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

项目摘要 阿尔茨海默病(AD)的特征是记忆障碍和潜在的神经病理，包括 斑块、淀粉样蛋白-β多肽、tau与神经炎症和神经元损伤/丢失，特别是在 内侧的颞叶。然而，最近的研究表明，前额叶发生了神经生理学变化。 阿尔茨海默病患者在大体神经病理之前出现皮层(PFC)，这可能是认知障碍的原因 在公元前的早期处理。假设PFC有助于自上而下地控制必要的存储器处理 对于最优决策，PFC内部的功能障碍可能会导致次优决策 通常先于AD患者的大体记忆丧失。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(在 应对不断变化的后果)。关键的是，早期阿尔茨海默病可能针对构成这些的大脑回路 前额叶依赖过程导致最佳认知加工的早期损害。因此， 了解阿尔茨海默病中受影响的神经回路是复杂认知缺陷的基础，可能会导致早期和 有效筛查AD风险，作为提高AD生活质量的重要治疗目标 病人。大鼠前脑皮质(PRL)与工作记忆和必要的灵活行为密切相关 用于在线决策。AD大鼠表现出年龄依赖的神经病理特征 (斑块，tau)与AD一致的在PRL依赖的认知任务中受损，在积累 神经病理学。关键的是，PRL依赖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功能的任务。因此，在体内靶向PRL功能可能会恢复这些认知 阿尔茨海默病大鼠模型的过程。在这里，我们的目标是使用非侵入性脑刺激来调节神经 恢复PRL-海马神经活动的振荡(目标1)和恢复PRL-眶前叶皮质神经活动(目标2) 工作记忆(延迟与位置任务不匹配)和灵活行为(反转学习)。

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.