Holographic reprogramming of memories during sleep in a mouse model of Alzheimers disease

知觉记忆的皮层活动被认为发生在神经元集合的有组织放电中。 记忆的形成可以分解为获取和巩固过程，其中信息是 分别获得和存储。记忆巩固被认为发生在我们睡觉的时候，当大脑处于一个 静止状态允许先前形成的神经元集合重新激活。虽然记忆再激活及其 随后的作用，在巩固已在很大程度上记录在案，刺激重演个别合奏 在睡眠中增强记忆力的结果只是间接探索。事实上，记忆力的损伤 重新激活改变记忆巩固，这可能有助于神经退行性疾病中的认知缺陷。 阿尔茨海默病（AD）等疾病。AD是美国痴呆症的主要原因，但 导致认知能力下降的网络机制尚不清楚。疾病进展与 伴随β淀粉样蛋白（Aβ）聚集的老年斑沉积以及神经变性。β淀粉样蛋白 然而，病理学已经显示出破坏皮质稳态和使神经元网络去稳定化， Aβ病理对睡眠介导的记忆再激活的干扰仍然未知。总目标 这个建议的一个重要目的是确定睡眠期间记忆再激活对记忆巩固的作用， 作为淀粉样变性小鼠模型中β淀粉样蛋白诱导的再活化损伤的特征。评估 在睡眠期间的记忆重新激活，我将使用3D技术监测数千个神经元的神经元钙活动。 全息双光子显微术与局部场电位同步记录神经元网络 体内活性。为了刺激特定的整体活动，我将激发先前观察到的单个细胞， 使用全息靶向光遗传学的合奏。在监视和刺激视觉皮层的同时， 在Go/No-Go学习任务后睡觉，我将测试刺激记忆再激活的假设， 在睡眠期间的一种药物会增强记忆巩固，并且在AD小鼠模型中记忆再激活被改变。我 将开始通过比较清醒-睡眠状态下光遗传学刺激后神经元整体稳定性 (Aim 1a）。然后，我将监测在清醒和清醒期间的靶向光遗传学刺激后的行为表现， 睡眠以确定行为结果的改善（目标1b）。由于它过度表达β淀粉样蛋白，我会 使用AD的5XFAD小鼠模型来评估Aβ斑块对睡眠期间整体再激活的影响 (Aim 2a）。最后，我将在5XFAD小鼠模型中监测神经元网络活动和行为，以评估 睡眠期间光遗传靶向重放后的细胞和行为增强（Aim 2b）。这个项目 将有助于阐明可能被β淀粉样蛋白病理学破坏的睡眠记忆处理阶段， 为AD神经认知症状的治疗提供了潜在的治疗靶点。神经元系综 活动及其与行为的关系将被检查。我将接受多项尖端研究的培训 这些技术我将能够在我作为一名独立研究科学家的整个职业生涯中使用和建立。

Cortical activity underlying perceptual memory is believed to occur in the organized firing of neuronal ensembles. Memory formation can be decomposed into acquisition and consolidation processes, wherein information is gained and stored respectively. Memory consolidation is thought to occur while we sleep, when the brain is in a quiescent state to allow previously formed neuronal ensembles to reactivate. While memory reactivation and its consequent role in consolidation has been largely documented, stimulating the replay of individual ensembles during sleep to enhance memory outcomes has been only indirectly explored. Indeed, impairments to memory reactivation alter memory consolidation and this may contribute to the cognitive deficits in neurodegenerative diseases such as Alzheimer’s disease (AD). AD is the leading cause of dementia in the United States, and yet the network mechanisms contributing to cognitive decline are unclear. The disease progression is associated with depositions of senile plaques of beta amyloid (Aβ) aggregates as well as neurodegeneration. Beta amyloid pathology has been shown to disrupt cortical homeostasis and desynchronize neuronal networks, however disturbances caused by Aβ pathology on sleep-mediated memory reactivation remain unknown. The overall goal of this proposal is to determine the role of memory reactivation on memory consolidation during sleep, as well as characterize beta amyloid induced impairments in reactivation in a mouse model of amyloidosis. To assess memory reactivation during sleep, I will monitor neuronal calcium activity from thousands of neurons using 3D holographic two-photon microscopy simultaneously with local field potential recordings of neuronal network activity in vivo. In order to stimulate specific ensemble activity, I will excite individual cells in previously observed ensembles using holographic targeted optogenetics. While monitoring and stimulating the visual cortex during sleep following a Go/No-Go set learning task, I will test the hypothesis that stimulating memory reactivation during sleep will enhance memory consolidation, and memory reactivation is altered in a mouse model of AD. I will begin by comparing neuronal ensemble stability following optogenetic stimulation across wake – sleep states (Aim 1a). I will then monitor behavioral performance following targeted optogenetic stimulation across wake and sleep to identify improvements in behavioral outcome (Aim 1b). Due to its overexpression of beta amyloid, I will use the 5XFAD mouse model of AD to evaluate the impact of Aβ plaques on ensemble reactivation during sleep (Aim 2a). Finally, I will monitor neuronal network activity and behavior in the 5XFAD mouse model to assess cellular and behavioral enhancements following optogenetic targeted replay during sleep (Aim 2b). This project will aid in the elucidation of sleep memory processing stages that may be disrupted by beta amyloid pathology, and provide potential therapeutic targets for the treatment of AD neurocognitive symptoms. Neuronal ensemble activity and its relation to behavior will be examined. I will be trained on a multitude of cutting-edge research techniques that I will be able to use and build upon throughout my career as an independent research scientist.