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

通过近红外光光遗传学延缓阿尔茨海默病小鼠模型的认知能力下降

• 批准号: 10392484
• 负责人: Mark Gomelsky
• 金额: $ 18.06万
• 依托单位: UNIVERSITY OF WYOMING
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392484
• 关键词: Adenylate Cyclase; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Animals; Brain; Brain region; Cells; Characteristics; Cyclic AMP; Data; Dementia; Development; Disease; Disease model; Elements; Engineering; Enzymes; Escherichia coli; Functional disorder; Goals; Homeostasis; Impaired cognition; Impairment; In Vitro; Intervention; Investigation; Knowledge; Learning; Light; Methodology; Mus; Mutagenesis; Mutation; Neurons; Optics; Patients; Pattern; Performance; Pre-Clinical Model; Process; Proteins; Regulation; Reporting; Rodent; Role; Sleep; Source; Synapses; Synaptic plasticity; Testing; Thalamic structure; The Sun; Wild Type Mouse; base; brain tissue; cellular pathology; cranium; design; early detection biomarkers; in vivo; innovation; insight; longitudinal human study; memory consolidation; mild cognitive impairment; mouse model; multidisciplinary; neuronal circuitry; neuronal excitability; neuropathology; non rapid eye movement; novel; nucleus reticularis; optogenetics; phosphoric diester hydrolase; sleep regulation; sleep spindle; sound; tool

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.

摘要 在睡眠期间，丘脑产生一种特征性的8-15 Hz的短暂脑电图模式， (EEG)主要发生在非快速眼动睡眠（NREMS）的轻阶段。 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）， 脑动力学早期AD相关变化的生物标志物。相反，通过以下方式促进睡眠振荡： 经颅刺激增强MCI患者记忆巩固。通过开发一套新颖、 非侵入性的，基于细菌光敏色素的光遗传学工具，以控制cAMP合成（腺苷酸 环化酶，AC）和分解（磷酸二酯酶，PDE），我们将使纺锤体可用于 非侵入性的操作，以避免其他睡眠节律。这些酶被光激活， 所谓近红外光学窗口（NIRW）。NIRW光激活模块适用于 在完整动物的丘脑神经元中对cAMP进行快速而持久的非侵入性操作， 这是因为近红外线的光穿透哺乳动物的头骨和脑组织的能力比任何 其他光谱区。我们将研究一个挑衅性的新假设，即细胞病理学和 由阿尔茨海默病（AD）相关突变引起的认知能力下降可以通过增强 在体睡眠时丘脑皮层纺锤波。我们将首先开发新的非侵入性光遗传学 工具来操纵交流和主轴振荡（目标1）。然后，我们将研究NIRW-AC和 NIRW-PDE双向调节AD相关神经病理学和认知功能的进展 通过他们的行动减少：纺锤波调节（目标2）。在完成这个项目后，我们将 已经开发出基因编码的NIRW光激活工具，允许非侵入性操作， 活体动物的脑深部区域。预计结果将为调查提供良好的基础， 疾病模型，涉及纺锤波和cAMP畸变，如AD，并提出新的非- 侵入性干预策略，以对抗由AD引起的脑痴呆。