Towards a biophysical model of human cortical neurophysiological signatures that incorporates cellular and cell type biophysics, transcriptomics, and morphology

项目摘要 在过去的十年中，单细胞级别的数据前所未有地积累，产生了独特的、 基因表达模式、形态和电生理特征的多模式集合。如此之高- 对大脑中神经元类型的分辨率普查构成了迈向机械论的关键一步 了解电路和脑计算。然而，将细胞身份和活动与电路和 神经生理信号仍然令人望而生畏。这项提议的中心目标是制定一套公开的 可用于测试有关角色的机械性假设的计算模型、工具和资源 神经回路功能的不同神经元类型，可用于分析神经数据，并可用于 确定大脑皮质功能的潜在生物标记物。建议的方法从构建 单个人类新皮质神经元的严格计算模型将转录、形态和 生理学。接下来，我们将神经元连接到大脑皮层回路，模拟它们的活动，并模拟相关的 从这些回路产生的神经生理信号。在所有步骤中，模型都受到指导，并进行比较 到，现有的最先进的测量。作为原则证明，我们使用人类大脑皮层电路模型 研究h通道携带的超极化激活的非特定阳离子电流ih的影响。 具体地说，我们最近发现，人类锥体FREM3神经元中ih的差异改变了它们的 突触整合特性。FREM3中沿人类2/3层的Ih深度梯度的存在 事实上，神经元是颗粒上皮层的基本组织原则。即便如此，它的作用以及它是如何 影响电路处理和相关的神经生理信号仍然未知。人类大脑皮层 电路模型提供了一个理想的试验台，其中关于FREM3和H深度梯度的作用的假设可以 接受测试。首先，我们假设，尽管FREM3模型的基本尖峰特性仍然广泛存在 如果不受深层次和浅层次FREM3 iH差异的影响，电路活动将受到显著影响，并且 符合检测梯度将沿皮质深度轴出现(由 FREM3)。此外，我们假设在电路的深处，FREM3既增加了ih，也增加了ih 符合检测，局部细胞外信号会在较慢的频段表现出较低的功率和较高的功率 为速度更快的汽车提供动力。因此，我们预计ih(浅层神经元)的减少会导致 低速伽马的功率和中高伽马频段的减少。为了检验这些假设，我们将 在我们的电路模型中实例化FREM3的iH电导中的特定扰动，同时保留所有其他 模型参数不受干扰。我们希望这些将与科学界共享的工具， 将促进细胞和细胞类型属性、神经生理学研究之间的对话 测量，以及阐明人脑回路功能的机械方法。

Project Summary The past decade has seen an unprecedented accumulation of data at the single-cell level giving rise to unique, multimodal sets of gene expression patterns, morphologies, and electrophysiology characteristics. This high- resolution census of neuronal types in the brain constitutes an essential step towards a mechanistic understanding of circuits and brain computations. However, linking cellular identity and activity to circuits and neurophysiological signals remains daunting. The central goal of this proposal is to develop a set of publicly available computational models, tools and resources that allow testing mechanistic hypotheses about the role of different neuronal types in neural circuit function, that can be used to analyze neural data, and can serve to identify potential biomarkers of cortical function in the brain. The proposed approach starts with building rigorous computational models of individual human neocortical neurons linking transcription, morphology, and physiology. Next, we connect neurons into cortical circuits, emulate their activity and simulate the associated neurophysiological signals generated from those circuits. At all steps, the models are guided by, and compared to, existing state-of-the-art measurements. As a proof-of-principle, we use a human cortical circuit model to study the impact of the hyperpolarization-activated non-specific cation current, Ih, carried by h-channels. Specifically, we recently showed that Ih differences within human pyramidal FREM3 neurons alter their synaptic integration properties. The existence of an Ih depth gradient along human layer 2/3 in FREM3 neurons in fact is a fundamental organizing principle of the supragranular cortex. Even so, its role and how it affects circuit processing and associated neurophysiological signals remains unknown. The human cortical circuit model provides an ideal testbed where hypotheses about the role of the FREM3 Ih depth gradient can be tested. First, we hypothesize that while fundamental spike properties of FREM3 models remain broadly unaffected by deep vs. superficial FREM3 Ih-differences, the circuit activity will be substantially affected and a coincidence detection gradient will emerge along the cortical depth axis (facilitated by the Ih gradient in FREM3). Furthermore, we hypothesize that deep in the circuit where FREM3 has both increased Ih and coincidence detection, the local extracellular signals will exhibit lower power in the slower bands and increased power in faster ones. Accordingly, we expect decreased Ih (superficial neurons) to lead to a relative increase in power in theta-slow gamma and a decrease in the mid-high gamma band. To test these hypotheses, we will instantiate specific perturbations in the Ih conductance of FREM3 in our circuit model while leaving all other model parameters unperturbed. We expect that these tools, which will be shared with the scientific community, will facilitate the dialogue between the study of cellular and cell type properties, neurophysiological measurements, and mechanistic approaches to elucidate function in human brain circuits.