Nicotinic enhancement of auditory-cognitive processing

烟碱增强听觉认知处理

• 批准号: 10307558
• 负责人: Raju Metherate
• 金额: $ 61.54万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307558
• 关键词: Acetylcholine; Acoustics; Address; Affect; Agonist; Alzheimer' s Disease; Animals; Attention; Auditory; Auditory area; Behavior; Behavioral; Brain; Cells; Cerebral cortex; Code; Cognition Disorders; Cognitive; Cre driver; Cues; Development; Disease; Electrophysiology (science); Environment; Exhibits; Goals; Hearing; Hippocampus (Brain); Hypersensitivity; Immunohistochemistry; Impairment; In Vitro; Injections; Interneurons; Knock-out; Mediating; Membrane Potentials; Memory; Mus; Neurons; Nicotine; Nicotinic Agonists; Nicotinic Receptors; Parvalbumins; Performance; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Pilot Projects; Play; Population; Positioning Attribute; Prefrontal Cortex; Rattus; Role; Sensory; Site; Slice; Somatostatin; Speech; Synapses; Synaptic Membranes; Synaptic plasticity; System; Techniques; Testing; Transgenic Mice; Vasoactive Intestinal Peptide; Virus; Wild Type Mouse; Work; auditory processing; cognitive enhancement; cognitive function; density; desensitization; designer receptors exclusively activated by designer drugs; directed attention; hippocampal pyramidal neuron; improved; in vivo; inhibitory neuron; interest; neural circuit; neurotransmitter release; novel; novel therapeutics; optogenetics; protein biomarkers; receptive field; receptor; relating to nervous system; response; sensory cortex; sound; success; vector

PROJECT SUMMARY / ABSTRACT For hearing, as for other senses, higher-level processing improves with attention-related release of the neurotransmitter acetylcholine and activation of nicotinic acetylcholine receptors (nAChRs) in the brain. Similarly, auditory-cognitive function is enhanced by systemic administration of nicotine to activate nAChRs, impaired by pharmacological blockade of nAChRs, and progressively diminished by disease-induced loss of nAChRs (e.g., in Alzheimer’s disease) that reduces the efficacy of endogenous acetycholine. It is widely agreed, therefore, that nAChRs are important for sensory-cognitive function. As a result, selective nicotinic agonists are being developed as treatments for cognitive disorders; however, to date these are only moderately successful and further progress requires a better understanding of how nAChRs regulate cortical processing. This project will test the hypothesis that nicotine produces its cognitive-enhancing effects by “sharpening” neural representations in two key regions, primary auditory (A1) and prefrontal (PFC) cortex, and that nicotine’s effects depend on activating a2 nAChRs located on inhibitory neurons that can be identified by the protein marker, vasoactive intestinal peptide (VIP). Aim 1 will determine how nAChRs regulate neural circuits in mouse A1 and PFC using in vitro brain slices and in vivo electrophysiological recordings. The use of transgenic mouse lines will enable recordings from identified neurons, including VIP neurons, and recordings from mice with a2 nAChRs “knocked out” or made hypersensitive. Aim 2 will determine how nicotine alters the activity of A1 and PFC neurons during auditory-cued behavior using high-density single-cell recordings in rats and mice performing a novel auditory-sequence memory task. Again, nicotine effects will be compared across wild-type, a2 knock-out and a2 hypersensitive mice. Aim 3 will use chemogenetic techniques to determine if suppression of VIP neurons or a2 nAChRs blocks nicotine’s effects on neural processing, in vitro and in vivo, and behavioral performance. This project will advance the understanding of nAChRs in auditory-cognitive function and the specific involvement of VIP interneurons and a2 nAChRs in A1 and PFC. Confirmation of an important role will guide development of more effective and selective drug therapies to enhance auditory- cognitive function.

项目摘要 /摘要 对于听力，至于其他感官，高级处理可以随着与注意力相关的释放而改善 神经递质乙酰胆碱和大脑中烟碱乙酰胆碱受体（NACHRS）的激活。 同样，通过全身性给予尼古丁激活NACHR，增强了听觉认知功能， 药物阻断NACHRS的障碍，并逐渐受到疾病诱导的丧失的减少 NACHR（例如，在阿尔茨海默氏病）降低了内源性乙烯胆碱的有效性。它是广泛的 因此，同意NACHR对于感觉认知功能很重要。结果，选择性烟碱 激动剂正在发展为认知障碍的治疗方法。但是，到目前为止，这些只是 中等成功和进一步的进步需要更好地了解NACHRS的皮质调节 加工。该项目将检验以下假设：尼古丁通过 在两个关键区域，主要听觉（A1）和前额叶（PFC）皮层中的“锐化”神经表示，以及 尼古丁的作用取决于激活位于抑制性神经元上的A2 NACHR，可以​​通过 蛋白质标记，血管活性肠肽（VIP）。 AIM 1将确定NACHR如何调节神经元 小鼠A1和PFC中的电路使用体外脑切片和体内电生理记录。使用 转基因小鼠线将启用来自已识别神经元的记录，包括VIP神经元和记录 来自A2 NACHRS的小鼠“被击倒”或使过敏。 AIM 2将决定尼古丁如何改变 使用大鼠中的高密度单细胞记录在听觉表现过程中A1和PFC神经元的活性 和执行新型听觉序列记忆任务的小鼠。同样，将在整个环境中比较尼古丁的作用 野生型，A2敲除和A2超敏小鼠。 AIM 3将使用化学发生技术来确定是否是否 抑制VIP神经元或A2 NACHRS会阻止尼古丁对神经化学的影响，体外和体内， 和行为表现。该项目将提高对听觉认知的NACHR的理解 VIP中间神经元和A2 NACHRS在A1和PFC中的功能和特定参与。确认 重要作用将指导开发更有效和选择性的药物疗法以增强听觉 - 认知功能。