Hippocampo-cortical circuit mechanisms of neuronal sequences during learning

项目摘要 这个项目的目标是了解神经元序列协调的电路机制， 海马体和新皮层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演行为。这些 重新激活是由同步网络事件协调的，这些事件被称为尖波波纹（SWR）， 海马体并传播到新皮层。已经提出，SWRs和相关的神经元序列介导 记忆巩固，计划和学习，但这些功能的直接证明仍然缺乏。此外，一些脑 以学习和记忆缺陷为特征的疾病与破坏的SWR有关。引导行为， 决策，新皮层被认为是概括在海马体编码的个人经验，以推断 环境保护和规则。SWRs引起新皮层活动，但下游皮层区域如何读出 海马代码在SWR期间传输，并使用此信息来指导目标导向行为是未知的。 我将在海马体及其主要皮层进行硅探针记录和光遗传学操作 行为大鼠和小鼠的靶区域，以测试在 目标导向行为的不同阶段。首先，我将使用一种新的光遗传学方法来闭环操纵 SWR直接测试SWR关联序列是否支持记忆引导行为。我的初步数据 支持这样的假设，即随着存储器需求的增加，SWR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的导航和空间学习是必要的和足够的。第二、 我将在目标导向的空间行为的背景下，研究SWRs对下游皮层目标的影响。我会 测试是否有一个特定的功能地形的海马-皮质相互作用，与背侧和腹侧海马 SWRs优先传播到压后和前额皮质。我假设大脑皮层 随着学习的进行，SWR过程中的同步性将逐渐增加，这一过程可能导致抽象的产生。 大脑皮层中的表征或模式，这些表征或模式将有助于未来的决策。最后，我将测试是否与SWR相关 皮质序列是局部产生的或从海马继承的，以及不同类别的中间神经元是如何 贡献给他们。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不同的细胞亚型。 通过使用创新的实验方法，该项目将为电路提供新的见解 神经元序列参与学习和记忆的机制和行为作用。这些知识也将 光到记忆缺陷的神经系统疾病，如阿尔茨海默病，精神分裂症和 智力残疾。它还可能为这些疾病的更具针对性的闭环干预开辟新途径。 在本项目培训期间培养的科学技能对于完成 我认为，这是一个直接的科学目标，并成为我未来独立实验室研究的支柱。

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.