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.

项目总结 注意力缺陷降低了阿尔茨海默病(AD)患者的生活质量，但神经功能障碍 这一早期减值的基础尚不清楚。在阿尔茨海默病小鼠模型中，兴奋性神经元过度活跃 淀粉样蛋白沉积附近，这可能导致潜在的行为信息处理缺陷 功能障碍。我们假设淀粉样蛋白沉积附近的皮质GABA能回路功能减退 与异常的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 阿尔茨海默病模型小鼠GABA能神经元主要亚型的电生理特性。我们 也将表征抑制性中间神经元的树突形态在AD小鼠模型和在 AD患者的死后皮质组织。检验GABA能区胆碱能信号的预测 中间神经元受损后，我们将测量乙酰胆碱调节皮质网络活动的能力。 我们还将调查在特定亚型的烟碱型乙酰胆碱受体是否被击倒 GABA能中间神经元可以概括神经病理。最后，我们将调查行为 通过确定激活新皮质中特定的GABA能神经元群体是否可以 减轻阿尔茨海默病小鼠模型的注意缺陷。这些实验利用了光学、 电生理学、分子和行为学方法梳理脑内电路水平的神经病理 AD小鼠模型。这一结果将使GABA能神经传递成为 突触Aβ与阿尔茨海默病的胆碱能学说积极的结果也将为确定目标提供证据。 治疗阿尔茨海默病注意力缺陷的特定细胞类型。