Prefrontal neural modulation to restore cognitive deficits in an Alzheimer's Disease rat model

前额神经调节可恢复阿尔茨海默病大鼠模型的认知缺陷

• 批准号: 10373174
• 负责人: Elizabeth A West
• 金额: $ 41.23万
• 依托单位: ROWAN UNIVERSITY SCHOOL/OSTEOPATHIC MED
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10373174
• 关键词: Affect; Alzheimer disease screening; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Attention; Behavior; Behavioral; Brain; Cognitive; Cognitive deficits; Complex; Decision Making; Dorsal; Exhibits; Face; Frequencies; Functional disorder; Future; Goals; Hippocampus (Brain); Human; Human Amyloid Precursor Protein; Impairment; Lead; Link; Measures; Medial; Mediating; Memory; Memory Loss; Memory impairment; Modeling; Neurofibrillary Tangles; Neuronal Dysfunction; Neuronal Injury; Neurons; Neurophysiology - biologic function; Pathology; Patients; Positioning Attribute; Predisposition; Prefrontal Cortex; Process; Protocols documentation; Quality of life; Rattus; Reversal Learning; Rewards; Rodent; Short-Term Memory; Temporal Lobe; Testing; Transgenic Organisms; age related; behavior change; behavioral impairment; cognitive control; cognitive function; cognitive process; cognitive task; flexibility; frontal lobe; gray matter; improved; in vivo; loss of function; memory process; mutant; neural circuit; neuroinflammation; neuropathology; neurophysiology; neuroregulation; noninvasive brain stimulation; overexpression; presenilin-1; relating to nervous system; response; tau Proteins; therapeutic target

Project Summary Alzheimer’s disease (AD) is characterized by memory impairments and underlying neuropathology, including plaques, amyloid-β peptides, tau, in conjunction with neuroinflammation, and neuronal injury/loss, particularly in the medial temporal lobe. Recent studies, however, suggest neurophysiological alterations in the prefrontal cortex (PFC) evident in AD patients prior to gross neuropathology which may contribute to deficits in cognitive processing early in AD. Given that the PFC contributes to top-down control of memory processing necessary for optimal decision-making, dysfunction within the PFC may contribute to suboptimal decision-making which often precedes gross memory loss in AD patients. Optimal decision-making requires functioning working memory processes (i.e., using information “online” to guide choices) and flexible behavior (the ability to shift behavior in response to changing consequences). Critically, early-stage AD may target brain circuits that underlie these prefrontal dependent processes leading to early impairment in optimal cognitive processing. As such, understanding neural circuits that are affected in AD underlie complex cognitive deficits may lead to earlier and effective screening for AD risk and serve as an important therapeutic target for improving the quality of life AD patients. The rat prelimbic cortex (PrL) is heavily implicated in working memory and flexible behavior necessary for online decision-making. AD rats that were developed to show age-dependent neuropathological signatures (plaques, tau) consistent with AD are impaired in PrL-dependent cognitive tasks prior to accumulation of neuropathology. Critically, these deficits in PrL-dependent tasks precede behavioral deficits in other memory tasks that do not depend on PrL function. As such, targeting the PrL function in vivo may restore these cognitive processes in the AD rat model. Here, we aim to use noninvasive brain stimulation that modulates neural oscillations to restore PrL-hippocampal neural activity (Aim 1) and PrL-orbitofrontal cortex neural activity (Aim 2) in working memory (delay nonmatch to position task) and flexible behavior (reversal learning), respectively.

项目概要 阿尔茨海默病 (AD) 的特点是记忆障碍和潜在的神经病理学，包括 斑块、β 淀粉样肽、tau 蛋白与神经炎症和神经元损伤/损失相关，特别是在 内侧颞叶。然而，最近的研究表明前额叶的神经生理学改变 AD 患者在进行大体神经病理学检查之前，大脑皮层（PFC）就很明显，这可能会导致认知缺陷 公元早期的处理。鉴于 PFC 有助于对内存处理进行自上而下的控制，这是必要的 对于最佳决策，PFC 内的功能障碍可能会导致次优决策，从而导致 通常先于 AD 患者的严重记忆丧失。最佳决策需要有效的工作记忆 流程（即使用“在线”信息来指导选择）和灵活的行为（改变行为的能力） 对变化的后果的反应）。至关重要的是，早期 AD 可能会针对这些基础的大脑回路 前额依赖过程导致最佳认知处理的早期损伤。像这样， 了解 AD 中受影响的神经回路是复杂认知缺陷的基础，可能会导致更早和更早的认知障碍。 有效筛查AD风险并作为改善AD生活质量的重要治疗靶点 患者。大鼠前边缘皮层 (PrL) 与工作记忆和灵活行为密切相关 用于在线决策。 AD 大鼠被培育成显示出年龄依赖性神经病理学特征 与 AD 一致的（斑块、tau）在 PrL 依赖性认知任务中在积累之前受到损害 神经病理学。重要的是，PrL 依赖性任务中的这些缺陷先于其他记忆中的行为缺陷 不依赖于 PrL 函数的任务。因此，靶向体内 PrL 功能可能会恢复这些认知功能。 AD大鼠模型中的过程。在这里，我们的目标是使用非侵入性脑刺激来调节神经 振荡以恢复 PrL-海马神经活动（目标 1）和 PrL-眶额皮质神经活动（目标 2） 分别在工作记忆（延迟与位置任务不匹配）和灵活行为（逆向学习）中。