Behavioral and pharmacological manipulation of time cell activity in the human mesial temporal lobe

项目摘要 情节记忆描述了我们将时间上连续的元素编织成对 丰富而连贯的体验。情景记忆的形成是通过退化而特别退化的 阿尔茨海默氏症等疾病。内侧颞叶的“时间细胞”的活动可能 提供了一种对时间信息进行编码的机制，这是形成这些信息所必需的 记忆，我们最近发表了人类海马体中时间细胞的证据 癫痫患者的微电极记录。这些细胞的尖峰率在 固定间隔内的特定时刻和时间单元组(集合)可以表示时间 空间‘类似于海马区细胞代表物理空间的方式， 对事件表示施加时间组织。在这份提案中，我们建立在初步的基础上 使用ESTABLISE研究时间细胞在神经元组装中灵活参与的数据 方法：研究方法。我们将通过在两个模型之间进行判决来测试时间单元如何支持串行存储器，一个 基于时间单元活动(“时间单元模型”)与一种不同的建议机制进行比较 回忆依赖于海马神经元尖峰放电相对于theta的一致相位偏移 振荡(“相位偏移模型”)。这项实验将测试关键的悬而未决的问题，即时间如何 细胞对情节记忆有贡献。最后，我们将测试胆碱能阻滞对时间的影响 电池和电池组件。这项新颖的实验建立在我们在我们的 对10名脑电受试者使用东莨菪碱的效果的建议， 确定在胆碱能阻滞剂的环境下，海马theta和Gamma振荡的变化。 我们的实验包括一些关键的创新，包括检查序列中的时间细胞活动 回忆、组装形成，尤其是在胆碱能神经支配的调节设置中。这个 我们建议收集的数据将填补与人类时间细胞活动相关的理解的关键空白 潜在地在人类颅内脑电受试者中建立胆碱能调制作为阐明 记忆过程中的生理模式，并模拟疾病的影响，如 阿尔茨海默氏症在这个人群中。

Project Summary Episodic memory describes our ability to weave temporally contiguous elements into recollections of rich and coherent experiences. Episodic memory formation is specifically degraded by degenerative conditions such as Alzheimer’s Disease. The activity of ‘time cells’ in the mesial temporal lobe may provide a mechanism for the coding of temporal information that is necessary for the formation of these memories, and we recently published evidence of time cells in the human hippocampus using microelectrode recordings from epilepsy patients. The spike rate of these cells reliably increases at specific moments within a fixed interval, and groups (assemblies) of time cells can represent a ‘temporal space’ analogous to the manner in which hippocampal place cells are held to represent physical space, imposing temporal organization on event representations. In this proposal, we build on preliminary data to investigate the flexible participation of time cells in neuronal assemblies using established methods. We will test how time cells support serial memory by adjudicating between two models, one based on time cell activity (`time cell model’) versus a different proposed mechanism by which serial recall depends on the consistent phase offset of the spiking of hippocampal neurons relative to theta oscillations (‘phase offset model’). This experiment will test key unresolved questions about how time cells contribute to episodic memory. Finally, we will test the impact of cholinergic blockade on time cells and cell assemblies. This novel experiment builds on the preliminary data we present in our proposal showing the effects of scopolamine administration in 10 intracranial EEG subjects, which identify alterations in hippocampal theta and gamma oscillations in the setting of cholinergic blockade. Our experiments include a number of key innovations, including examining time cell activity during serial recall, assembly formation, and especially in the setting of modulation of cholinergic innervation. The data we propose to collect will fill key gaps in understanding related to time cell activity in humans and potentially establish cholinergic modulation in human intracranial EEG subjects as a method to elucidate physiological patterns during mnemonic processing and to model the effects of disorders such as Alzheimer’s Disease in this population.