基于放电阈值调制海马时间编码的阈下场效应机理研究

The subthreshold electric fields can precisely affect the firing timing of hippocampal pyramidal neurons in the suprathreshold synaptic activity background,which implies that the subthreshold electric fields are able to accurately modulate the temporal coding of hippocampus. However, the biophysical mechanism underlying that the subthreshold electric fields participate the neural coding is not clear yet. Dynamic spike threshold can flexibly shape the neuonal temporal coding for suprathreshold stmulus,in term of which the underlying mechanism of hippocampal temporal coding modulated by subthreshold electric fields can be explained. The Soma and axon are the important areas of the onset of action potentials, which contain abundant slowly inactivating iron channels. It is suggested that soma-axonal subthreshold properties are the determining factor of spike threhold and subthreshold electric fields can remarkably interfere the subthreshold activities of neurons.Therefore,the biophysical mechanism of dynamic spike thershold is explained in this project from the view of soma-axonal subthreshold dynamics, and then the key role of dynamic spike threshold underlying that subthreshold electric fields participate hippocampal temporal coding is revealed. In this project, we for the first time establish the models of the electric field effects on hippocampus which contain slowly inactivating iron channels in soma-axon. Based on these models,we research how the firing threshold depends on the soma-axonal subthreshold oscillations and the dynamics of the slowly inactivating iron channels, and how the process influences the spike coding properties of hippocampal neural population. And thus combining the experiment data with the theoretical analysis of spike threshold, the mechanism of field effects underlying how subthreshold electric fields precisely modulate hippocampal temporal coding is shown.

研究发现阈下电场能够在阈上突触活动背景下精确影响海马神经元的放电时刻，暗示了阈下电场具有精确调制海马时间编码的能力，但其生物物理机制尚不清楚。动态的放电阈值可灵活塑造神经元对阈上刺激的时间编码，从放电阈值角度能够阐释阈下电场调制海马时间编码的潜在机理。胞体和轴突是动作电位起始的重要区域，包含丰富的阈下活动的慢失活离子通道，我们认为胞体-轴突的阈下特性是决定放电阈值的关键因素，且阈下电场对神经元的阈下活动具有显著的干预能力。因此，项目提出从胞体-轴突的阈下动力学角度阐释动态放电阈值的生物物理机制，进而揭示阈下电场通过调制放电阈值参与海马时间编码的机理。项目首次建立包含胞体-轴突慢失活离子通道的海马场效应模型；研究放电阈值对胞体-轴突阈下振荡以及慢失活离子通道动力学的依存性，以及该过程对海马核团放电编码特性的影响；结合放电阈值的实验数据和理论分析，阐释阈下电场精确调制海马时间编码的场效应机理。

阈下电场作为脑调制技术被广泛应用于神经疾病的治疗以及脑功能研究中。目前人们对阈下电场如何参与神经编码的生物物理机制尚不清楚。.放电阈值可灵活塑造神经元对阈上刺激的时间编码，从放电阈值角度能够阐释阈下电场调制海马时间编码的潜在机理。项目揭示了放电阈值的生物物理机制，阐释了阈下电场调制放电阈值参与海马时间编码的场效应机理。主要结果包括：.1、采集了大鼠离体切片的锥体神经元以及在体脊髓背角神经元的动作电位序列，分析了放电阈值曲线的动态变化特性。.2、建立了海马锥体神经元场效应模型以及场效应耦合的海马核团模型。.3、基于FPGA的高速和实时硬件仿真平台模拟了大规模海马核团网络。.4、得到了神经元阈下振荡对阈下电场的敏感性机制：离子通道在低频段对塑造阈下振荡特性具有重要的作用，且其空间异质性使得阈下振荡具有空间依赖性。.5、得到了电场阈值与神经元放电起始的阈下电流竞争机制：神经形态通过调节径向电流，改变离子电流在阈下膜电位处的竞争关系，从而影响电场对神经元起始放电的调制作用。.6、建立了放电阈值动态的流形与神经元输入-输出特性之间的生物物理联系：跨膜的超极化电流在放电起始前激活程度的差异是导致两类阈值流形的决定因素。.7、得到了神经元形态调节放电阈值的生物物理机制：神经形态通过调节内部径向电流影响放电阈值特性，进而改变放电起始对阈下电场的敏感性。.8、得到阈下电场调制放电时间编码的共振机制：阈下电场效应在神经元的固有频率及谐波处被局部最大化，内生电场能够促进集群对于弱信号的检测和传递。.9、分析放电阈值流形对神经元相响应特性曲线的影响，预测了两类不同阈值流形的神经元集群同步特性的定性差异。.10、研制了多线圈阵列低强度深部经颅磁刺激系统，与传统线圈比较，刺激深度与聚焦性上均有所改善。.项目研究有助于帮助理解低强度环境电磁场以及脑内自生的电场对大脑节律的影响，为电磁刺激术治疗神经系统疾病的临床研究提供重要的理论依据。