Babola Travis A, Donovan Naomi, Darcy Sean S, Spjut Catalina D, Kanold Patrick O
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland 21205.
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland 21205
eNeuro. 2025 Feb 27;12(2). doi: 10.1523/ENEURO.0465-24.2025. Print 2025 Feb.
Transgenic mice provide unprecedented access to manipulate and visualize neural circuits; however, those on a C57BL/6 background develop progressive hearing loss, significantly confounding systems-level and behavioral analysis. While outbreeding can limit hearing loss, it introduces strain variability and complicates the generation of complex genotypes. Here, we propose an approach to preserve hearing by crossing transgenic mice with congenic B6.CAST- mice, which maintain low-threshold hearing into adulthood. Widefield and two-photon imaging of the auditory cortex revealed that 2.5-month-old C57BL/6 mice exhibit elevated thresholds to high-frequency tones and widespread cortical reorganization, with most neurons responding best to lower frequencies. In contrast, C57BL/6 mice exhibited robust neural responses across tested frequencies and sound levels (4-64 kHz, 30-90 dB SPL) and retained low thresholds into adulthood. Our approach offers a cost-effective solution for generating complex genotypes and facilitates more interpretable systems neuroscience research by eliminating confounding effects from hearing loss.
转基因小鼠为操纵和可视化神经回路提供了前所未有的途径；然而，那些具有C57BL/6背景的小鼠会出现进行性听力损失，这严重干扰了系统水平和行为分析。虽然远交可以限制听力损失，但它会引入品系变异性，并使复杂基因型的产生变得复杂。在这里，我们提出了一种方法，通过将转基因小鼠与同源的B6.CAST-小鼠杂交来保护听力，后者在成年后仍保持低阈值听力。对听觉皮层的广角和双光子成像显示，2.5个月大的C57BL/6小鼠对高频音调的阈值升高，并且皮层广泛重组，大多数神经元对较低频率反应最佳。相比之下，C57BL/6小鼠在测试的频率和声音水平（4-64 kHz，30-90 dB SPL）范围内表现出强烈的神经反应，并且成年后仍保持低阈值。我们的方法为产生复杂基因型提供了一种经济有效的解决方案，并通过消除听力损失的混杂效应，促进了更具可解释性的系统神经科学研究。
