Deconstructing neural circuits underlying olfactory episodic memory

概念：我以前在哪里，什么时候闻到过苹果派的味道？探测环境中的化学信号和记住独特嗅觉事件的要素的能力，对于理解现在、形成对未来的预测以及为生存和繁殖选择行为至关重要。例如，动物利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是如何检测和处理特定的气味来感知气味的。然而，我们的大脑是如何形成关于独特嗅觉事件的详细背景信息的记忆的，这一点尚不清楚。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，由海马体和嗅觉皮层之间的硬连线连接和嗅觉记忆的上下文元素的强大行为读出组成。在本提案中，我们使用这个系统来研究嗅觉情景记忆的神经机制。

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.