Nicotinic enhancement of auditory-cognitive processing

项目摘要/摘要 对于听力，就像对于其他感官一样，更高水平的加工会随着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型乙酰胆碱受体(NAChRs)的激活。 同样，通过全身注射尼古丁来激活nAChRs，听觉认知功能也会得到增强。 通过对nAChRs的药理阻断而受损，并因疾病导致的 NAChRs(例如，在阿尔茨海默病中)，它会降低内源性乙酰胆碱的疗效。它是广泛存在的 因此，一致认为nAChRs对感觉-认知功能很重要。因此，选择性尼古丁 激动剂正在被开发用于治疗认知障碍；然而，到目前为止，这些只是 要取得适度的成功和进一步的进展，需要更好地理解nAChRs如何调节皮质 正在处理。该项目将验证尼古丁通过以下途径产生认知增强作用的假设 在两个关键区域--初级听觉(A1)和前额叶(PFC)皮质--的“锐化”神经表现，以及 尼古丁的作用依赖于激活位于抑制性神经元上的a2 nAChRs，这种受体可以通过 蛋白标记物血管活性肠肽(VIP)。目标1将确定nAChRs如何调节神经 使用体外脑片和体内电生理记录的小鼠A1和PFC中的电路。对.的使用 转基因小鼠品系将能够记录已识别的神经元，包括VIP神经元，以及记录 来自nAChRs为2的小鼠的基因被“敲除”或变得过敏。目标2将确定尼古丁如何改变 高密度单细胞记录下大鼠听觉提示行为中A1和PFC神经元的活动 以及执行一种新的听觉序列记忆任务的小鼠。同样，尼古丁的影响将在不同的地区进行比较 野生型、a2基因敲除和a2超敏小鼠。目标3将使用化学遗传技术来确定 在体外和体内，抑制VIP神经元或a2 nAChRs可以阻断尼古丁对神经加工的影响， 和行为表现。该项目将促进对nAChRs在听觉认知中的理解 A1和PFC中VIP中间神经元和a2nAChRs的功能和特异性参与。确认一份 重要作用将指导更有效和更有选择性的药物治疗的发展，以增强听力- 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.