Gonschorek Dominic, Goldin Matías A, Oesterle Jonathan, Schwerd-Kleine Tom, Arlinghaus Ryan, Zhao Zhijian, Schubert Timm, Marre Olivier, Euler Thomas
Werner Reichardt Centre for Integrative Neuroscience, University of Tübingen, Tübingen, Germany.
Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.
Elife. 2025 Jan 9;13:RP98742. doi: 10.7554/eLife.98742.
Neuromodulators have major influences on the regulation of neural circuit activity across the nervous system. Nitric oxide (NO) has been shown to be a prominent neuromodulator in many circuits and has been extensively studied in the retina. Here, it has been associated with the regulation of light adaptation, gain control, and gap junctional coupling, but its effect on the retinal output, specifically on the different types of retinal ganglion cells (RGCs), is still poorly understood. In this study, we used two-photon Ca imaging and multi-electrode array (MEA) recordings to measure light-evoked activity of RGCs in the ganglion cell layer in the ex vivo mouse retina. This approach allowed us to investigate the neuromodulatory effects of NO on a cell type-level. Our findings reveal that NO selectively modulates the suppression of temporal responses in a distinct subset of contrast-suppressed RGC types, increasing their activity without altering the spatial properties of their receptive fields. Given that under photopic conditions, NO release is triggered by quick changes in light levels, we propose that these RGC types signal fast contrast changes to higher visual regions. Remarkably, we found that about one-third of the RGC types, recorded using two-photon Ca imaging, exhibited consistent, cell type-specific adaptational response changes throughout an experiment, independent of NO. By employing a sequential-recording paradigm, we could disentangle those additional adaptational response changes from drug-induced modulations. Taken together, our research highlights the selective neuromodulatory effects of NO on RGCs and emphasizes the need of considering non-pharmacological activity changes, like adaptation, in such study designs.
神经调质对整个神经系统中神经回路活动的调节具有重要影响。一氧化氮（NO）已被证明是许多神经回路中一种重要的神经调质，并已在视网膜中得到广泛研究。在这里，它与光适应、增益控制和缝隙连接耦合的调节有关，但其对视网膜输出，特别是对不同类型视网膜神经节细胞（RGC）的影响仍知之甚少。在本研究中，我们使用双光子钙成像和多电极阵列（MEA）记录来测量离体小鼠视网膜神经节细胞层中RGC的光诱发活动。这种方法使我们能够在细胞类型水平上研究NO的神经调节作用。我们的研究结果表明，NO选择性地调节对比抑制型RGC特定子集中时间反应的抑制，增加它们的活动而不改变其感受野的空间特性。鉴于在明视觉条件下，光水平的快速变化会触发NO的释放，我们提出这些RGC类型将快速对比变化信号传递到更高的视觉区域。值得注意的是，我们发现使用双光子钙成像记录的约三分之一的RGC类型在整个实验中表现出一致的、细胞类型特异性的适应性反应变化，与NO无关。通过采用顺序记录范式，我们可以将这些额外的适应性反应变化与药物诱导的调节区分开来。综上所述，我们的研究突出了NO对RGC的选择性神经调节作用，并强调在这类研究设计中需要考虑非药理学活性变化，如适应性。
