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

摘要/摘要 20多年的研究表明，听觉系统过程在痴呆症中的重要性得到了证实 听力损失、认知能力下降和皮质萎缩1、2、3。报告显示，患痴呆症的风险增加 听力损失大于24dBSPL4的60岁以上人群增加36%。此外，关系 已知听力与AD、轻度认知障碍(MCI)或相关痴呆(RD)之间存在， 也延伸到故障的网状激活系统5。网状觉醒系统可能是一个机械环节 听力损失和痴呆之间的关系，因为它的激活是诱导大脑中依赖学习的可塑性所必需的 作为记忆形成基础的听觉皮质(ACX)。网状结构的唤醒与学习效应 形成是由ACX上的基底前脑(胆碱能(ACh)输入的主要来源)介导的，这是 对于学习到的声音，需要和充分地诱导大脑皮层重新调谐7，8和行为长期记忆。 事实上，一种解释为什么听力损失与AD/RD10、11的皮质加速损失有关的解释可能失败了 ACH介导的学习诱导过程未能将ACX整合到更大的，而且可能 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12，13的机制 恢复和维持记忆的皮质功能所必需的依赖活动的转录过程。如果 成功地，我们之前的工作表明，ACX可塑性也可以降低20-30dBSPL的声诱发阈值 (从而提高中枢对重要声音的敏感度)，当应用于治疗时，可以额外 抵消与AD14风险相关的外周听力损失。亲本R01旨在研究 表观遗传和胆碱能机制在听觉学习、记忆和学习诱导中的协同作用 皮质可塑性。在这里，我们建议在早发的下一代模型(NexGenMo)中研究这种协同作用 携带瑞典家族性淀粉样前体突变的CRISPR/Cas9转基因大鼠的AD 蛋白质(APPS)15.母体R01中的数据显示，一种药理学的组蛋白-脱乙酰基酶3(HDAC3)抑制剂 可以提高在听觉联想辨别任务中的表现，并有助于形成高度 野生型大鼠的声音特异性长期记忆。促进学习和记忆的敏锐度似乎是 由ACX胆碱能调节关键基因的表观遗传调节所介导，使其能够“重新调节”到 学习(并随后记住)声音。在这里，我们建议在应用程序上使用HDAC3-Inhibitor 纯合子APPS/S与对照组APPH/h大鼠的“疾病”背景。如果HDAC3抑制能挽救观察到的 听觉学习和记忆缺陷成功地增强了大脑皮层对重要声音的表征，它 可以防止那些重要声音或整个记忆网络的未来记忆丢失，这 可能最终保护大脑皮层免于萎缩，延缓进展为AD/RD。其中的初步数据是 首次对NexGenMo进行行为学验证，用于AD的早期检测，并为测试奠定了基础 寻找ACX中HDAC3/ACH的适时协同作用，以挽救痴呆患者的听觉和认知功能。

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.