Hippocampo-cortical circuit mechanisms of neuronal sequences during learning

项目总结 这个项目的目标是了解神经序列协调的潜在电路机制。 海马体和新皮质及其在学习和记忆中的作用。参与最近一次体验的细胞是 以有序序列的形式重新激活，这些有序序列以时间压缩的方式重述行为。这些 重新激活由称为尖波波动(SWR)的同步网络事件协调，这些事件源自 海马体并传播到新皮质。已有研究提出，SWRs和相关的神经元序列在 记忆巩固、计划和学习，但仍缺乏对这些功能的直接证明。此外，还有几个大脑 以学习和记忆障碍为特征的疾病与SWR中断有关。引导人们的行为， 决策，新大脑皮层被认为是通过在海马体中编码的个人经验来概括以进行推断 环境规章制度。SWR牵涉新皮质活动，但下游皮质区域如何读出 在SWRS过程中传递的海马区代码以及使用该信息来指导目标导向行为尚不清楚。 我将在海马体及其主要皮质进行硅探针记录和光遗传操作 以大鼠和小鼠的行为靶区为靶区，测试SWR序列在大、中、小鼠行为中的功能作用和电路机制 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进行闭环操作 SWR来直接测试SWR关联的序列是否支持内存引导行为。我的初步数据 支持SWR随着内存需求的增加而变长从而允许延长重放事件的假设， 这些延长的序列对于记忆引导导航和空间学习是必要的，也是充分的。第二, 我将在以目标为导向的空间行为的背景下，研究SWR对下游皮质目标的影响。这就做 测试与背侧和腹侧的海马-皮质相互作用是否有特定的功能地形图 SWRs优先向脾后皮质和前额叶皮质扩散。我假设海马区皮质 SWR期间的同步性将随着学习而逐渐增加，这一过程可能会导致生成摘要 大脑皮层中的表征或图式，这将有助于未来的决策。最后，我将测试SWR是否与 皮质序列是局部产生的或继承自海马体，以及不同类别的中间神经元是如何 为他们做贡献。为了实现这一点，我将记录并光遗传操作转基因小鼠中的不同细胞亚型。 通过使用一种创新的实验方法，拟议的项目将为电路提供新的见解 参与学习和记忆的神经元序列的机制和行为作用。这一知识也将被抛弃 揭示阿尔茨海默病、精神分裂症和精神分裂症等神经疾病记忆缺陷的潜在机制 智力残疾。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的途径。 在本项目培训期间培养的科学技能将对实现 目前的科学目标，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.