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

知觉记忆背后的大脑皮层活动被认为发生在神经元群的有组织的放电中。 记忆的形成可以分解为获得和巩固过程，其中信息是 分别获取和存储。记忆巩固被认为是在我们睡觉的时候发生的，当大脑处于 静止状态，允许先前形成的神经元群重新激活。而记忆的重新激活及其 在合并中的后续作用在很大程度上已经被记录在案，刺激了个人合奏的重演 在睡眠过程中增强记忆的结果还只是间接地被探索过。事实上，记忆力的损害 重新激活改变记忆巩固，这可能导致神经退行性变的认知缺陷 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。疾病的进展与 伴随着β-淀粉样蛋白(A-β)聚集的老年斑的沉积以及神经变性。β淀粉样蛋白 然而，病理已被证明扰乱了大脑皮层的稳态并使神经元网络失去同步性。 Aβ病理对睡眠介导的记忆重新激活造成的干扰仍不清楚。总目标 这一建议的目的是确定记忆重新激活在睡眠期间记忆巩固中的作用 在淀粉样变性的小鼠模型中，β淀粉样蛋白诱导的再激活损伤是其特征。评估 在睡眠期间记忆重新激活，我将使用3D监控数千个神经元的神经元钙活动 全息双光子显微镜同时记录神经元网络的局域场电位 活体内活动。为了刺激特定的整体活动，我将在前面观察到的情况下刺激单个细胞 使用全息靶向光遗传学的合奏。同时监测和刺激视觉皮质 睡眠在进行/不进行设置学习任务后，我将测试刺激记忆重新激活的假设 睡眠将增强记忆巩固，在AD小鼠模型中，记忆重新激活被改变。我 将首先比较不同唤醒-睡眠状态下光遗传刺激后神经元整体的稳定性 (目标1a)。然后，我将监测靶向光遗传刺激后的行为表现 睡眠以确定行为结果的改善(目标1b)。由于其过度表达β淀粉样蛋白，我将 用5XFAD小鼠模型评估A-β斑块对睡眠期间整体激活的影响 (目标2a)。最后，我将监测5XFAD小鼠模型中神经元网络的活动和行为，以评估 睡眠期间光遗传靶向重播后的细胞和行为增强(目标2b)。这个项目 将有助于阐明可能被β淀粉样蛋白病理破坏的睡眠记忆处理阶段， 为AD神经认知症状的治疗提供潜在的治疗靶点。神经元集合 我们将考察活动及其与行为的关系。我将接受大量尖端研究方面的培训 作为一名独立研究科学家，我将能够在整个职业生涯中使用和建立这些技术。

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.