Functions of Nicotine Receptors in Sensory Neocortex

感觉新皮质尼古丁受体的功能

• 批准号: 9303195
• 负责人: Raju Metherate
• 金额: $ 33.24万
• 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 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303195
• 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; Impairment; 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; Recruitment Activity; Regulation; Rodent; Role; Sensory; Signal Transduction; Somatostatin; Source; Spatial Distribution; Specific qualifier value; Speech; Stimulus; Synapses; System; Testing; Whole-Cell Recordings; auditory processing; cognitive function; density; distraction; drug development; hippocampal pyramidal neuron; improved; in vivo; notch protein; postsynaptic; presynaptic; public health relevance; receptive field; response; sound; therapeutic development; therapy 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(申请人提供)：对于听力，与其他感官一样，对环境刺激的感知随着大脑中烟碱型乙酰胆碱受体(NAChRs)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，但通过阻断nAChRs(使用其他药物)或疾病导致的nAChRs丢失(即在神经退行性疾病中，如阿尔茨海默病)，听觉认知功能会受到损害。因此，人们普遍认为nAChRs对于最佳的听觉认知功能很重要。因此，虽然尼古丁类药物正在被开发用于治疗各种认知障碍，但到目前为止，这种方法还没有被用于治疗听觉处理障碍。在听觉注意过程中，nAChRs的激活被认为改善了注意过滤--增强了对重要刺激的处理，并抑制了分散注意力的刺激，这似乎涉及到缩小听觉系统中的频率感受野(RF)。我们假设nAChRs的激活将缩小初级听觉皮质(A1)的RF调谐，并增强缩小的RF内的处理，nAChRs的这些细胞活动有助于注意过滤。目标1将确定nAChRs的激活如何改变 A1，使用音频诱发电流源密度(CSD)曲线来确定频率RF。目的2将确定涉及丝裂原活化蛋白激酶(MAPK)的细胞内信号转导的尼古丁激活如何在A1中招募神经元亚群，特别是中间神经元。目标3将确定在已识别的中间神经元中激活nAChRs和MAPK是如何改变声音处理的。这些目标将确定A1中nAChRs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尼古丁机制，从而帮助开发治疗听觉加工障碍的药物。