Neuromodulatory mechanisms underlying vagus nerve stimulation therapy for Alzheimer's disease

迷走神经刺激疗法治疗阿尔茨海默病的神经调节机制

• 批准号: 10117356
• 负责人: Mark L Andermann
• 金额: $ 43.75万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10117356
• 关键词: 3-Dimensional; APP-PS1; Acute; Adrenergic Agents; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s disease therapy; Amyloid beta-Protein; Anatomy; Animals; Anorexia Nervosa; Antiinflammatory Effect; Anxiety; Arousal; Arthrogryposis; Attention; Awareness; Axon; Behavior; Behavioral; Bradycardia; Brain; Brain Stem; Calcium; Cardiovascular Diseases; Cardiovascular system; Chronic; Cognition; Cognitive deficits; Collaborations; Communication; Conscious; Corpus striatum structure; Coughing; Cyclic AMP; Data; Dendritic Spines; Detection; Development; Disease; Disease Progression; Dopamine; Drug resistance; Eating Disorders; Electric Stimulation; Esthesia; Face; Foundations; Funding; Future; Goals; Hippocampus (Brain); Human; Image; Impaired cognition; Individual; Inflammation; Inflammatory; Interoception; Irritable Bowel Syndrome; Memory; Mental Depression; Microglia; Molecular; Monitor; Morphology; Mus; Nausea and Vomiting; Neck; Nerve; Neurons; Norepinephrine; Nucleus solitarius; Obesity; Organ; Pain; Pathway interactions; Peripheral; Phagocytes; Pharyngeal structure; Pressoreceptors; Presynaptic Terminals; Protocols documentation; Reporting; Research; Science; Signal Transduction; Sleep Apnea Syndromes; Stretching; Subliminal Stimulation; Sudden infant death syndrome; Synapses; Synaptic plasticity; Testing; Vagus nerve structure; Vertebral column; afferent nerve; association cortex; awake; chemotherapy; clinical efficacy; density; experimental study; improved; locus ceruleus structure; mouse genetics; mouse model; neuroregulation; novel; novel strategies; oAβ; optical sensor; optogenetics; parent grant; respiratory; restoration; sensor; theories; two-photon; vagus nerve stimulation

SUMMARY/ABSTRACT Cognitive deficits in Alzheimer's disease (AD) have been associated with synapse loss and chronic inflammatory activation of microglia in cortex and hippocampus. Arousal-promoting locus coeruleus (LC) neurons densely project to memory-related regions of association cortex, where they release norepinephrine (NE). This NE release facilitates synaptic plasticity in neurons and drives anti-inflammatory effects in local microglia. Notably, LC neurons are among the first to degenerate in AD. Together, these findings have led to the hypothesis that early loss of LC neurons may impair cognition in AD via decreased arousal, decreased synaptic plasticity, and increased synapse loss due to inflammatory activation of phagocytic microglia. Further, recent theories posit that sustained peripheral inflammation in aging and AD may ultimately drive degeneration of LC neurons, via dysregulation of the pathway from the vagus nerve to LC via the nucleus of the solitary tract. Accordingly, chronic vagus nerve stimulation (VNS) has been used to treat drug-resistant depression, a risk factor for AD. Further, chronic VNS has shown promise in preliminary studies in AD patients, resulting in improved cognition and delayed disease progression. The behavioral effects of VNS are hypothesized to be due to increased activation of the remaining LC neurons and a resulting increase in NE release in cortex and hippocampus. However, animal studies show that VNS does not drive release of NE at low stimulation intensities. At higher intensities, VNS delivery in humans can result in uncomfortable sensations (e.g. in the throat and neck) and cough/bradycardia due to off-target effects of bulk electric stimulation of the vagus nerve. These off-target effects represent serious obstacles to clinical efficacy. Here, we propose to develop novel strategies for improved VNS via chronic stimulation of specific subsets of vagal nerve afferents innervating particular organs. Our goal is to use mouse models to develop a stimulation protocol that effectively drives NE release in cortex at levels sufficient to regulate arousal, synaptic plasticity, and microglial activation, but that does not drive conscious awareness of the stimulation. First, we will develop protocols for stimulation of specific genetically and anatomically defined sets of vagal afferents, to improve both release of NE and tolerability. We will then use 3D two-photon imaging in awake mice to ask if, at vagal afferent stimulation intensities below the threshold for behavioral detection, sufficient NE is released to drive molecular signaling in cortical dendritic spines and microglia. We will then use this stimulation approach to revert inflammatory activation of microglia in a model of Alzheimer's disease. We are uniquely poised to rapidly achieve this goal, by building on efforts in our lab involving studies of conscious awareness of stimulation of specific vagal afferent subtypes in mice (DP1 parent grant), our preliminary data imaging/stimulating LC axons in cortex and imaging Aβ-evoked changes in cortical microglia. These experiments will support a novel research direction to strategies for understanding and treatment of AD.

总结/摘要 阿尔茨海默病（AD）的认知缺陷与突触丢失和慢性 皮质和海马中小胶质细胞的炎性活化。促芳香素蓝斑 神经元密集地投射到与记忆相关的联合皮层区域，在那里它们释放去甲肾上腺素 （NE）。这种NE释放促进神经元中的突触可塑性，并在局部刺激中驱动抗炎作用。 小胶质细胞值得注意的是，LC神经元是AD中最先退化的神经元之一。总之，这些发现导致了 LC神经元的早期损失可能通过降低唤醒、降低认知功能损害AD的假设， 突触可塑性，以及由于吞噬性小胶质细胞的炎性激活而增加的突触损失。此外，本发明还 最近的理论认为，在衰老和AD中持续的外周炎症可能最终导致退化 LC神经元，通过从迷走神经经孤束核到LC的通路失调 道。因此，慢性迷走神经刺激（VNS）已被用于治疗耐药性抑郁症， AD的危险因素。此外，慢性VNS在AD患者的初步研究中显示出前景，导致 改善认知和延缓疾病进展。VNS的行为效应被假设为 由于剩余LC神经元的激活增加，导致皮质中NE释放增加， 海马体。然而，动物研究表明，在低刺激下，VNS不驱动NE的释放 强度在较高强度下，人中的VNS递送可导致不舒服的感觉（例如，在心脏中）。 咽喉和颈部）和由于迷走神经的大量电刺激的脱靶效应引起的咳嗽/心动过缓。 这些脱靶效应是临床疗效的严重障碍。在这里，我们建议开发新的 通过慢性刺激迷走神经传入的特定子集来改善VNS的策略 支配特定的器官。我们的目标是使用小鼠模型来开发一种刺激方案， 有效地驱动NE在皮质中的释放，其水平足以调节唤醒、突触可塑性， 小胶质细胞激活，但这并不驱动有意识的刺激意识。一是 开发用于刺激特定遗传学和解剖学定义的迷走神经传入集合的方案， 改善NE释放和耐受性。然后，我们将在清醒的小鼠中使用3D双光子成像来询问， 当迷走神经传入刺激强度低于行为检测阈值时，释放足够的NE， 驱动皮质树突棘和小胶质细胞中的分子信号。然后我们将使用这种刺激方法 来逆转阿尔茨海默病模型中小胶质细胞的炎症激活。我们有能力 快速实现这一目标，通过建立在我们实验室的努力，涉及有意识的意识， 刺激小鼠特定迷走神经传入亚型（DP 1父母授权），我们的初步数据 成像/刺激皮质中的LC轴突和成像皮质小胶质细胞中的Aβ诱发的变化。这些 实验将支持一个新的研究方向，以了解和治疗AD的策略。