Linking hippocampal plasticity to mental health: Sharp/wave ripple related replay

描述(申请人提供)：对经历和环境的记忆进行编码和回忆的能力允许通过随后的行为变化来适应世界。在哺乳动物中，海马体被认为是参与学习，特别是情节记忆的神经回路的关键组成部分。海马体负责整合记忆的编码、存储和回忆，将构成经验的时空信息和感觉信息绑定在一起。在探索过程中，海马区CA1区的初级兴奋性神经元，即锥体细胞，以显著的空间精确度发出信号。这一现象导致这些细胞被称为Place细胞。当动物在积极探索时，当动物穿过神经元相应的空间场时，放置细胞就会被激发。最耐人寻味的是一种被称为重播的现象，即放置单元在时间上被压缩，但在空间上是保守的顺序。重播发生在被称为涟漪的高频事件中，在积极探索之后，睡眠和安静的清醒都会发生4-6。涟漪干扰导致空间学习减少，进一步支持涟漪事件、重播和学习之间的关联。这些研究支持了这样一种假设，即重演与空间学习有关，而不仅仅是空间学习的副产品。我们的初步数据和发表的报告表明，海马区的突触可塑性可能调节SWR事件，并可能重演，可能在异常可塑性和空间学习缺陷之间提供联系。此外，许多精神障碍的小鼠模型存在海马区突触可塑性异常和空间学习障碍。我们有几个不同的小鼠模型的初步数据，这些数据显示了它们的SWR事件的变化，支持了SWR事件是连接可塑性和学习的电路水平基序的假设。这一建议试图刻画高频涟漪事件和海马区重播之间的关系，将我们对这一现象的理解与突触可塑性联系起来，并开始了解其在疾病中的作用。实验1.建立SWR事件与重放之间的明确关系，2.系统研究突触可塑性变化对SWR事件的影响，3.开始将这些变化与神经系统疾病联系起来。具体地说，我们将研究精神分裂症的小鼠模型。这种小鼠之前已经被证明有工作记忆障碍，并表现出与人类疾病有关的表型。这里概述的研究计划是一种新的方法，将允许前所未有的了解突触可塑性在调节神经回路和最终行为方面的作用。这项研究有可能发现新的学习机制，并在研究小鼠疾病模型中神经回路被破坏的方式方面证明是有用的。

DESCRIPTION (provided by applicant): The ability to encode and recall memories of experiences and environments allows adaptation to the world through subsequent behavioral change. In mammals, the hippocampus is known to be a key component of the neural circuitry involved in learning, particularly episodic memory. The hippocampus is responsible for integrating the encoding, storage and recall of memories, binding the spatio-temporal and sensory information that constitutes experience. Primary excitatory neurons of the CA1 region of the hippocampus, the pyramidal cells, fire with remarkable spatial precision during exploration. This phenomenon has led these cells to be known as place cells. When an animal is actively exploring, place cells fire as the animal passes through a neurons' corresponding spatial field. Most intriguing is a phenomena known as replay, where place cells fire in a temporally compressed, but spatially conserved order. Replay occurs during high frequency events, known as ripples, which take place in both sleep and quiet wake after active exploration4-6. Ripple disruption leads to reduced spatial learning, further supporting the association between ripple events, replay and learning. These studies provide support for the hypothesis that replay is involved in and is not simply a byproduct of spatial learning. Our preliminary data together with published reports suggest that synaptic plasticity in the hippocampus may be tuning SWR events, and likely replay, potentially providing the link between aberrant plasticity and spatial learning defects. Furthermore, many mouse models of mental disorders have abnormal hippocampal synaptic plasticity and impaired spatial learning. We have preliminary data from several distinct mouse models that show changes to their SWR events supporting the hypothesis that SWR events are a circuit level motif connecting plasticity to learning. This proposal seeks to characterize the relationship between high frequency ripple events and hippocampal replay, to connect our understanding of this phenomenon to synaptic plasticity and begin to understand its role in disease. The experiments outlined in this proposal 1. Establish a clear relationship between SWR events and replay, 2. Systematically study the effects of synaptic plasticity changes on SWR events, and 3. Begin to relate these changes to neurological disease. Specifically, we will be examining a mouse model of schizophrenia. This mouse has been previously shown to have working memory impairments and show phenotypes relatable to the human disorder. The research plan outlined here is a novel approach that will allow an unprecedented understanding of the role of synaptic plasticity on regulating neural circuits and ultimately behavior. This research has the potential to uncover new mechanisms of learning and should prove informative in studying the way in which neural circuits are disrupted in mouse models of disease.