Nicotinic enhancement of auditory-cognitive processing

烟碱增强听觉认知处理

• 批准号: 10056218
• 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/10056218
• 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.

项目概要/摘要 对于听觉来说，与其他感官一样，更高层次的处理会随着注意力相关的释放而得到改善。 神经递质乙酰胆碱和大脑中烟碱乙酰胆碱受体（nAChR）的激活。 同样，通过全身施用尼古丁来激活 nAChR，听觉认知功能得到增强， 因 nAChR 的药理学阻断而受损，并因疾病引起的 nAChR 丧失而逐渐减弱 nAChR（例如，在阿尔茨海默病中）会降低内源性乙酰胆碱的功效。它被广泛 因此，一致认为 nAChR 对于感觉认知功能很重要。结果，选择性烟碱 激动剂正在被开发用于治疗认知障碍；然而，迄今为止，这些只是 取得一定的成功和进一步的进展需要更好地了解 nAChRs 如何调节皮质 加工。该项目将测试尼古丁通过以下方式产生认知增强作用的假设： “锐化”两个关键区域的神经表征，初级听觉皮层（A1）和前额叶皮层（PFC），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，这些神经元可以通过以下方式识别： 蛋白质标记物，血管活性肠肽（VIP）。目标 1 将确定 nAChRs 如何调节神经 使用体外脑切片和体内电生理记录研究小鼠 A1 和 PFC 中的电路。使用 转基因小鼠品系将能够记录已识别神经元（包括 VIP 神经元）和记录 来自 a2 nAChRs“被敲除”或变得过敏的小鼠。目标 2 将确定尼古丁如何改变 使用高密度单细胞记录观察大鼠听觉提示行为期间 A1 和 PFC 神经元的活动 以及执行新的听觉序列记忆任务的小鼠。再次，尼古丁的影响将被比较 野生型、a2 敲除小鼠和 a2 过敏小鼠。目标 3 将使用化学遗传学技术来确定是否 抑制 VIP 神经元或 a2 nAChR 可阻断尼古丁对体外和体内神经处理的影响， 和行为表现。该项目将促进对听觉认知中 nAChR 的理解 A1 和 PFC 中 VIP 中间神经元和 a2 nAChR 的功能和具体参与。确认 重要的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。