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.

项目摘要 阿尔茨海默病（AD）的特征在于记忆障碍和潜在的神经病理学，包括 斑块、淀粉样蛋白-β肽、tau蛋白，与神经炎症和神经元损伤/丧失相关，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， 在AD患者中，在大体神经病理学之前明显存在皮质（PFC），这可能导致认知功能缺陷 在AD早期处理。鉴于PFC有助于自上而下控制记忆处理的必要性， 对于最佳决策，前额叶皮层功能障碍可能导致次优决策， 通常在AD患者出现严重记忆丧失之前出现。最佳决策需要工作记忆 过程（即，使用“在线”信息来指导选择）和灵活的行为（在 改变的后果）。至关重要的是，早期AD可能会针对这些疾病背后的大脑回路 前额叶依赖性过程导致最佳认知过程的早期损伤。因此，在本发明的一个方面， 了解在AD中受影响的神经回路是复杂认知缺陷的基础， 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 在线决策。显示年龄依赖性神经病理学特征的AD大鼠 与AD一致的斑块（tau蛋白）在PRL依赖性认知任务中受损， 神经病理学关键的是，这些缺陷在PRL依赖的任务之前的行为缺陷，在其他记忆 不依赖于PrL功能的任务。因此，在体内靶向PrL功能可以恢复这些认知功能。 在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， 振荡以恢复PrL-海马神经活动（Aim 1）和PrL-眶额皮质神经活动（Aim 2） 在工作记忆（延迟不匹配位置任务）和灵活行为（反向学习）。