Dependence of memory on precisely coordinated oscillations

项目摘要 健康的认知过程与明确的脑震荡有关，这不仅是一个迹象， 不仅是大脑区域内神经元活动的精确计时， 大脑区域之间的模式。与这一概念相一致，至少在一个周期中振荡活动的某些方面， 在任何主要的精神和神经疾病中，大脑区域的一个子集都受到破坏。然而，在这方面， 振荡中断和行为受损之间存在因果关系的证据仍然存在 稀疏。特别是，在不影响大脑回路的情况下操纵大脑回路内的时间一直是一个挑战。 同时破坏神经元群体的其他放电统计，例如它们的放电， 稀疏性或发射率。初步数据表明，光遗传节律刺激 内侧隔PV神经元的频率高于内源性θ频率（≥ 10 Hz） 改变海马发放时间，但不改变其他发放统计数据，如空间发放模式， 发射率和θ相位进动。此外，我们发现8 Hz的刺激对 记忆性能，而在≥10 Hz的刺激导致记忆障碍，这是相当的， 严重到完全海马损伤。因此我们假设， 的神经元活动导致的神经元网络之间的协调的损失， 海马体、内侧内嗅皮层和内侧前额叶皮层，使得这些大脑 区域不再支持空间工作记忆。我们将实现三个目标来解决这个问题 假说. (1)确定记忆缺陷出现的最小时间偏移，并测量 海马神经活动的协调，同时在有和没有记忆缺陷的频率刺激。 (2)确定θ频率的操作是否严重改变了 内侧内嗅皮层（mEC）。(3)确定内源性内的振荡是否 θ频率范围是海马和内侧海马之间协调所必需的 前额叶皮层（mPFC）。在这三个目标中，我们将执行LFP和单个单元记录， 小鼠执行空间交替任务。将比较任务的两个版本，延迟版本是 依赖于海马和前额叶功能，以及连续版本，其被包括作为对照。 当小鼠执行任务时，内侧隔区将以不会导致 或者受到导致记忆缺陷的频率刺激。这些条件将是 比较，以确定过渡期海马、mEC和mPFC神经活动的关键变化， 记忆受损总之，在行为任务中， 将为精确计时和记忆功能之间的因果关系以及 协调大脑区域之间信息交换的振荡。

Project Summary Healthy cognitive processing is associated with well-defined brain oscillations, which are not only an indication of accurate timing of neuronal activity within brain regions, but also of the coordination of neural activity patterns between brain regions. Consistent with this notion, some aspects of oscillatory activity in at least a subset of brain regions are disrupted in any of the major psychiatric and neurological diseases. However, evidence for a causal link between disrupted oscillations and impaired behavior has remained sparse. In particular, it has been challenging to manipulate timing within brain circuits without simultaneously disrupting other firing statistics of neuronal populations, such as their firing sparsity or firing rate. Preliminary data are presented which indicate that optogenetic rhythmic stimulation of medial septal PV neurons at frequencies that are higher than the endogenous theta frequency (≥ 10 Hz) alters hippocampal spike timing, but without changing other firing statistics, such as spatial firing patterns, firing rate, and theta phase precession. Furthermore, we found that stimulation at 8 Hz was without effect on memory performance while stimulation at ≥10 Hz resulted in a memory impairment that was comparable in its severity to a complete hippocampal lesion. We therefore hypothesize that minor shifts in the timing of neuronal activity result in a loss of coordination between neuronal networks in the hippocampus, medial entorhinal cortex, and medial prefrontal cortex, such that these brain regions can no longer support spatial working memory. We will perform three aims to address this hypothesis. (1) Determine the minimal time shift at which memory deficits emerge and measure the coordination of hippocampal neural activity while stimulating at frequencies with and without memory deficits. (2) Determine whether manipulations of theta frequency critically alter firing patterns in medial entorhinal cortex (mEC). (3) Determine whether oscillations within the endogenous theta frequency range are necessary for the coordination between hippocampus and medial prefrontal cortex (mPFC). In each of the three aims, we will perform LFP and single unit recordings while mice perform a spatial alternation task. Two versions of the task will be compared, a delayed version which is dependent on hippocampal and prefrontal function, and a continuous version, which is included as a control. While mice are performing the task, the medial septal area will be stimulated at frequencies that do not result in memory deficits or stimulated at frequencies that result in memory deficits. These conditions will be compared to identify the critical changes in neural activity in hippocampus, mEC, and mPFC at the transition to the memory impairment. Taken together, the combined manipulations and recordings in the behavioral task will provide evidence for a causal relation between precise timing and memory function and for a role of oscillations in coordinating the exchange of information between brain regions.