Division of Clinical and Computational Neuroscience, Krembil Brain Institute, University Health Network, Toronto, Ontario M5T 1M8, Canada.
Departments of Medicine, Neurology and Physiology, University of Toronto, Toronto, Ontario M5S 3H2, Canada.
eNeuro. 2023 Aug 29;10(8). doi: 10.1523/ENEURO.0215-23.2023. Print 2023 Aug.
Discerning the contribution of specific ionic currents to complex neuronal dynamics is a difficult, but important, task. This challenge is exacerbated in the human setting, although the widely characterized uniqueness of the human brain compared with preclinical models necessitates the direct study of human neurons. Neuronal spiking frequency preference is of particular interest given its role in rhythm generation and signal transmission in cortical circuits. Here, we combine the frequency-dependent gain (FDG), a measure of spiking frequency preference, and novel analyses to dissect the contributions of individual ionic currents to the suprathreshold features of human layer 5 (L5) neurons captured by the FDG. We confirm that a contemporary model of such a neuron, primarily constrained to capture subthreshold activity driven by the hyperpolarization-activated cyclic nucleotide gated (h-) current, replicates key features of the FDG both with and without h-current activity. With the model confirmed as a viable approximation of the biophysical features of interest, we applied new analysis techniques to quantify the activity of each modeled ionic current in the moments before spiking, revealing unique dynamics of the h-current. These findings motivated patch-clamp recordings in analogous rodent neurons to characterize their FDG, which confirmed that a biophysically detailed model of these neurons captures key interspecies differences in the FDG. These differences are correlated with distinct contributions of the h-current to neuronal activity. Together, this interdisciplinary and multispecies study provides new insights directly relating the dynamics of the h-current to suprathreshold spiking frequency preference in human L5 neurons.
辨别特定离子电流对复杂神经元动力学的贡献是一项困难但重要的任务。在人类环境中，这一挑战更加严峻，尽管与临床前模型相比，人类大脑的特征具有广泛的独特性，但需要直接研究人类神经元。神经元放电频率偏好是一个特别有趣的问题，因为它在皮质回路中的节律产生和信号传递中起作用。在这里，我们结合频率相关增益（FDG），这是一种衡量放电频率偏好的方法，以及新的分析方法，来剖析单个离子电流对 FDG 捕获的人类第 5 层（L5）神经元的超阈值特征的贡献。我们证实，这种神经元的现代模型主要受超极化激活环核苷酸门控（h-）电流驱动的亚阈值活动的限制，无论是在有 h-电流活动还是没有 h-电流活动的情况下，都复制了 FDG 的关键特征。在模型被证实是对感兴趣的生物物理特征的可行近似之后，我们应用新的分析技术来量化在放电前瞬间每个模拟离子电流的活动，揭示了 h-电流的独特动力学。这些发现促使我们在类似的啮齿动物神经元中进行膜片钳记录以描述它们的 FDG，这证实了这些神经元的生物物理详细模型捕捉到了 FDG 中关键的种间差异。这些差异与 h-电流对神经元活动的独特贡献相关。总的来说，这项跨学科和多物种的研究提供了新的见解，直接将 h-电流的动力学与人类 L5 神经元的超阈值放电频率偏好联系起来。
