分布的和功能多样的梨状神经元，这些神经元的活动是必要的 有足够的嗅觉学习和记忆能力。目标1：确定如何操纵 气味记忆痕迹细胞会改变行为。我们将使用基于CFOS启动子活性的基因标签(Fos- 标记“)以可视化和操纵在嗅觉过程中被激活的梨状神经元的活动 学习。我们的初步数据为Fos标记梨状融合的必要性提供了强有力的证据 气味恐惧记忆回忆。目标2：确定学习如何改变人的气味反应特性 梨形合奏。我们将对清醒的、行为中的气味诱发活动进行慢性双光子成像 小鼠，在厌恶和食欲嗅觉条件作用之前、期间和之后。我们还将有选择地分析 Fos标记梨状神经元的反应特性是恐惧气味记忆回忆所必需的。我们会 检验嗅觉学习选择性地增强刺激检测和编码的假设 构成嗅觉记忆痕迹的神经元的辨别能力。目的3：确定分子 嗅觉记忆痕迹细胞的识别和连通性。要驱动行为，梨形合奏必须 将气味信息传送到下游目标区域。使用我们之前识别的一组标记基因和 单细胞转录学我们将确定被激活的梨状神经元的分子特性 在学习过程中，我们将追踪它们的轴突投射。我们将测试嗅觉学习的假设 促进梨状皮质与任务相关靶区的功能连接。该项目具有创新性。 因为IS结合了最先进的遗传、行为、成像和分子方法来识别 用于嗅觉学习和记忆的细胞和神经电路基板。它意义重大，因为它将有一个 对阿尔茨海默病患者记忆丧失的神经生物学理解产生了强烈的影响。

Project Summary/Abstract Learning and memory are fundamental brain functions, yet their underlying cellular and neural circuit mechanisms remain poorly understood. Odor memories are exceptionally robust in humans and animals, of outstanding importance for survival and reproduction, and highly susceptible to neurodegenerative disorders including Alzheimer Disease. The olfactory (piriform) cortex, where odor perception is thought to first emerge, has long been suggested to encode odor memories. However, the cellular substrates and circuit mechanisms of olfactory learning are unknown. Our long-term goal is to understand the cellular and neural circuit mechanisms of odor perception and memory. The objective of this proposal is to provide a mechanistic cellular/molecular understanding of how odor memories are encoded and expressed. To achieve this objective we have developed activity-based intersectional genetic approaches in mice that allow us to identify and manipulate the activity of piriform neurons that were activated during olfactory learning. Our overall hypothesis is that odors activate sparse, distributed and functionally diverse piriform neurons, whose activity is necessary and sufficient for olfactory learning and memory. Aim 1: To determine how manipulating the activity of odor memory trace cells alters behavior. We will use genetic tagging based on cFos promoter activity (“Fos- tagging”) to visualize and manipulate the activity of piriform neurons that were activated during olfactory learning. Our preliminary data provide strong evidence for the necessity of Fos-tagged piriform ensembles for odor fear memory recall. Aim 2: To determine how learning alters the odor response properties of piriform ensembles. We will perform chronic two-photon imaging of odor-evoked activity in awake, behaving mice, before, during, and after aversive and appetitive olfactory conditioning. We will also selectively analyze the response properties of Fos-tagged piriform neurons that are essential for fear odor memory recall. We will test the hypothesis that olfactory learning selectively enhances the encoding of stimulus detection and discriminability in neurons constituting an olfactory memory trace. Aim 3: To determine the molecular identity and connectivity of olfactory memory trace cells. To drive behaviors, piriform ensembles must convey odor information to downstream target areas. Using our previously identified set of marker genes and single cell transcriptomics we will determine the molecular identities of piriform neurons that are activated during learning, and we will trace their axonal projections. We will test the hypothesis that olfactory learning facilitates functional connectivity of piriform cortex with task-relevant target areas. This project is innovative because is combines state-of-the-art genetic, behavioral, imaging and molecular approaches to identify the cellular and neural circuit substrates for olfactory learning and memory. It is significant because it will have a strong impact on the understanding of the neurobiology of memory loss in Alzheimer Disease patients.