神经元对于高频电刺激的动态响应

深部脑刺激(deep brain stimulation,DBS)在许多神经系统疾病的临床治疗上都展现出良好的应用前景,然而,其作用机制尚不明确.常规DBS采用高频刺激(high frequency stimulation,HFS)的脉冲序列,这种窄脉冲最容易激活神经元结构中的轴突部分,通过轴突的投射,将HFS的作用传播至下游神经元.因此,为了探讨DBS的作用机制,并鉴于海马脑区是治疗癫痫和痴呆症等疾病的重要靶点,我们研究了海马区轴突HFS对于下游神经元的作用.对麻醉大鼠的海马CA1区传入神经通路Schaffer侧支施加1 min的100 Hz高频刺激,记录并提取下游CA1区锥体神经元和中间神经元的单元锋电位.计算锋电位的发放率,以及它们与刺激脉冲之间的锁相值(phase-locking value,PLV)和潜伏期,以定量分析HFS期间神经元动作电位发放的变化趋势.结果显示,在传入轴突上施加HFS时,初期会诱发下游神经元群体同步产生动作电位(即群峰电位).在HFS后期(群峰电位消失之后),两类神经元的单元锋电位发放仍然持续,并且发放率较稳定.但是,锋电位与刺激脉冲之间的锁相性逐渐减弱、潜伏期逐渐延长.而且,与中间神经元相比较,锥体神经元锋电位的锁相性更弱、潜伏期更长.这些结果表明,持续的轴突HFS可以诱导下游神经元产生非同步的活动,高频脉冲刺激引起的不完全轴突传导阻滞可能是导致该现象产生的主要原因.本文的研究为揭示脑刺激的作用机制提供了重要信息.

Dynamic Responses of Neurons to High Frequency Stimulation

Deep brain stimulation (DBS) has shown great potential for treating various neurological disorders in clinic. However, the mechanisms of DBS are not clear yet. Regular DBS uses high frequency stimulation (HFS) of pulse sequences. The narrow pulses facilitate the activation of axon fibers most readily among all elements of a neuronal structure. Through the projection of axons, the effects of HFS can spread to downstream neurons. Therefore, to explore the mechanisms of DBS, we investigated the effects of axonal HFS on the downstream neurons in hippocampus, as it has been an important target for treating diseases such as epilepsy and dementia. One-minute HFS at 100 Hz was applied to the afferent fibers of hippocampal CA1 region (i.e., the Schaffer collaterals) in anesthetized rats. Single unit spikes of pyramidal cells and interneurons in the downstream CA1 region were recorded and analyzed. Firing rates of spikes, phase-locking values (PLV) between spikes and stimulation pulses, as well as spike latencies were calculated to quantify the changes of neuronal action potential firing during the HFS periods. Results showed that during the initial period of HFS, synchronized action potentials (i.e., population spikes, PS) generated in the population of neurons. During the late period of HFS (after the disappearance of PS events), both types of neurons continued to fire unit spikes with stable rates. However, the phase-locking relationship between spikes and stimulation pulses decreased gradually, while the latencies of spikes increased gradually. In addition, compared to interneurons, the unit spikes of pyramidal cells had smaller phase-locking values and longer latencies. These results indicate that prolonged axonal HFS can generate asynchronous activity in the downstream neurons. Partial block in axon conduction induced by high-frequency pulse stimulation might be one major cause underlying the phenomena. The present study provides important information for revealing the mechanisms of DBS.