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.

摘要/摘要 阿尔茨海默病 (AD) 的认知缺陷与突触丧失和慢性 皮质和海马中小胶质细胞的炎症激活，促进唤醒蓝斑（LC）。 神经元密集投射到关联皮层的记忆相关区域，在那里释放去甲肾上腺素 (NE) 的这种 NE 释放促进神经元的突触可塑性并驱动局部的抗炎作用。 值得注意的是，LC 神经元是 AD 中最先退化的神经元之一。 假设 LC 神经元的早期缺失可能会通过觉醒程度降低、认知能力下降而损害 AD 患者的认知能力。 突触可塑性，以及由于吞噬小胶质细胞的炎症激活而导致的突触损失增加。 最近的理论认为，衰老和 AD 中持续的外周炎症可能最终导致退化 LC 神经元，通过从迷走神经到 LC 的通路失调（通过孤立神经核） 因此，慢性迷走神经刺激（VNS）已被用于治疗耐药性抑郁症。 此外，慢性 VNS 在 AD 患者的初步研究中显示出希望，从而导致 AD 的危险因素。 VNS 的行为效应被认为可以改善认知并延缓疾病进展。 由于剩余 LC 神经元的激活增加以及皮质和 然而，动物研究表明，VNS 在低刺激下不会驱动 NE 释放。 在较高强度下，VNS 递送可能会导致人体产生不舒服的感觉（例如，在 由于迷走神经大量电刺激的脱靶效应，导致喉咙和颈部）和咳嗽/心动过缓。 这些脱靶效应对临床疗效构成了严重障碍，我们建议开发新的药物。 通过长期刺激迷走神经传入的特定亚群来改善 VNS 的策略 我们的目标是使用小鼠模型开发一种刺激方案 有效地驱动皮层中的 NE 释放，其水平足以调节觉醒、突触可塑性和 小胶质细胞的激活，但这并不能驱动意识的刺激。 制定刺激特定遗传和解剖学定义的迷走神经传入组的协议，以 然后，我们将在清醒的小鼠中使用 3D 双光子成像来询问是否，在 迷走神经传入刺激强度低于行为检测阈值，足够的 NE 被释放 然后我们将使用这种刺激方法来驱动皮质树突棘和小胶质细胞中的分子信号传导。 恢复阿尔茨海默病模型中小胶质细胞的炎症激活，我们有独特的准备。 通过我们实验室研究的努力，包括有意识地认识到 刺激小鼠特定迷走神经传入亚型（DP1亲本资助），我们的初步数据 对皮质中的 LC 轴突进行成像/刺激并对皮质小胶质细胞中 Aβ 诱发的变化进行成像。 实验将为理解和治疗 AD 的策略提供新的研究方向。