Laboratorio de Neuroanatomía, Departamento de Anatomía, and Centro Interdisciplinario de Neurociencia, NeuroUC, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, 8330023, Chile.
Department of Cell Biology and Anatomy and the Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112.
J Neurosci. 2018 Sep 19;38(38):8295-8310. doi: 10.1523/JNEUROSCI.0651-18.2018. Epub 2018 Aug 13.
Action potentials (APs) in nigral dopaminergic neurons often exhibit two separate components: the first reflecting spike initiation in the dendritically located axon initial segment (AIS) and the second the subsequent dendro-somatic spike. These components are separated by a in the ascending phase of the somatic extracellular waveform and in the temporal derivative of the somatic intracellular waveform. Still, considerable variability exists in the presence and magnitude of the across neurons. To systematically address the contribution of AIS, dendritic and somatic compartments to shaping the two-component APs, we modeled APs of previously electrophysiologically characterized and 3D-reconstructed male mouse and rat dopaminergic neurons. A parsimonious two-domain model, with high (AIS) and lower (dendro-somatic) Na conductance, reproduced the notch in the temporal derivatives, but not in the extracellular APs, regardless of morphology. The notch was only revealed when somatic active currents were reduced, constraining the model to three domains. Thus, an initial AIS spike is followed by an actively generated spike by the axon-bearing dendrite (ABD), in turn followed mostly passively by the soma. The transition from being a source compartment for the AIS spike to a source compartment for the ABD spike satisfactorily explains the extracellular somatic notch. Larger AISs and thinner ABD (but not soma-to-AIS distance) accentuate the AIS component. We conclude that variability in AIS size and ABD caliber explains variability in AP extracellular waveform and separation of AIS and dendro-somatic components, given the presence of at least three functional domains with distinct excitability characteristics. Midbrain dopamine neurons make an important contribution to circuits mediating motivation and movement. Understanding the basic rules that govern the electrical activity of single dopaminergic neurons is therefore essential to reveal how they ultimately contribute to movement and motivation as well as what goes wrong in associated disorders. Our computational study focuses on the generation and propagation of action potentials and shows that different morphologies and excitability characteristics of the cell body, dendrites and proximal axon can explain the diversity of action potentials shapes in this population. These compartments likely make differential contributions both to normal dopaminergic signaling and could potentially underlie pathological dopaminergic signaling implicated in addiction, schizophrenia, Parkinson's disease, and other disorders.
动作电位 (APs) 在黑质多巴胺神经元中通常表现出两个独立的成分：第一个反映位于树突状轴突起始段 (AIS) 的尖峰起始，第二个是随后的树突 - 体棘波。这些成分在体细胞外波形的上升相和体细胞内波形的时间导数中分离。尽管如此，在神经元之间， 仍然存在相当大的变异性。为了系统地解决 AIS、树突和体细胞隔间对形成双成分 APs 的贡献，我们对先前通过电生理特性和 3D 重建的雄性小鼠和大鼠多巴胺能神经元进行了 APs 建模。一个简约的双域模型，具有较高的 (AIS) 和较低的 (树突 - 体) Na 电导，再现了时间导数中的凹陷，但不在细胞外 APs 中，无论形态如何。只有当体细胞主动电流减少时，凹陷才会显现出来，从而将模型限制为三个域。因此，初始 AIS 尖峰后跟随带有轴突的树突 (ABD) 主动产生的尖峰，然后体部主要被动跟随。从 AIS 尖峰的源隔间转变为 ABD 尖峰的源隔间，很好地解释了细胞外体部的凹陷。较大的 AIS 和较细的 ABD（但不是体部到 AIS 的距离）突出了 AIS 成分。我们得出的结论是，AIS 大小和 ABD 口径的变异性解释了 AP 细胞外波形和 AIS 与树突 - 体部成分分离的变异性，因为存在至少三个具有不同兴奋性特征的功能域。中脑多巴胺神经元对介导动机和运动的电路做出了重要贡献。因此，了解支配单个多巴胺能神经元电活动的基本规则对于揭示它们最终如何为运动和动机做出贡献以及相关疾病中出现的问题至关重要。我们的计算研究集中在动作电位的产生和传播上，表明细胞体、树突和近端轴突的不同形态和兴奋性特征可以解释该群体中动作电位形状的多样性。这些隔间可能对正常的多巴胺能信号传递有不同的贡献，并且可能是成瘾、精神分裂症、帕金森病和其他疾病中涉及的病理性多巴胺能信号传递的基础。
