Xu Zheng, Xue Binghan, Kao Joseph P Y, Kanold Patrick O
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland 20215.
Department of Biology, University of Maryland, College Park, Maryland 20742.
eNeuro. 2025 Feb 6;12(2). doi: 10.1523/ENEURO.0378-24.2024. Print 2025 Feb.
A common impairment in aging is age-related hearing loss (presbycusis), which manifests as impaired spectrotemporal processing. Presbycusis can be caused by a dysfunction of the peripheral and central auditory system, and these dysfunctions might differ between the sexes. To date, the circuit mechanisms in the central nervous system responsible for age-related auditory dysfunction remain mostly unknown. In the auditory cortex (ACtx), aging is accompanied by alteration in normal inhibitory (GABA) neurotransmission and changes in excitatory (NMDA and AMPA) synapses, but which circuits are affected has been unclear. Here we investigated how auditory cortical microcircuits change with age and if sex-dependent differences existed. We performed laser-scanning photostimulation (LSPS) combined with whole-cell patch-clamp recordings from layer (L) 2/3 cells in the primary auditory cortex (A1) in young adult (2-3 months) and aged (older than 18 months) male and female CBA/CaJ mice which have normal peripheral hearing. We found that L2/3 cells in aged male animals display functional hypoconnectivity of inhibitory circuits originating from L2/3 and L4. Compared with cells from young adult mice, cells from aged male mice have weaker excitatory connections from L2/3. We also observed an increased diversity of excitatory and inhibitory inputs. These results suggest a sex-specific reduction and diversification in excitatory and inhibitory intralaminar cortical circuits in aged mice compared with young adult animals. We speculate that these unbalanced changes in cortical circuits contribute to the functional manifestations of age-related hearing loss in both males and females.
衰老过程中一种常见的损伤是年龄相关性听力损失（老年性聋），其表现为频谱时间处理功能受损。老年性聋可能由外周和中枢听觉系统功能障碍引起，而且这些功能障碍在性别之间可能存在差异。迄今为止，中枢神经系统中导致年龄相关性听觉功能障碍的神经回路机制大多仍不清楚。在听觉皮层（ACtx）中，衰老伴随着正常抑制性（GABA）神经传递的改变以及兴奋性（NMDA和AMPA）突触的变化，但哪些神经回路受到影响尚不清楚。在这里，我们研究了听觉皮层微回路如何随年龄变化以及是否存在性别依赖性差异。我们对年轻成年（2 - 3个月）和老年（18个月以上）的雄性和雌性CBA/CaJ小鼠的初级听觉皮层（A1）第2/3层细胞进行了激光扫描光刺激（LSPS）并结合全细胞膜片钳记录，这些小鼠具有正常的外周听力。我们发现老年雄性动物的第2/3层细胞表现出来自第2/3层和第4层的抑制性回路功能连接减弱。与年轻成年小鼠的细胞相比，老年雄性小鼠的细胞从第2/3层获得的兴奋性连接较弱。我们还观察到兴奋性和抑制性输入的多样性增加。这些结果表明，与年轻成年动物相比，老年小鼠的兴奋性和抑制性层内皮质回路存在性别特异性的减少和多样化。我们推测，这些皮质回路的不平衡变化导致了雄性和雌性年龄相关性听力损失的功能表现。
