Synaptic and circuit mechanisms of hippocampal place-cell sequences

海马位置细胞序列的突触和回路机制

• 批准号: 8926470
• 负责人: David J Foster
• 金额: $ 40.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8926470
• 关键词: Affect; Alzheimer' s Disease; Animals; Attention; Autistic Disorder; Automobile Driving; Back; Behavior; Behavioral; Brain; Cells; Complex; Data; Dependence; Disease; Environment; Epilepsy; Episodic memory; Event; Exhibits; Fostering; Future; Generations; Genetic; Goals; Health; Hippocampus (Brain); Imagination; Learning; Light; Link; Location; Mediating; Memory; Modeling; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nature; Neurons; Neurosciences; Pattern; Pharmaceutical Preparations; Phase; Population; Proton Pump; Rattus; Receptor Activation; Reporting; Rest; Retrieval; Role; Running; Schizophrenia; Shapes; Signal Transduction; Sleep; Stroke; Synaptic plasticity; System; Testing; Thinking; Time; Viral; Work; awake; base; brain cell; density; entorhinal cortex; experience; follow-up; insight; interest; memory encoding; memory process; memory retrieval; neural circuit; normal aging; novel; optogenetics; place fields; relating to nervous system; research study; response; spatial memory; two-dimensional

DESCRIPTION (provided by applicant): We aim to study how neural activity at the level of single unit responses in the hippocampus mediates the known roles of synaptic plasticity and hippocampal neural circuitry in learning and memory. In particular, we are interested in the synaptic plasticity and circuit mechanisms responsible for the activation of hippocampal units in the rat in precise sequences that depict past and future behavioral trajectories. (1) Pioneering work has established that place field responses can reflect multiple aspects of memory and exhibit a complex dependence upon mechanisms of synaptic plasticity, and yet experience-dependent changes to place fields tend to be rather subtle and challenging to detect. In contrast, trajectory-specific place-cell sequences can be detected after very little experience. We will examine the dependence of this possible learning effect on mechanisms associated with synaptic plasticity, with particular attention to the interesting counter-hypothesis that the sequences may exist prior to experience. Preliminary data show that synaptic plasticity is required during experience in order to encode replay memory, whereas the generation of replay per se does not require synaptic plasticity if the underlying memories have already been formed. We will pursue these experiments to understand how multiple mechanisms of synaptic plasticity shape place-cell sequences. (2) A central role for CA3 in the generation of replay is a longstanding but untested prediction. Previous studies using genetic silencing of CA3 input found preserved ripple patterns in CA1, but these studies may have allowed compensatory effects due to the long time course of suppression. We will pursue an optogenetic approach for instantaneous suppression. Preliminary data show that ripples and ripple-associated spiking are in fact dependent upon CA3 input to the locally recorded CA1 region. We will also online decode replay sequences in real-time, to selectively disrupt sequences and also sequence subcomponents. We will dissect the contribution of CA3 to replay initiation, direction, propagation and termination. (3) During the theta exploratory state, CA1 units are driven by two major inputs: CA3 and entorhinal cortex (EC), which recent reports show may interact in complex ways, both within and across different theta cycles. These hypothesized interactions have not been tested directly, and so we will utilize our optogenetic approach to examine CA1 unit activity during this state. Preliminary data show that in contrast to ripples, CA1 spiking is only partially reduced when CA3 input is suppressed during theta, unmasking the EC contribution. We will examine place fields, phase precession, theta sequences, and the synchronization of CA1 low/high gamma with CA3/EC, either with or without CA3 input. Taken together, these specific aims represent a unique approach that utilizes the power of ultra-high density unit recording together with pharmacological and optogenetic manipulation, to deliver insights into the neural basis of learning and memory. Our results will have a major impact on understanding those diseases that impair hippocampal learning and memory such as Alzheimer's disease, epilepsy, stroke and normal aging.

描述（由申请人提供）：我们的目标是研究海马中单个单元反应水平的神经活动如何介导突触可塑性和海马神经回路在学习和记忆中的已知作用。我们特别感兴趣的是负责以描绘过去和未来行为轨迹的精确序列激活大鼠海马单位的突触可塑性和电路机制。 (1) 开创性的工作已经确定，地点场反应可以反映记忆的多个方面，并表现出对突触可塑性机制的复杂依赖，然而，地点场的依赖于经验的变化往往相当微妙且难以检测。相比之下，只需很少的经验就可以检测到特定于轨迹的位置单元序列。我们将研究这种可能的学习效应对突触可塑性相关机制的依赖性，特别关注有趣的反假设，即序列可能先于经验而存在。初步数据表明，在体验过程中需要突触可塑性来编码重放记忆，而如果底层记忆已经形成，则重放本身的生成不需要突触可塑性。我们将进行这些实验，以了解突触可塑性的多种机制如何塑造位置细胞序列。 (2) CA3 在重放生成中的核心作用是一个长期存在但未经检验的预测。先前使用 CA3 输入基因沉默的研究发现 CA1 中保留了波纹模式，但这些研究可能由于长时间的抑制而产生了补偿效应。我们将采用光遗传学方法进行瞬时抑制。初步数据表明，纹波和纹波相关尖峰实际上取决于 CA3 输入到本地记录的 CA1 区域。我们还将实时在线解码重播序列，以选择性地破坏序列并对子组件进行排序。我们将剖析 CA3 对重放启动、方向、传播和终止的贡献。 (3) 在 θ 探索状态期间，CA1 单元由两个主要输入驱动：CA3 和内嗅皮层 (EC)，最近的报告显示，这两个输入可能在不同 θ 周期内和跨不同 θ 周期以复杂的方式相互作用。这些假设的相互作用尚未经过直接测试，因此我们将利用我们的光遗传学方法来检查该状态下 CA1 单元的活性。初步数据显示，与波纹相比，当 CA3 输入在 theta 期间被抑制时，CA1 尖峰仅部分减少，从而揭示了 EC 的贡献。我们将检查位置场、相位进动、theta 序列以及 CA1 低/高伽马与 CA3/EC 的同步（无论有或没有 CA3 输入）。总而言之，这些具体目标代表了一种独特的方法，利用超高密度单元记录的力量以及药理学和光遗传学操作，来深入了解学习和记忆的神经基础。我们的研究结果将对了解那些损害海马学习和记忆的疾病（如阿尔茨海默病、癫痫、中风和正常衰老）产生重大影响。