Cortical GABAergic Circuits in Alzheimer's Disease

阿尔茨海默病中的皮质 GABA 能回路

• 批准号: 9293204
• 负责人: CHUN-HAY ALEX KWAN
• 金额: $ 20.91万
• 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/9293204
• 关键词: Acetylcholine; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Attention; Attentional deficit; Autopsy; Behavior; Behavioral; Biological Markers; Brain Diseases; Cholinesterase Inhibitors; Cognitive; Defect; Deposition; Electrophysiology (science); 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; beta amyloid pathology; cell type; cholinergic; data management; donepezil; excitatory neuron; experimental study; 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; receptor expression; reconstruction; relating to nervous system; 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 注意力缺陷降低了阿尔茨海默病（AD）患者的生活质量，然而，神经系统的 这种早期减值的基础尚不清楚。在AD小鼠模型中，兴奋性神经元过度活跃， 淀粉样蛋白沉积附近，这可能导致行为背后的信息处理缺陷， 功能障碍我们假设淀粉样沉积物附近的皮质GABA能回路功能减退， 与异常的网络活动和注意力缺陷有关。为了验证这一假设，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小鼠模型和AD小鼠模型中抑制性中间神经元的树突形态。 AD患者的死后皮质组织为了验证GABA能神经元中胆碱能信号传导的预测， 当中间神经元受损时，我们将测量乙酰胆碱调节皮质网络活动的能力。 我们还将研究是否敲低特定亚型的烟碱乙酰胆碱受体， GABA能中间神经元可以再现神经病理学。最后，我们将调查行为 通过确定激活新皮层中特定的GABA能神经元群体是否可以 缓解AD小鼠模型中的注意力缺陷。这些实验利用了光学， 电生理学、分子和行为学的方法来梳理分离电路水平的神经病理学， AD小鼠模型。这些结果将把GABA能神经传递定位为一个整合点， AD的突触Abeta和胆碱能理论。一个积极的结果也将提供证据， 用于治疗AD中的注意力缺陷的特定细胞类型。