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

项目摘要 情景记忆描述了我们将时间上连续的元素编织成回忆的能力， 丰富而连贯的经验。情景记忆的形成是由退行性 如阿尔茨海默氏病。颞叶内侧的“时间细胞”活动可能 提供了一种机制，用于编码时间信息，这是必要的，为形成这些 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。这些细胞的尖峰速率可靠地增加， 固定间隔内的特定时刻，并且时间单元的组（集合）可以表示“时间”。 空间“类似于海马定位细胞被保持以代表物理空间的方式， 在事件表示上强加时间组织。在本提案中，我们建立在初步的 数据来研究神经元组装中时间细胞的灵活参与， 方法.我们将通过在两个模型之间进行判断来测试时间单元如何支持串行存储器， 基于时间单元活动（“时间单元模型”）与不同的拟议机制， 回忆依赖于海马神经元相对于θ波发放的一致相位偏移 振荡（“相位偏移模型”）。这个实验将测试关键的未解决的问题， 细胞有助于情景记忆。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。这项新的实验建立在我们在我们的研究中提出的初步数据的基础上。 该提案显示东莨菪碱给药对10名颅内EEG受试者的影响， 在胆碱能阻滞的情况下，确定海马θ和γ振荡的改变。 我们的实验包括一些关键的创新，包括检查时间细胞活动在连续 回忆，组装形成，特别是在胆碱能神经支配的调节设置。的 我们计划收集的数据将填补与人类时间细胞活动相关的理解方面的关键空白， 潜在地在人类颅内EEG受试者中建立胆碱能调节，作为阐明 生理模式在记忆处理，并模拟疾病的影响， 老年痴呆症在这个人群中。

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.