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Ionic basis of neuronal hyperexcitability

神经元过度兴奋的离子基础

基本信息

批准号：
7735252
负责人：
JOHN CLAY
金额：
$ 39.52万
依托单位：
NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

The most significant accomplishment of this project during the current fiscal year has been the implementation of a control theory strategy from the physics literature for suppressing rhythmic firing in alkalinized squid giant axons. Squid axons are robust pacemaker cells firing at 25 Hz for hours on end when the intracellular pH is elevated to 7.8, or higher. They do have what is known as a "fixed point" at -55 mV where the net membrane current is zero when the cell is held at that potential in voltage clamp conditions. However, voltage clamp methodology is not relevant to deep brain stimulation. Moreover, the fixed point is unstable. Rhythmic firing resumes immediately after the voltage clamp is turned off. We have suppressed firing with a technique knows as a dynamic clamp in which the voltage waveform is monitored in real time and a current signal proportional to the voltage is injected back into the cell with a delay. The reference point for the delay is the time of the maximum overshoot of the most recent action potential. When the delay is at the 60% point of the unperturbed pacemaker cycle and the feedback gain is at the appropriate level, firing stops immediately. The cell is close to its fixed point and so the current injected by the feedback circuit immediately drops to zero, or close to zero. The membrane potential moves away from the fixed point since this point is unstable, but the feedback circuit applies current to keep it from moving more than a few mV away from that point. This is a mechanism for suppressing hyperexcitability in which very little current is required once firing has ceased. A flat baseline can never be achieved, but firing of action potentials is eliminated. We are currently investigating the relevance of these results for deep brain stimulation methodologies.

在本财政年度，该项目最重要的成就是实施了物理学文献中的控制理论战略，用于抑制碱化鱿鱼巨轴突的节律性放电。鱿鱼轴突是强健的起搏细胞，当细胞内pH值升高到7.8或更高时，以25 Hz连续数小时放电。它们确实在-55 mV处具有所谓的“固定点”，其中当细胞在电压钳条件下保持在该电位时，净膜电流为零。然而，电压钳方法与深部脑刺激无关。此外，不动点是不稳定的。在电压钳位关闭后，节律性放电立即恢复。我们已经用一种称为动态箝位的技术抑制了放电，在该技术中，电压波形被真实的监测，并且与电压成比例的电流信号被延迟地注入回电池中。延迟的参考点是最近动作电位的最大过冲的时间。当延迟处于未扰动起搏器周期的60%点并且反馈增益处于适当水平时，击发立即停止。电池接近其固定点，因此由反馈电路注入的电流立即下降到零或接近零。膜电位从固定点移开，因为该点是不稳定的，但是反馈电路施加电流以防止其从该点移开超过几mV。这是一种抑制过度兴奋的机制，一旦放电停止，只需要很少的电流。一个平坦的基线永远无法实现，但动作电位的放电被消除了。我们目前正在研究这些结果与脑深部电刺激方法的相关性。