Functions of Nicotine Receptors in Sensory Neocortex

感觉新皮质尼古丁受体的功能

• 批准号: 8598620
• 负责人: Raju Metherate
• 金额: $ 34.87万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598620
• 关键词: Acoustics; Alzheimer' s Disease; Attention; Auditory; Auditory Perceptual Disorders; Auditory area; Auditory system; Brain; Characteristics; Cognition Disorders; Cognitive; Cortical Column; Data; Development; Disease; Disinhibition; Distant; Dose; Electrophysiology (science); Environment; Exhibits; Frequencies; Genetic; Goals; Green Fluorescent Proteins; Hearing; Human; Image; In Vitro; Interneurons; Label; Lateral; Lead; Life; Mediating; Mitogen-Activated Protein Kinases; Modality; Mus; Muscimol; Neocortex; Neurodegenerative Disorders; Neurons; Nicotine; Nicotinic Agonists; Nicotinic Receptors; Noise; Pathway interactions; Perception; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Play; Process; Recruitment Activity; Regulation; Relative (related person); Rodent; Role; Sensory; Signal Transduction; Somatostatin; Source; Spatial Distribution; Specific qualifier value; Speech; Stimulus; Synapses; System; Testing; Whole-Cell Recordings; cognitive function; density; distraction; hippocampal pyramidal neuron; improved; in vivo; notch protein; postsynaptic; presynaptic; public health relevance; receptive field; receptor; response; sound; therapeutic development; two-photon

DESCRIPTION (provided by applicant): For hearing, as for the other senses, the perception of environmental stimuli improves with activation of nicotinic acetylcholine receptors (nAChRs) in the brain. For example, auditory-cognitive function is enhanced by administration of the drug nicotine, but impaired by blocking nAChRs (using other drugs) or by disease- induced loss of nAChRs (i.e., in neurodegenerative diseases, such as Alzheimer's Disease). It is widely thought, therefore, that nAChRs are important for optimal auditory-cognitive function. Although, as a result, nicotinic drugs are being developed to treat a variety of cognitive disorders, such approaches to date have not been used to treat auditory processing disorders. During auditory attention, activation of nAChRs is thought to improve attentional filtering-the enhanced processing of important stimuli and suppression of distracting stimuli that appears to involve narrowing of frequency receptive fields (RFs) in the auditory system. We hypothesize that activation of nAChRs will narrow RF tuning in primary auditory cortex (A1) and enhance processing within narrowed RFs, and that these cellular actions of nAChRs contribute to attentional filtering. Aim 1 will determine how activation of nAChRs alters spectral integration in A1, using tone-evoked current- source density (CSD) profiles to determine frequency RFs. Aim 2 will determine how nicotinic activation of intracellular signal transduction involving mitogen-activated protein kinase (MAPK) recruits subpopulations of neurons, especially interneurons, in A1. Aim 3 will determine how activating nAChRs and MAPK in identified interneurons alters acoustic processing. These Aims will identify mechanisms by which nAChRs in A1 can enhance auditory processing, and specify the contributions of nAChR subtypes and neuron subpopulations. Our long-term goal is to understand nicotinic mechanisms of auditory-cognitive function, and thereby aid the development of pharmacological treatments for auditory processing disorders.

描述（由申请人提供）：对于听觉，与其他感官一样，对环境刺激的感知随着大脑中烟碱乙酰胆碱受体（nAChR）的激活而改善。例如，服用尼古丁药物可以增强听觉认知功能，但阻断 nAChR（使用其他药物）或疾病引起的 nAChR 丧失（即神经退行性疾病，如阿尔茨海默病）会损害听觉认知功能。因此，人们普遍认为 nAChR 对于最佳听觉认知功能很重要。因此，尽管正在开发烟碱类药物来治疗各种认知障碍，但迄今为止此类方法尚未用于治疗听觉处理障碍。在听觉注意力过程中，nAChR 的激活被认为可以改善注意力过滤，即增强对重要刺激的处理和抑制分散注意力的刺激，这似乎涉及听觉系统中频率感受野 (RF) 的缩小。我们假设 nAChR 的激活将缩小初级听觉皮层 (A1) 中的 RF 调谐范围并增强狭窄 RF 内的处理，并且 nAChR 的这些细胞作用有助于注意力过滤。目标 1 将确定 nAChR 的激活如何改变光谱积分 A1，使用音调诱发电流源密度 (CSD) 曲线来确定频率 RF。目标 2 将确定涉及丝裂原激活蛋白激酶 (MAPK) 的细胞内信号转导的烟碱激活如何招募 A1 中的神经元亚群，尤其是中间神经元。目标 3 将确定激活已识别的中间神经元中的 nAChR 和 MAPK 如何改变声学处理。这些目标将确定 A1 中的 nAChR 增强听觉处理的机制，并明确 nAChR 亚型和神经元亚群的贡献。我们的长期目标是了解听觉认知功能的烟碱机制，从而帮助开发针对听觉处理障碍的药物治疗方法。