Hippocampo-cortical circuit mechanisms of neuronal sequences during learning

项目概要 该项目的目标是了解跨神经元序列协调的电路机制 海马体和新皮质及其在学习和记忆中的作用。参与最近经历的细胞是 以有序序列的形式重新激活，以时间压缩的方式重述行为。这些 重新激活是由同步网络事件（称为尖波纹波（SWR））协调的，这些同步网络事件起源于 海马体并传播到新皮质。有人提出 SWR 和相关神经元序列介导 记忆巩固、计划和学习，但仍然缺乏这些功能的直接证明。另外，几个大脑 以学习和记忆缺陷为特征的疾病与 SWR 紊乱有关。指导行为和 决策时，新皮质被认为可以概括海马体中编码的个人经验来推断 环境规律和规则。 SWR 带动新皮质活动，但下游皮质区域如何读出 在 SWR 期间传输的海马代码并使用此信息来指导目标导向的行为尚不清楚。 我将在海马体及其主要皮质中进行硅探针记录和光遗传学操作 行为大鼠和小鼠的目标区域，以测试 SWR 序列在 目标导向行为的不同阶段。首先，我将使用一种新颖的光遗传学方法来闭环操作 SWR 直接测试 SWR 关联序列是否支持内存引导行为。我的初步数据 支持这样的假设：SWR 随着内存需求的增加而变得更长，从而允许延长重放事件， 这些延长的序列对于记忆引导导航和空间学习来说是必要且充分的。第二， 我将在目标导向的空间行为的背景下研究 SWR 对下游皮质目标的影响。我会 测试海马-皮质相互作用是否存在特定的功能拓扑，包括背侧和腹侧海马 SWR 优先传播到压后皮质和前额叶皮质。我假设海马皮质 SWR 期间的同步性将随着学习而逐渐增加，并且这个过程可能导致抽象的生成 大脑皮层中的表征或模式将有助于未来的决策。最后我会测试是否与SWR相关 皮质序列是本地生成的或从海马体继承的，以及不同类别的中间神经元如何 为他们做出贡献。为了实现这一目标，我将记录并光遗传学操纵转基因小鼠中的不同细胞亚型。 通过使用创新的实验方法，拟议的项目将为电路提供新颖的见解 参与学习和记忆的神经元序列的机制和行为作用。这些知识也会流失 深入了解阿尔茨海默病、精神分裂症等神经疾病中记忆缺陷的机制 智力障碍。它还可能为对这些疾病进行更有针对性的闭环干预开辟新途径。 在该项目培训期间培养的科学技能对于实现这一目标至关重要 近期的科学目标，并成为我未来独立实验室开展研究的支柱。

PROJECT SUMMARY The goal of this project is to understand the circuit mechanisms underlying neuronal sequence coordination across hippocampus and neocortex and their role in learning and memory. Cells that participated in a recent experience are reactivated in the form of ordered sequences that recapitulate behavior in a temporally compressed manner. These reactivations are coordinated by synchronous network events known as sharp-wave ripples (SWRs) that originate in the hippocampus and propagate to the neocortex. It has been proposed that SWRs and associated neuronal sequences mediate memory consolidation, planning and learning but a direct proof of these functions is still lacking. Additionally, several brain disorders characterized by learning and memory deficits have been related to disrupted SWRs. To guide behavior and decision making, the neocortex is believed to generalize across individual experiences encoded in the hippocampus to infer environmental regularities and rules. SWRs entrain neocortical activity, but how downstream cortical areas read out the hippocampal code transmitted during SWRs and use this information to guide goal-oriented behavior is unknown. I will perform silicon probe recordings and optogenetic manipulations in the hippocampus and its main cortical target regions of behaving rats and mice to test the functional role and circuit mechanisms of SWR sequences during the different phases of goal-oriented behavior. First, I will use a novel optogenetic approach for closed-loop manipulation of SWRs to directly test whether SWRs associated sequences support memory-guided behavior. My preliminary data supports the hypothesis that SWRs became longer with increased memory demands thus allowing extended replay events, and that those prolonged sequences are necessary and sufficient for memory-guided navigation and spatial learning. Second, I will examine the impact of SWRs on downstream cortical targets, in the context of goal-oriented spatial behavior. I will test if there is a specific functional topography of hippocampo-cortical interactions, with dorsal and ventral hippocampal SWRs propagating preferentially to retrosplenial and prefrontal cortices. I hypothesized that hippocampo –cortical synchrony during SWRs will gradually increase with learning and that this process could lead to the generation of abstract representations, or schemas, in the cortex that will facilitate future decisions. Finally, I will test whether SWR-associated cortical sequences are locally generated or inherited from the hippocampus and how different classes of interneurons contribute to them. To achieve this, I will record and optogenetically manipulate different cell sub-types in transgenic mice. By using an innovative experimental approach, the proposed project will provide novel insights into the circuit mechanisms and behavioral role of neuronal sequences involved in learning and memory. This knowledge will also shed light into the mechanisms underlying memory deficits in neural disorders such as Alzheimer disease, schizophrenia and intellectual disability. It may also open new avenues for more targeted, closed-loop interventions in these disorders. The scientific skills developed during the training period of this project will be crucial for the accomplishment of the immediate scientific goals and become the pillars for the research I will develop in my future independent laboratory.