GRM7基因影响老年性聋患者兴奋/抑制性神经递质平衡的影像遗传学研究

Presbycusis (PC) is the principal cause of hearing disability in the elderly. However, the biological mechanisms of PC still remain unclear. Glutamate (Glu) and gamma-aminobutyric acid (GABA) are the main excitation and inhibitory neurotransmitters in the brain. Magnetic resonance spectroscopy studies found increased Glu concentrations in the auditory cortex in patients with presbycusis. Our study has found decreased GABA concentrations in the auditory cortex in patients with presbycusis using spectral editing techniques, and changed functional connectivity was also found in the Heschl's gyrus (HG) of auditory network in our preliminary study. The GRM7 gene is a susceptibility gene for PC. Animal studies have shown the GRM7 gene encoding protein regulates concentrations of Glu and GABA in the brain. Therefore, we hypothesize that Glu/GABA ratios of auditory cortex can be used as a sensitive imaging parameter of PC, and the single nucleotide polymorphisms of GRM7 gene could affect Glu/GABA ratios. In the current design, large sample of PC patients and matched normal controls will be recruited. The specific auditory function and single nucleotide polymorphism for the GRM7 gene of all the subjects will be tested. Then changes of Glu/GABA ratios and functional connectivity in the auditory cortex, and their relationship in patients with PC will be investigated using spectral editing techniques and resting-state fMRI. Finally, the relationships between individual genotypes and Glu/GABA ratios will be explored based on imaging genetics approach. In conclusion, our project aims to elucidate the biological mechanisms of PC from levels of genetics, brain and auditory function, and may provide the imaging markers for the diagnosis and treatment of PC.

老年性聋（PC）是老年人听力残疾的首要原因，但是PC的神经生物学机制仍不明确。Glu和GABA是脑内主要兴奋和抑制性神经递质。磁共振波谱证实PC患者听觉皮层Glu含量增加，我们利用波谱编辑技术发现患者该区域GABA含量降低，预实验显示听觉网络内颞横回的功能连接异常。动物研究发现PC易感基因GRM7编码的蛋白可调节Glu和GABA含量。因此，本课题假设听觉皮层Glu/GABA比值可作为PC的敏感影像学指标，其改变受GRM7基因多态性调控。研究拟招募大样本PC患者和健康对照者，评估特异性听觉功能并检测GRM7基因多态性；然后联合波谱编辑技术和静息态功能磁共振分析PC患者听觉皮层内Glu/GABA比值和功能连接的改变及其相互关系；并利用影像遗传学方法分析GRM7基因多态性与Glu/GABA比值的关系。本课题将同时从基因、脑和听觉功能水平研究PC的神经生物学机制，为PC的诊断和治疗提供影像学标记。

老年性聋（PC）是老年人最常见的慢性疾病之一。研究表明，PC不仅是耳蜗病变的结果，更主要取决于中枢听觉系统的改变。但目前对PC患者中枢听觉系统，特别是听觉皮层的研究较少。本项目以PC患者为研究对象，同时从基因、脑和听觉功能等三个水平研究PC的神经生物学机制，重要研究结果包括：.（1）明确了PC患者听觉功能的损害模式，并发现听觉功能的2个指标与认知损害密切相关；明确了PC患者听觉和认知相关脑区的结构和功能重塑：患者听力损失程度与听觉皮层的萎缩程度密切相关，默认网络节点的皮层萎缩与认知损害密切相关；PC患者听觉和认知脑区的自发性活动异常。.（2）明确了PC患者听觉和认知脑区在功能连接水平发生重构。而且，PC患者听觉皮层的兴奋/抑制性神经递质平衡与听觉皮层-韦尼克区（控制言语理解）之间的功能连接密切相关，揭示了PC言语识别能力下降的神经化学机制。.（3）明确了PC患者听觉网络和认知网络的重构模式：听觉网络与默认网络的网络间功能连接明显降低；PC患者听力损害程度与认知网络间的功能连接强度密切相关，PC患者语言学习记忆能力下降与听觉网络与默认网络的功能连接强度密切相关。.（4）明确了中国汉族北方人群GRM7基因的单核苷酸多态性——rs11928865与PC显著相关。而且，GRM7基因多态性可能是PC患者听觉皮层内Glu含量改变的遗传学基础。.（5）开发了脑区神经递质含量与功能连接相融合（代谢-功能耦合）的研究方法，并进一步验证了代谢-功能耦合的研究方法也适用于其它疾病模型。. 本项目明确了PC患者听觉皮层在结构、功能和代谢等三个维度的重塑机制，阐明了听觉皮层功能连接改变与兴奋/抑制性神经递质平衡的相互关系，并利用影像遗传学方法揭示了GRM7基因多态性与听觉皮层神经递质改变的关系。而且，我们发现PC患者听力损失与其认知损害密切相关；PC患者认知脑区也存在结构和功能重构。由于PC患者需要剥夺更多的认知资源去理解听觉信号减弱的言语信息，长期以往可能触发了从听觉到认知系统的级联式改变。