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.

项目总结/摘要 学习和记忆是大脑的基本功能，但它们的细胞和神经回路 机制仍然知之甚少。气味记忆在人类和动物中非常强大， 对生存和繁殖具有突出的重要性，并且非常容易患神经退行性疾病 包括老年痴呆症嗅觉（梨状）皮层，气味感知被认为是第一次出现， 一直被认为是气味记忆的编码。然而，细胞基质和电路机制 嗅觉学习是未知的。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。本提案的目的是提供一种机制， 气味记忆是如何编码和表达的细胞/分子理解。为实现这一目标 我们已经在小鼠中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 气味激活了稀疏的、分布的、功能多样的梨状神经元， 足够嗅觉学习和记忆。目的1：确定如何操纵的活动， 气味记忆跟踪细胞改变行为。我们将使用基于cFos启动子活性的遗传标记（“Fos-1”）。 标记”）来可视化和操纵在嗅觉期间被激活的梨状神经元的活动 学习我们的初步数据提供了强有力的证据，证明了Fos标记的梨状神经丛对于 气味恐惧记忆回忆。目的2：确定学习如何改变气味反应特性， 梨状集合体我们将在清醒、行为和睡眠状态下对气味诱发的活动进行慢性双光子成像。 小鼠，之前，期间和之后厌恶和食欲嗅觉条件反射。我们还将有选择地分析 Fos标记的梨状神经元的反应特性，这对恐惧气味记忆回忆至关重要。我们将 测试嗅觉学习选择性增强刺激检测编码的假设， 嗅觉记忆痕迹的神经元的辨别能力。目的3：确定 嗅觉记忆痕迹细胞的同一性和连通性。为了驱动行为，梨状神经丛必须 将气味信息传递到下游目标区域。使用我们先前鉴定的标记基因组， 单细胞转录组学，我们将确定激活的梨状神经元的分子身份， 我们将追踪它们的轴突投射。我们将检验嗅觉学习 促进梨状皮质与任务相关目标区域的功能连接。这个项目是创新的 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。这是重要的，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的影响。