Cell type specific vulnerability to aging

项目摘要：认知能力下降已经是一个重大且日益严重的公共卫生问题。 认知能力下降的原因有多种。特别是，听觉是人类的核心。 沟通和年龄相关的听力损失(ARHL、老年性耳聋)本身就是一种常见的疾病 这是由于听觉通路的年龄相关变化所致。听力损失和衰老都是 与认知能力下降有关，增加阿尔茨海默病(AD)的风险。在许多 4例老年性耳聋患者外周神经功能正常，提示中枢性听觉功能发挥较大作用 系统失灵。然而，与年龄相关的中枢神经系统变化 这些功能缺陷的原因在很大程度上是未知的，因为功能和分子 中央电路的复杂性。由于缺乏知识，因此无法进行有针对性的干预。我们 假设中枢神经系统正常衰老和阿尔茨海默病的关键变化是 神经元去分化，即其功能、转录和连接功能的丧失 这种去分化在AD中发生得更快。 我们通过一系列分子和细胞神经成像实验来验证这一假说。 在老年动物和AD模型中，该模型探索了分子、连接和 ARHL的生理关联并准确识别哪些听觉皮质回路是 受年龄的影响。根据初步数据显示，终身听力训练可以防止 至少在A1中与年龄相关的一些变化，然后我们通过 由于认知功能的参与而产生的可塑性。为了实现我们的目标，我们在 大尺度单核RNAseq空间分辨星图中单个细胞的水平 原位测序、下一代基于条形码的连接技术和活体双光子成像。 我们还使用培训程序来逆转一些与年龄相关的变化。

Project Summary: Cognitive decline is an already significant and increasing public health issue. Multiple factors contribute to cognitive decline. In particular, hearing is central to human communication and age-related hearing loss (ARHL, presbycusis) by itself is a common ailment due to age-related changes along the auditory pathway. Both hearing loss and aging are associated with cognitive decline, increasing the risk for Alzheimer's disease (AD). In many cases of presbycusis peripheral function is normal, pointing to a large role of central auditory system dysfunctions. However, the age-related changes in the central nervous system that underlie these functional deficits are largely unknown due to the functional and molecular complexity of central circuits. This lack of knowledge precludes targeted interventions. We hypothesize that the key changes in normal aging and AD in the central nervous system is the dedifferentiation of neurons, that is the loss of their functional, transcriptional, and connectional identities, and that this dedifferentiation occurs more rapidly in AD. We test this hypothesis by a series of molecular and cellular neuro-imaging experiments in both aged animals and an AD model, which explores the molecular, connectomic, and physiological correlates of ARHL and identifies precisely which auditory cortical circuits are impacted by aging. Based on preliminary data showing that lifelong auditory training can prevent at least some of the age-related changes in A1, we then develop therapeutic strategies through plasticity induced by engagement of cognitive functions. To achieve our goals, we integrate at the level of single cells across large scale single-nucleus RNAseq, spatially resolved STARmap in situ sequencing, next-generation barcode-based connectomics, and in vivo 2-photon imaging. We also use training procedures to reverse some of the age-related changes.