Nicotinic enhancement of auditory-cognitive processing

项目概要/摘要 对于听觉，就像其他感官一样，高层次的处理随着与注意力相关的释放而改善。 神经递质乙酰胆碱和脑中烟碱乙酰胆碱受体（nAChR）的活化。 类似地，全身给予尼古丁以激活nAChR， 通过药理学阻断nAChR受损，并通过疾病诱导的 nAChR（例如，在阿尔茨海默病中），其降低内源性乙酰胆碱的功效。人们普遍 因此，同意nAChRs对感觉认知功能很重要。因此，选择性尼古丁 正开发激动剂作为认知障碍的治疗;然而，迄今为止，这些仅 要想获得中等程度的成功和进一步的进展，需要更好地了解nAChRs如何调节皮质神经元的功能。 处理.该项目将通过以下方式验证尼古丁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（A1）和前额叶（PFC）皮层， 尼古丁的作用取决于激活位于抑制性神经元上的α 2 nAChR， 血管活性肠肽（VIP）蛋白标志物。目的1将确定nAChRs如何调节神经元的 使用体外脑切片和体内电生理记录在小鼠A1和PFC中的电路。使用 转基因小鼠品系将能够记录来自鉴定的神经元，包括VIP神经元， 来自α 2 nAChR“敲除”或变得过敏的小鼠。目标2将确定尼古丁如何改变 高密度单细胞记录大鼠行为线索诱导过程中A1和PFC神经元的活动 和小鼠进行一项新的记忆序列任务。同样，尼古丁的作用将在 野生型、α 2敲除和α 2过敏小鼠。目标3将使用化学遗传学技术来确定是否 在体外和体内，VIP神经元或α 2 nAChR的抑制阻断尼古丁对神经加工的作用， 和行为表现。该项目将促进对nAChRs在神经认知中的理解， VIP中间神经元和a2 nAChR在A1和PFC中的功能和特异性参与。 重要的作用将指导开发更有效和选择性的药物治疗，以提高听觉- 认知功能

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.