Odor Memory Traces in the Mouse Olfactory Cortex

小鼠嗅觉皮层的气味记忆痕迹

• 批准号: 10307522
• 负责人: Alexander Fleischmann
• 金额: $ 44.59万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307522
• 关键词: Alzheimer' s Disease; Alzheimer' s disease patient; Animals; Area; Axon; Behavior; Behavioral; Brain; Brain Diseases; Cells; Chronic; Data; Desire for food; Detection; Fright; Genes; Genetic; Glean; Goals; Hippocampus (Brain); Human; Image; Learning; Memory; Memory Loss; Methods; Molecular; Molecular Analysis; Mus; Neurobiology; Neurodegenerative Disorders; Neurons; Odors; Olfactory Cortex; Olfactory Learning; Property; Reproduction; Shapes; Smell Perception; Stimulus; System; Testing; Work; awake; base; conditioning; experience; experimental study; fear memory; genetic approach; innovation; insight; memory encoding; memory recall; neural circuit; neuromechanism; olfactory bulb; piriform cortex; predictive modeling; promoter; relating to nervous system; response; transcriptomics; two-photon

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.

项目概要/摘要 学习和记忆是基本的大脑功能，但其底层的细胞和神经回路 机制仍知之甚少。人类和动物的气味记忆异常强烈 对生存和繁殖非常重要，并且极易患神经退行性疾病 包括阿尔茨海默病。嗅觉（梨状）皮层被认为是气味感知首先出现的地方， 长期以来一直有人建议对气味记忆进行编码。然而，细胞基质和电路机制 嗅觉学习的作用尚不清楚。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。该提案的目的是提供一种机制 细胞/分子对气味记忆如何编码和表达的理解。为了实现这一目标 我们在小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 操纵嗅觉学习过程中激活的梨状神经元的活动。我们的总体假设 气味激活稀疏、分布且功能多样的梨状神经元，其活动是必要的 并足以进行嗅觉学习和记忆。目标 1：确定如何操纵 气味记忆微量细胞改变行为。我们将使用基于 cFos 启动子活性的基因标记（“Fos- 标记”）来可视化和操纵嗅觉过程中激活的梨状神经元的活动 学习。我们的初步数据为 Fos 标记梨状群的必要性提供了强有力的证据 气味恐惧记忆回忆。目标 2：确定学习如何改变气味反应特性 梨状体群。我们将对清醒、行为时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调节之前、期间和之后。我们也会有选择性地分析 Fos 标记的梨状神经元的反应特性对于恐惧气味记忆回忆至关重要。我们将 检验嗅觉学习选择性增强刺激检测编码的假设 构成嗅觉记忆痕迹的神经元的可辨别性。目标 3：确定分子 嗅觉记忆痕迹细胞的身份和连接性。为了驱动行为，梨状肌群必须 将气味信息传递到下游目标区域。使用我们之前确定的一组标记基因和 单细胞转录组学我们将确定被激活的梨状神经元的分子身份 在学习过程中，我们将追踪他们的轴突投影。我们将检验嗅觉学习的假设 促进梨状皮层与任务相关目标区域的功能连接。这个项目很创新 因为它结合了最先进的遗传、行为、成像和分子方法来识别 嗅觉学习和记忆的细胞和神经回路基质。这很重要，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的理解产生了强烈影响。