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

AD 的 NexGenMo，用于治疗听觉学习、记忆的缺陷，并通过操纵听觉系统的可塑性来挽救这种缺陷

• 批准号: 10287976
• 负责人: Kasia Bieszczad
• 金额: $ 39.18万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10287976
• 关键词: Acetylcholine; Acoustic Stimulation; Acoustics; Adult; Age; Age-Years; Age-associated memory impairment; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease related dementia; Amyloid beta-Protein Precursor; Animal Model; Area; Arousal; Atrophic; Auditory; Auditory area; Auditory system; Behavior; Behavioral; Brain; Brain Diseases; CRISPR/Cas technology; Cholinergic Receptors; Chromatin; Cognitive; Cognitive remediation; Complex; Cues; Data; Dementia; Discrimination; Disease; Early Diagnosis; Early Onset Familial Alzheimer' s Disease; Electrophysiology (science); Enzymes; Epigenetic Process; Event; Failure; Familial Dementias; Family; Future; Gatekeeping; Gene Expression; Genes; Genetic; Genetic Transcription; HDAC3 gene; Hearing; Hearing problem; Histology; Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; Human Characteristics; Impaired cognition; Impairment; Knock-in; Lead; Learning; Life; Link; Mediating; Memory; Memory Loss; Memory impairment; Modeling; Molecular Conformation; Mutation; Neurobiology; Neurodegenerative Disorders; Neuromodulator; Neuronal Plasticity; Neurophysiology - biologic function; Parents; Pathogenicity; Performance; Peripheral; Persons; Pharmaceutical Preparations; Pharmacology; Pre-Clinical Model; Presenile Alzheimer Dementia; Process; Quantitative Reverse Transcriptase PCR; Rat Protein; Rattus; Receptor Up-Regulation; Reporting; Research; Reticular Formation; Rewards; Risk; Sensory; Source; Swedish mutation; System; Testing; Therapeutic; Therapeutic Intervention; Time; Training; Transcription Initiation; Transcription Process; Translating; Treatment Efficacy; Validation; Work; aged; auditory discrimination; basal forebrain; base; behavioral impairment; cerebral atrophy; cholinergic; cognitive function; dementia risk; drug efficacy; druggable target; early onset; epigenetic regulation; experience; genetic variant; healthy aging; hearing impairment; histone modification; human disease; improved; in vivo; inhibitor/antagonist; innovation; life history; long term memory; mild cognitive impairment; mutant; neuroregulation; next generation; novel; pre-clinical research; precision medicine; preservation; prevent; progressive neurodegeneration; promoter; relating to nervous system; small molecule; social; sound; synergism; transcriptome sequencing; transmission process; young adult

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.

摘要/摘要 痴呆症中听觉系统过程的重要性通过20多年的研究验证了链接 在听力损失，认知能力下降和皮质萎缩症之间1,2,3。报告表明，痴呆症的风险增加 60岁以上的人的听力损失大于24dB SPL4。此外，人际关系 知道听力能力和AD之间存在，轻度认知障碍（MCI）或相关痴呆症（RD）， 还扩展到失败的网状激活系统5。网状唤醒系统可能是机械链接 在听力损失和痴呆之间 构成内存形成基础的听觉皮层（ACX）6。网状的唤醒和学习效果 格式由ACX上的基本前脑（胆碱能（ACH）输入的主要来源）介导， 对于学习的声音而言，必要且足以诱导皮质重新调整7,8和行为长期存储器9。 实际上，解释了为什么听力损失与AD/RD10,11的加速皮质损失有关 ACH介导的学习引起的过程，该过程未能将ACX整合到更大的范围内，甚至可能 神经保护性，内存网络。一个令人兴奋的潜在解决方案是靶向表观遗传组的靶向机制12,13 恢复和维持与活动函数不可或缺的记忆函数的共同的转录过程。如果 成功，我们先前的工作表明，ACX可塑性也可以将声音诱发的阈值降低20-30 dB SPL （增强对重要声音的中央敏感性），当对此进行治疗时，可以另外 抵消与发展AD14风险相关的外围听力损失。父母R01的目的是学习 在听觉学习，记忆和学习引起的表观遗传和胆碱能机制之间的协同作用 皮质可塑性。在这里，我们建议在早期发作的下一代模型（Nexgenmo）中研究这种协同作用 CRISPR/CAS9中的广告一般修饰的大鼠，具有余的大鼠，具有瑞典淀粉样蛋白前体的瑞典家族突变 蛋白质（应用）15。母体R01中的数据表明，药物组蛋白 - 二乙基酶3（HDAC3） - 抑制剂 可以提高听觉关联歧视任务的表现，并促进高度形成 野生型大鼠的音调长期记忆。促进的学习和记忆敏锐度似乎是 通过对ACX中胆碱能调节的关键基因的表观遗传调节介导的，使其“重新调查”到 学会了（随后记住）声音。在这里，我们建议在应用程序上使用HDAC3抑制剂 纯合应用中的“疾病”背景与控制Apph/H大鼠。如果抑制HDAC3可以挽救观察到 听觉学习和记忆定义以成功增强重要声音的皮质表示 可以保护这些重要声音或整个内存网络的未来记忆丧失， 最终可以保护皮质免受萎缩和延迟发展为AD/RD。内部的初步数据是 此NexgenMo的首次行为验证，用于对AD的早期检测，并为测试奠定了基础 为了获得ACX中HDAC3/ACH协同作用，以挽救痴呆症的听觉和认知功能。