Deconstructing neural circuits underlying olfactory episodic memory

概念：我在哪里、什么时候闻到了苹果派的味道？探测环境中的化学信号和记住独特嗅觉事件的元素的能力对于理解现在、形成对未来的预测以及选择生存和繁殖的行为至关重要。例如，动物使用嗅觉和嗅觉记忆来定位捕食者、食物、社会等级、交配伙伴和照顾者。几十年的研究揭示了嗅觉系统如何检测和处理特定的气味来感知气味。然而，我们的大脑如何形成关于独特嗅觉事件的详细背景信息的记忆仍是未知的。为了解决这一知识差距，我们开创了一个嗅觉情景记忆的模型系统，由海马体和嗅觉皮质之间的硬连线连接组成，并对嗅觉记忆的上下文元素进行稳健的行为读出。在目前的方案中，我们使用这个系统来研究嗅觉情景记忆的神经机制。 目的：为了在电路水平上了解嗅觉记忆是如何在大脑中形成和表达的，我们结合了解剖学示踪、活动依赖细胞标记以及活体脑成像和操作。通过结合上述方法的初步发现，我们最近发现，来自海马体的神经信号在嗅皮层内进行空间组织，以承载不同的嗅觉记忆的空间和时间背景。作为NSERC的一项为期五年的提案，我们将专注于了解嗅觉事件是如何由嗅觉皮质中的特定细胞代表的，并证明它们的活动可以被操纵来改变记忆。接下来，我们将扩展我们的发现，以研究嗅觉皮质的活动如何随着时间的推移而演变，以忠实地概括嗅觉记忆。 我们的具体短期目标是： 研究1.我们将使用TRAP方法识别以前嗅核(AON)为代表的嗅觉记忆痕迹。 研究2：我们将利用光基因操作来确定AON在嗅觉记忆中的因果作用。 研究3.我们将通过钙成像演示如何在AON内形成和稳定一种独特的嗅觉记忆痕迹，并在记忆回忆过程中通过钙成像重新激活。 意义：大量的人脑成像研究表明，在回忆嗅觉发作的过程中，嗅觉区域被重新激活。然而，潜在的神经机制仍不清楚。该研究计划将首次证明Aon是嗅觉情景记忆的仓库，并为情景气味记忆的形成和回忆的普遍机制提供了新的见解。鉴于其新颖性和预期的概念进步，我们预计拟议的研究将引起自然科学和工程领域的许多领域的极大兴趣。

Concept: Where and when did I smell that apple pie before? Ability to detect chemical signals in the environment and remember elements of a unique olfactory event is essential for making sense of the present, forming predictions about the future, and the selection of behaviours for survival and reproduction. For example, animals use olfaction and olfactory memory to locate predators, foods, social hierarchy, mating partners, and caregivers. Decades of research have revealed how specific odours are detected and processed by the olfactory system to perceive odours. However, it remains unknown how our brain forms a memory of detailed contextual information about unique olfactory events. To address this knowledge gap, we have pioneered a model system for olfactory episodic memory, constituted by a hard-wired connectivity between the hippocampus and the olfactory cortex, and a robust behavioural readout of contextual elements of olfactory memory. In the present proposal, we use this system to study a neural mechanism underlying olfactory episodic memory. Objectives: To understand how olfactory memory is formed and expressed in brain at circuit level, we use a combination of anatomical tracing, activity-dependent cell labeling, and live brain imaging and manipulation. By combining the preliminary findings of the above approaches, we have recently discovered that neural signals from hippocampus are spatially organized within the olfactory cortex to carry distinct spatial and temporal context of olfactory memory. As a five year NSERC proposal, we will focus on understanding how olfactory events are represented by specific cells within the olfactory cortex and demonstrate that their activity can be manipulated to alter the memory. Next, we will expand our findings to investigate how the activity of olfactory cortex evolves over time to faithfully recapitulate olfactory memory. Our specific short-term objectives are: Study 1. We will identify the olfactory memory trace that is represented by the anterior olfactory nucleus (AON) using the TRAP approach. Study 2. We will determine a causal contribution of the AON in olfactory memory using optogenetic manipulation. Study 3. We will demonstrate how a unique olfactory memory trace is formed and stabilized within the AON, and later reactivated during memory recall in a hippocampus-dependent manner using calcium imaging. Significance: Numerous human brain imaging studies have shown that olfactory areas are reactivated during recollection of olfactory episodes. However, the underlying neural mechanism remains unknown. The proposed research program will demonstrate for the first time that the AON is the storehouse of olfactory episodic memory, and provide a novel insight into the universal mechanism of episodic odour memory formation and recall. Given its novelty and the expected conceptual advance, we expect the proposed research to be of great interest to many fields in the natural sciences and engineering.