A New Computational Model for Neuro-Glio-Vascular Coupling: Astrocyte Activation Can Explain Cerebral Blood Flow Nonlinear Response to Interictal Events

Developing a clear understanding of the relationship between cerebral blood flow (CBF) response and neuronal activity is of significant importance because CBF increase is essential to the health of neurons, for instance through oxygen supply. This relationship can be investigated by analyzing multimodal (fMRI, PET, laser Doppler…) recordings. However, the important number of intermediate (non-observable) variables involved in the underlying neurovascular coupling makes the discovery of mechanisms all the more difficult from the sole multimodal data. We present a new computational model developed at the population scale (voxel) with physiologically relevant but simple equations to facilitate the interpretation of regional multimodal recordings. This model links neuronal activity to regional CBF dynamics through neuro-glio-vascular coupling. This coupling involves a population of glial cells called astrocytes via their role in neurotransmitter (glutamate and GABA) recycling and their impact on neighboring vessels. In epilepsy, neuronal networks generate epileptiform discharges, leading to variations in astrocytic and CBF dynamics. In this study, we took advantage of these large variations in neuronal activity magnitude to test the capacity of our model to reproduce experimental data. We compared simulations from our model with isolated epileptiform events, which were obtained in vivo by simultaneous local field potential and laser Doppler recordings in rats after local bicuculline injection. We showed a predominant neuronal contribution for low level discharges and a significant astrocytic contribution for higher level discharges. Besides, neuronal contribution to CBF was linear while astrocytic contribution was nonlinear. Results thus indicate that the relationship between neuronal activity and CBF magnitudes can be nonlinear for isolated events and that this nonlinearity is due to astrocytic activity, highlighting the importance of astrocytes in the interpretation of regional recordings.

清晰阐释脑血流（cerebral blood flow, CBF）响应与神经元活动之间的关联具有重要学术价值，因为脑血流增加对神经元健康至关重要，例如通过为神经元提供氧气。可通过分析多模态（功能磁共振成像fMRI、正电子发射断层扫描PET、激光多普勒等）记录来研究这一关联。然而，潜在神经血管耦合过程中涉及大量不可观测的中间变量，使得仅依靠多模态数据难以揭示其背后的机制。本研究提出了一种基于体素群体尺度构建的新型计算模型，该模型采用符合生理学特征但形式简洁的方程，以便于对区域多模态记录数据进行解读。该模型通过神经-胶质-血管耦合机制，将神经元活动与区域脑血流动力学关联起来。这一耦合过程涉及被称为星形胶质细胞（astrocytes）的胶质细胞群体，星形胶质细胞通过参与神经递质（谷氨酸glutamate与γ-氨基丁酸GABA）的循环代谢，并作用于邻近血管，实现这一耦合。在癫痫状态下，神经元网络会产生痫样放电，进而引发星形胶质细胞活动与脑血流动力学的变化。本研究利用神经元活动强度的这类显著变化，检验了模型重现实验数据的能力。我们将模型模拟结果与孤立性痫样放电事件的实验数据进行对比：该实验通过向大鼠局部注射荷包牡丹碱后，同步采集在体局部场电位与激光多普勒信号完成。研究结果表明，低强度放电以神经元贡献为主，而高强度放电则存在显著的星形胶质细胞贡献。此外，神经元对脑血流的贡献呈线性关系，而星形胶质细胞的贡献则呈非线性关系。综上，研究结果显示：对于孤立性痫样事件，神经元活动与脑血流强度之间的关系可呈现非线性特征，且该非线性源于星形胶质细胞的活动，这凸显了星形胶质细胞在区域记录数据解读中的重要性。