Dependence of memory on precisely coordinated oscillations

项目摘要 大脑振荡被认为是认知功能的关键，在所有主要的 神经和精神障碍，如阿尔茨海默病、癫痫、抑郁症，以及 精神分裂症越来越多的人对理解神经元之间的关系感兴趣， 计算和振荡模式在健康和患病的大脑，因为振荡模式 可以通过非侵入性和侵入性刺激装置进行治疗。虽然大多数大脑 节律是由神经元起搏器或局部回路产生的，呼吸产生节律性的 大脑活动的外部循环。鼻气流刺激嗅觉神经元， 嗅球（OB）中的呼吸相关振荡（RRO）。RRO已被广泛证明 传播到皮质区，包括梨状皮质（PC），前额叶皮质区，外侧内嗅区 皮质（IEC）和海马（HC）。在HC中，RRO可以与起搏器并行检测- 产生θ振荡，这对记忆功能和频率重叠至关重要。不 很清楚这两种类型的振荡在多大程度上只是平行现象或功能上 协调以支持神经计算。我们假设RRO和θ振荡不 全局耦合，但跨大脑区域的神经元亚群与每个区域同步， 不同记忆阶段的振荡模式。为了解决这个问题，我们将执行 记录和操纵的局部场电位（LFPs）和神经元放电模式的气味- 引导工作记忆任务，其中两种类型的振荡都很突出。在目标1中，我们 确定RRO、θ振荡和高频振荡是否协调 在嗅觉工作记忆任务中，通过记录LFP和/或单个单位， OB、前PC、lEC、腹侧HC、背侧HC和内侧前额叶皮质（mPFC）。这些脑 因为RRO和正则θ振荡在所有这些区域都有报道， 因为这些大脑区域被认为对工作记忆的表现至关重要。 在目标2中，我们将使用光遗传学来改变RRO和经典theta的频率 振荡，以确定在哪些阶段的工作记忆，他们是关键的任务 性能最后，在目标3中，我们将使用气味引导工作的匹配/非匹配版本。 记忆任务，以确定初始感觉代码如何转换为活动模式， 在保留时间间隔内保持信息性。总之，我们的目标将揭示神经元如何 在工作记忆期间，活动模式通过两种类型的振荡来协调。一种机械的 对支持记忆计算的脑振荡的理解是设计 以及应用脑刺激疗法来改善神经和精神疾病患者的记忆。

PROJECT SUMMARY Brain oscillations are thought to be critical for cognitive functions and are disrupted in all major neurological and psychiatric disorders, such as Alzheimer’s disease, epilepsy, depression, and schizophrenia. There has been increasing interest in understanding the relation between neural computations and oscillatory patterns in the healthy and diseased brain because oscillation patterns can be targeted for treatment with noninvasive and invasive stimulation devices. While most brain rhythms are generated by either neuronal pacemakers or local circuits, breathing generates rhythmic brain activity by an external loop. Nasal air flow stimulates olfactory sensory neurons which generate respiration-related oscillations (RROs) in the olfactory bulb (OB). RROs have been shown to widely propagate to cortical areas, including piriform cortex (PC), prefrontal cortical areas, lateral entorhinal cortex (lEC), and hippocampus (HC). In HC, RROs can be detected in parallel with pacemaker- generated theta oscillations, which are critical for memory function and overlap in frequency. It is not clear to what extent the two types of oscillations are merely parallel phenomena or functionally coordinated to support neural computations. We hypothesize that RROs and theta oscillations do not globally couple, but that subpopulations of neurons across brain regions are synchronized with each oscillation pattern across different memory phases. To address this question, we will perform recordings and manipulations of local field potentials (LFPs) and neuronal firing patterns in odor- guided working memory tasks, where both types of oscillations are prominent. In Aim 1, we will determine whether RROs, theta oscillations, and oscillations at higher frequencies are coordinated across brain regions in an olfactory working memory task by recording LFPs and/or single-units in the OB, anterior PC, lEC, ventral HC, dorsal HC, and medial prefrontal cortex (mPFC). These brain regions are included because RROs and canonical theta oscillations have been reported in all of these regions and because these brain regions are thought to be critical for working memory performance. In Aim 2, we will then use optogenetics to change the frequency of RROs and canonical theta oscillations to determine during which phases of working memory they are critical for task performance. Finally, in Aim 3, we will use a match/non-match version of the odor-guided working memory task to determine how the initial sensory code is transformed into activity patterns that remain informative over the retention interval. Taken together, our aims will reveal how neuronal activity patterns are coordinated by two types of oscillations during working memory. A mechanistic understanding of brain oscillations that support memory computations is foundational for devising and applying brain stimulation therapies to improve memory in neurological and psychiatric diseases.