How does activity of CA3 engram neurons affect CA1 spatial codes?

海马锥体神经元可以通过局部的放电模式或定位细胞来编码动物的空间位置。对人类和动物的研究表明，海马体在空间和情景记忆中起着关键作用。在很大程度上，人们认为长期空间记忆是由细胞集合产生的，这些细胞在与长期记忆相关的一段时间内保持其空间编码特性。然而，最近，在海马体中表现出了令人惊讶的不稳定程度。事实上，海马区的空间表征既有动态方面，也有稳定方面。在啮齿动物中，代表环境的一组海马细胞每天都有更替，这可能有助于区分不同访问的代表。然而，单独的CA1神经位置场可以表现出长期的稳定性。总体而言，支持海马区表征翻转和稳定性的机制是完全未知的。经历协调活动依赖可塑性的神经元集合不仅代表经验，而且具有学习和记忆回忆的功能，因此很大程度上被认为是细胞记忆印记。印迹神经元的活动在系统记忆巩固中起着关键作用。由于海马区的表征被认为支持记忆的形成和巩固，印记神经元对这些表征的动力学也应该是重要的。尽管如此，这个问题在很大程度上还没有得到探索，主要是因为技术上的困难。在这个项目中，我们建议结合我们实验室的互补专业知识来研究导致海马CA1区表征的周转和特异性的系统机制。具体地说，我们将研究CA3印记神经元的活动如何影响CA1空间表征的周转、特异性和方向性。为了实现这些目标，我们将利用我们实验室的尖端技术和分析框架。我们将结合广场头安装显微镜-记录小鼠探索不同环境时CA1区的神经元活动-与光遗传学-控制CA3印记神经元的活动-并使用先进的分析工具来研究强制重新激活CA3印记神经元对CA1神经元活动模式的影响。

Hippocampal pyramidal neurons can encode the spatial location of an animal through localized firing patterns, or place cells. Studies on humans and animals have shown a critical role for the hippocampus in spatial and episodic memory. It is largely thought that long-term spatial memory arises from ensembles of cells that retain their spatial coding properties over time periods relevant to long-term memory. Recently, however, a surprising level of instability has been demonstrated in the hippocampus. In fact, hippocampal spatial representations have both dynamic and stable facets. In rodents, there is day-to-day turnover in the set of hippocampal cells representing environments, which might help distinguish the representations of the different visits. However, individual CA1 neural place fields can exhibit long-term stability. Overall, the mechanisms supporting turnover versus stability of hippocampal representations are completely unknown.Ensembles of neurons undergoing coordinated activity-dependent plasticity not only represent experience but are also functional for learning and memory recall, thus they are largely believed to be cellular memory engrams. The activity of engram neurons has a key role in systems memory consolidation. As hippocampal representations are postulated to support memory formation and consolidation, engram neurons should also be important for the dynamics of these representations. Still, this issue is largely unexplored mostly owing to technical difficulties. In this project we propose to combine the complementary expertise of our laboratories to investigate the systems mechanisms that lead to turnover and specificity of representations in hippocampal CA1. Specifically, we will investigate how activity of CA3 engram neurons affects turnover, specificity and directionality of CA1 spatial representations. To achieve these aims we will take advantage of our laboratories’ cutting-edge technologies and analysis frameworks. We will combine Wide Field Head Mounted microscopes - to record neuronal activity in the CA1 of mice as they explore different environments - with optogenetics - to control the activity of CA3 engram neurons – and used advanced analysis tools to investigate the effects of forced re-activation of CA3 engram neurons on activity patters of CA1 neurons.