A NexGenMo of AD for deficits in auditory learning, memory, and its rescue by manipulating plasticity in the auditory system

摘要/总结 20多年的研究证实了听觉系统过程在痴呆症中的重要性， 听力损失、认知能力下降和皮质萎缩之间的关系1，2，3。报告显示痴呆症的风险增加 对于听力损失大于24dB SPL4的60岁以上的人，减少36%。此外，关系 已知存在于听力能力和AD、轻度认知障碍（MCI）或相关痴呆（RD）之间， 也延伸到失败的网状激活系统5。网状唤起系统可能是一个机械的联系 听力损失和痴呆之间的联系，因为它的激活是诱导学习依赖的可塑性所必需的， 听觉皮层（ACx）是记忆形成的基础。网状核的唤醒和学习效应 形成是由基底前脑（胆碱能（ACh）输入的主要来源）介导的ACx， 必要和足够的诱导皮层重新调谐7，8和行为的长期记忆9学习的声音。 事实上，解释为什么听力损失与AD/RD的加速皮质损失有关10，11可能失败 由ACh介导的学习诱导过程未能将ACx整合到更大的， 神经保护记忆网络一个令人兴奋的潜在解决方案是靶向表观基因组的机制12，13 以恢复和维持与记忆皮层功能不可或缺的活性依赖性转录过程。如果 我们先前工作已经表明ACx可塑性也可以使声诱发阈值降低20 - 30 dB SPL (thus增加对重要声音的中枢敏感性），当在治疗上应用时， 抵消与发展AD 14风险相关的外周听力损失。母体R01旨在研究 表观遗传机制和胆碱能机制在听觉学习、记忆和学习诱发的 皮质可塑性在这里，我们建议研究这种协同作用的下一代模型（NexGenMo）的早发性 CRISPR/Cas9转基因大鼠中的AD，这些大鼠携带淀粉样蛋白前体的瑞典家族突变 蛋白质（APPs）15.母体R01中的数据显示，药理学组蛋白-脱乙酰酶3（HDAC 3）-抑制剂 可以提高听觉联想辨别任务的表现，并促进高度 野生型大鼠的声音特异性长期记忆。促进学习和记忆敏锐度似乎是 通过ACx中胆碱能调节关键基因的表观遗传调控介导，使其"重新调谐"， 学习（并随后记住）声音。在这里，我们建议在APP上使用HDAC3抑制剂 在纯合APP/s与对照APPh/h大鼠中的"疾病"背景。如果HDAC3抑制可以挽救观察到的 听觉学习和记忆缺陷，以成功地增强重要声音的皮质表征，它 可能会防止未来对这些重要声音或整个记忆网络的记忆丢失， 可能最终保护皮质免于萎缩并延缓AD/RD的进展。内部的初步数据是 这是有史以来第一次对NexGenMo进行行为验证，用于AD的早期检测，并为测试奠定了基础。 在ACx中适当的HDAC3/ACh协同作用，以挽救痴呆症的听觉和认知功能。

ABSTRACT/SUMMARY Significance of auditory system processes in dementia is validated by over 20 years of research showing links between hearing loss, cognitive decline and cortical atrophy1,2,3. Reports show that the risk of dementia increases by 36% for those over the age of 60 years with a hearing loss greater than 24dB SPL4. Furthermore, relationships known to exist between hearing abilities and AD, mild cognitive impairment (MCI) or related dementias (RD), also extend to the failing reticular activating system5. The reticular arousal system may be a mechanistic link between hearing loss and dementia because its activation is required to induce learning-dependent plasticity in the auditory cortex (ACx) that underlies memory formation6. Arousal and learning effects of the reticular formation are mediated by the basal forebrain (primary source of cholinergic (ACh) input) on ACx, which is necessary and sufficient to induce cortical re-tuning7,8 and behavioral long-term memory9 for learned sounds. Indeed, an explanation for why hearing loss is related to accelerated cortical loss in AD/RD10,11 may be failing learning-induced processes mediated by ACh that fail to integrate the ACx into larger, and perhaps neuroprotective, memory networks. An exciting potential solution is to target mechanisms of the epigenome12,13 to restore and maintain activity-dependent transcriptional processes integral to cortical functions for memory. If successful, our prior work has shown ACx plasticity can also reduce sound-evoked threshold by 20-30 dB SPL (thus increasing central sensitivity to significant sounds), which when applied therapeutically, could additionally offset peripheral hearing losses associated with the risk for developing AD14. The parent R01 is aimed to study the synergy between epigenetic and cholinergic mechanisms on auditory learning, memory and learning-induced cortical plasticity. Here, we propose to study this synergy in a next-generation model (NexGenMo) of early-onset AD in CRISPR/Cas9 genetically modified rats that harbor a Swedish familial mutation of amyloid precursor protein (APPs)15. Data in the parent R01 showed that a pharmacological histone-deacetylase 3 (HDAC3)-inhibitor could improve performance in an auditory associative discrimination task and facilitate the formation of highly sound-specific long-term memory in wildtype rats. Facilitated learning and memory acuity appears to be mediated by epigenetic regulation of key genes for cholinergic modulation in ACx that enable its “re-tuning” to learned (and subsequently remembered) sounds. Here, we propose to use the HDAC3-inhibitor on the APP “disease” background in homozygous APPs/s vs. control APPh/h rats. If HDAC3-inhibition can rescue observed auditory learning and memory deficits to successfully enhance cortical representations of important sounds, it may be protective against future memory loss of those significant sounds, or of entire memory networks, which may ultimately protect the cortex from atrophy and delay progression to AD/RD. Preliminary data within is the first ever behavioral validation of this NexGenMo for early-life detection of AD and lays the groundwork to test for an opportune HDAC3/ACh synergy in ACx for the rescue of auditory and cognitive functions in dementia.