Cortical GABAergic Circuits in Alzheimer's Disease

阿尔茨海默病中的皮质 GABA 能回路

• 批准号: 8849045
• 负责人: CHUN-HAY ALEX KWAN
• 金额: $ 20.81万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8849045
• 关键词: Acetylcholine; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Attentional deficit; Behavior; Behavioral; Biological Markers; Brain; Cholinesterase Inhibitors; Cognitive; Defect; Deposition; Exhibits; Face; Foundations; Functional disorder; Future; Goals; Hippocampus (Brain); Human; Hyperactive behavior; Immunohistochemistry; Impairment; Interneurons; Intervention; Knowledge; Lead; Link; Measures; Mediating; Microscopy; Molecular; Morphology; Mus; Neocortex; Nerve Degeneration; Neurobehavioral Manifestations; Neurons; Nicotinic Receptors; Optics; Outcome; Pathology; Patients; Pattern; Performance; Physiology; Play; Population; Positioning Attribute; Prefrontal Cortex; Property; Quality of life; Reaction Time; Research; Research Personnel; Role; Sample Size; Seizures; Signal Transduction; Synapses; Testing; Tissues; Viral; Work; amyloid imaging; base; cell type; cholinergic; data management; donepezil; excitatory neuron; frontal lobe; functional disability; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; human subject; in vivo; information processing; inhibitory neuron; knock-down; mouse model; neuropathology; neuroregulation; neurotransmission; novel; optogenetics; reconstruction; relating to nervous system; research study; small hairpin RNA; spatiotemporal; statistics; theories; tool; two-photon

PROJECT SUMMARY Attentional deficits diminish the quality of life for Alzheimer's disease (AD) patients, however the neural basis for this early impairment is not understood. In mouse models of AD, excitatory neurons are hyperactive near amyloid deposits, which could contribute to defects in information processing underlying behavioral dysfunctions. We hypothesize that hypofunction of cortical GABAergic circuits near amyloid deposits is associated with the aberrant network activity and attentional deficits. To test this hypothesis, we will measure the electrophysiological properties of the major subtypes of GABAergic neurons in an AD mouse model. We will also characterize the dendritic morphologies of the inhibitory interneurons in an AD mouse model and in post-mortem cortical tissue from AD patients. To test the prediction that cholinergic signaling in GABAergic interneurons is compromised, we will measure the ability of acetylcholine to modulate cortical network activity. We will also investigate whether knocking down nicotinic acetylcholine receptors in specific subtypes of GABAergic interneurons can recapitulate the neuropathology. Finally, we will investigate the behavioral relevance by determining whether activating specific GABAergic neuronal populations in the neocortex can alleviate attentional deficits in an AD mouse model. These experiments leverage a combination of optical, electrophysiological, molecular, and behavioral approaches to tease apart the circuit level neuropathology in an AD mouse model. The results will position GABAergic neurotransmission as a point of integration for the synaptic Abeta and cholinergic theories of AD. A positive outcome will also provide evidence for targeting specific cell types for treating attentional deficits in AD.

项目摘要 注意缺陷降低了阿尔茨海默氏病（AD）患者的生活质量，但是神经 不了解这种早期障碍的基础。在AD的鼠标模型中，兴奋性神经元是多动的 靠近淀粉样蛋白沉积物，这可能导致信息处理基本行为的缺陷 功能障碍。我们假设淀粉样蛋白沉积物附近的皮质GABA能电路的功能不全是 与异常网络活动和注意力缺陷有关。为了检验这一假设，我们将测量 AD小鼠模型中GABA能神经元主要亚型的电生理特性。我们 还将表征AD小鼠模型中抑制性中间神经元的树突形态 AD患者的验尸皮质组织。测试GABA能信号传导的预测 中间神经元受到损害，我们将测量乙酰胆碱调节皮质网络活性的能力。 我们还将调查是否在特定亚型的特定亚型中敲击烟碱乙酰胆碱受体。 GABA能中间神经元可以概括神经病理学。最后，我们将研究行为 通过确定新皮层中是否激活特定的GABA能神经元种群来相关性 在AD鼠标模型中减轻注意力缺陷。这些实验利用了光学的组合， 电生理，分子和行为方法，以分开电路水平的神经病理学 AD鼠标模型。结果将将GABA能神经传递定位为 AD的突触Abeta和胆碱能理论。积极的结果还将为目标提供证据 用于治疗AD注意力缺陷的特定细胞类型。