Delaying cognitive decline in mouse models of Alzheimer's disease via near-infrared light optogenetics

摘要 在睡眠过程中，丘脑会产生8-15赫兹的脑电信号。 (EEG)波，主要发生在非快速眼动睡眠(NREMS)的光线阶段。 纺锤体减少可能导致AD患者的学习障碍和轻度认知障碍(MCI)，是一种 早期AD相关脑动力学改变的生物标志物。相反，通过以下方式促进睡眠振荡 经颅刺激可增强MCI患者的记忆巩固。通过开发一套新颖的， 控制cAMP合成(腺苷)的基于细菌光敏色素的非侵入性光遗传工具 循环酶，AC)和分解(磷酸二酯酶，PDE)，我们将使纺锤可用于 避免其他睡眠节律的非侵入性操作。这些酶是由光在体内激活的 所谓近红外光学窗口(NIRW)。NIRW光敏模块适用于 对完整动物丘脑神经元中cAMP的快速、持久和非侵入性操作， 因为近红外光能更好地穿透哺乳动物的头骨和脑组织 其他光谱区域。我们将检验一个具有挑衅性的新假设，即细胞病理学和 阿尔茨海默病(AD)相关突变导致的认知能力下降可以通过增强 在体睡眠中丘脑皮质纺锤波。我们将首先开发新的非侵入性光遗传 操纵交流和主轴振荡的工具(目标1)。然后，我们将检查NIRW-AC和 NIRW-PDE双向调节AD相关神经病理和认知的进展 通过他们的行动递减：纺锤波调节(目标2)。在这个项目完成后，我们将 已经开发出基因编码的NIRW光激活工具，允许在 活体动物的大脑深层区域。预计结果将为#年的调查提供可靠的基础。 涉及纺锤波和cAMP异常的疾病模型，如阿尔茨海默病，并提示新的非 侵入性干预策略对抗阿尔茨海默病引起的脑痴呆。

ABSTRACT During sleep, the thalamus generates a characteristic brief pattern of 8-15 Hz electroencephalographic (EEG) waves that predominantly occur during light stages of non-rapid eye-movement sleep (NREMS). Reduced spindle may cause impaired learning and Mild Cognitive Impairment (MCI) in AD and is a biomarker for early AD-related changes in brain dynamics. Conversely, promoting sleep oscillations by transcranial stimulation enhances memory consolidation in MCI. By developing a set of novel, noninvasive, bacteriophytochrome-based optogenetic tools to control cAMP synthesis (adenylate cyclase, AC) and breakdown (phosphodiesterase, PDE), we will make spindles accessible for noninvasive manipulations that spare other sleep rhythms. These enzymes are activated by light in the so-called near-infrared optical window (NIRW). The NIRW light-activated modules are suitable for the rapid yet long-lasting and noninvasive manipulation of cAMP in thalamic neurons in intact animals, because NIRW light penetrates through mammalian skulls and brain tissues better than the light of any other spectral region. We will examine a provocative novel hypothesis that cellular pathology and cognitive decline caused by Alzheimer’s disease (AD) related mutations can be restored via enhancing thalamocortical spindles waves during sleep in vivo. We will first develop novel noninvasive optogenetic tools to manipulate AC and spindle oscillations (Aim 1). Then, we will examine whether NIRW-AC and NIRW-PDE bi-directionally modulate the progression of AD–related neuropathology and cognitive decline via their actions re: spindle wave regulations (Aim 2). Upon completion of this project, we will have developed genetically encoded NIRW-light activated tools, allowing noninvasive manipulation in deep brain regions of live animals. Results are expected to provide a sound basis for investigation in disease models that involve spindle wave and cAMP aberrations, such as AD, and suggest novel non- invasive intervention strategies to counteract brain dementias caused by AD.