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.

项目总结