Physical-chemical Aspects Of Cell & Tissue Excitability

细胞和组织的兴奋性是一种基本的生理功能，使有机体能够感知环境并对其做出反应。这项工作的主要目标是解释细胞和组织兴奋性的关键物理化学特征，其中许多方面仍然知之甚少。被广泛接受的神经兴奋性理论不能解释我们已经证明的几个异常现象，这些现象是兴奋发生所必需的。这些变化包括神经轴突浅层原生质层的可逆性体积、温度和光学变化，这些变化与动作电位波形的到达相一致。我们已经获得了进一步的证据，这些物理变化伴随着神经细胞、纤维和突触中发生的相变，这种相变是由钙等二价阳离子与钠、钾等单价阳离子交换引起的。我们之前用灌流轴突进行的实验清楚地表明，二价/一价阳离子交换是神经纤维以“全有或全无”方式兴奋的一种机制。为了了解这些温度和体积变化的物理化学基础，特别是二价/一价阳离子交换如何引起生物分子组装的这种变化，我们在几乎生理条件下研究了合成的仿生阴离子聚合物凝胶中的这些过程。研究这些凝胶模型系统的行为的一个优点是，它们的结构、组成和成分之间的相互作用可以仔细控制，不像在活组织中那样。特别是，在合成聚丙烯酸酯凝胶中，Ferenc Horkay观察到，周围液体中二价阳离子浓度的微小变化可以导致凝胶中链刚性的显著变化，即使离子结合很弱且完全可逆。各种基于物理、化学和聚合物物理的技术，包括中子、X射线和光散射，以及渗透膨胀和机械加载，为在广泛的长度范围内研究这些生物相关现象提供了补充信息。这些基础研究正在加深对神经兴奋背后的物理机制的理解。 我们还在研究中枢神经系统和外周神经系统通过电磁感应(磁刺激)进行刺激的生物物理学方面。佩德罗·米兰达使用有限元方法进行了详细的计算，以预测磁刺激期间大脑中感应的电场和电流密度分布。以前，我们发现组织的异质性和电导率的各向异性都会显著地扭曲感应场，甚至在某些区域产生兴奋性或抑制性的热点。这些现象在解释或推断兴奋区域或位置以及确定神经兴奋的来源方面都可能产生重大的临床后果。最近，我们集中讨论了大脑皮层兴奋的可能物理机制。长期目标是将我们的神经组织磁刺激宏观模型与中枢神经系统和三叉神经节神经兴奋性的微观模型结合起来。

Excitability of cells and tissues is an essential physiological function that allows organisms to sense their environment and respond to it. The primary goal of this work is to explain key physical-chemical features of cell and tissue excitability, many aspects of which are still poorly understood. Widely accepted theories of nerve excitability do not explain several anomalous phenomena that we have shown are necessary for excitation to occur. These include reversible volume, temperature, and optical changes of the superficial protoplasmic layer of nerve axons, which coincide with the arrival of the action potential waveform. We have obtained further evidence that these physical changes accompany a phase transition that occurs in nerve cells, fibers, and synapses caused by the exchange of divalent cations like calcium with monovalent cations like sodium and potassium. Our previous experiments with perfused axons clearly implicate divalent/monovalent cation exchange as a mechanism by which nerve fibers can be excited in an "all or none" manner. To understand the physical chemical basis of these temperature and volumetric changes, particularly how divalent/monovalent cation exchange can induce such changes in biomolecular assemblies, we are studying these processes in synthetic "biomimetic" anionic polymer gels under nearly physiological conditions. An advantage of studying the behavior of these gel model systems is that their structure, composition, and the interactions among their components can be carefully controlled, unlike in living tissue. In particular, in synthetic polyacrylate gels, Ferenc Horkay has observed that minute changes in the concentration of divalent cations in the surrounding liquid can induce significant changes in chain stiffness in the gel, even if ion binding is weak and completely reversible. Various physical chemical and polymer physics-based techniques, including neutron, x-ray and light scattering, as well as osmotic swelling, and mechanical loading provide complementary information with which to study these biologically relevant phenomena over a wide range of length scales. These basic studies are leading to a deeper understanding of the physical mechanisms underlying nerve excitation. We are also investigating biophysical aspects of stimulation by electromagnetic induction (magnetic stimulation) in the central and peripheral nervous systems. Pedro Miranda has performed detailed calculations using a finite element method (FEM), to predict the electric field and current density distributions induced in the brain during magnetic stimulation. Previously, we found that both tissue heterogeneity and anisotropy of the electrical conductivity contribute significantly to distort the induced fields, and even to create excitatory or inhibitory "hot spots" in some regions. These phenomena could have significant clinical consequences both in interpreting or inferring the region or locus of excitation and in determining the source of nerve excitation. More recently, we have focussed on possible physical mechanisms of cortical excitation. Longterm goals are to marry our macroscopic models of magnetic stimulation in nerve tissue with microscopic models of nerve excitability in the CNS and PNS.