Synaptic integration and intrinsic firing properties of basal ganglia neurons

在细胞神经生理学部分的研究集中在兴奋性和中脑多巴胺系统的神经元整合的原则。最近，我们的实验室进行了重大的努力，以了解纹状体多巴胺信号是如何形成的配体门控受体，多巴胺能轴突终端。虽然多巴胺能神经元的轴突的作用是传递躯体信息，但它们的终末也直接接收来自乙酰胆碱释放神经元的局部输入，这可能影响纹状体多巴胺的释放。细胞之间的这种交流是如何绕过树突的，这是一个悬而未决的问题。在我们实验室最近发表的一项研究中（克雷默等人，神经元2022），我们使用直接电生理学贴片记录技术来测量成年小鼠纹状体内多巴胺能神经元轴突的阈下膜电压，从而解决了这个问题。虽然解剖学研究表明多巴胺能轴突在很大程度上缺乏经典的突触，我们的数据表明，多巴胺能神经元轴突上的信号在功能上类似于传统的树突状突触的信号。此外，我们还研究了自发胆碱能输入到轴突的整合。我们发现，在某些情况下，自发胆碱能输入可以启动轴突局部产生的自发动作电位。在与哈佛医学院的Pascal Kaeser博士的实验室的相关合作研究中，我们的实验室还贡献了来自多巴胺能轴突的穿孔斑数据，证明通过胆碱能中间神经元的同步光学刺激激活轴突烟碱受体可以导致局部产生的轴突动作电位，其可能是纹状体多巴胺释放的基础（Liu等人，Science 2022）。总之，这些观察结果违背了神经系统中单向信息流的经典概念。相反，他们证明，类似于树突和索马，轴突可能是整合和产生多巴胺信号的重要场所。因此，这些研究为理解多巴胺能神经元中的信息流建立了框架，指出了治疗物质使用障碍和帕金森病的可能的新靶点。 在另一项研究中，我们一直在研究钠漏电导（NALCN）在不同多巴胺神经元亚群中减缓自发放电（称为起搏）的作用。我们已经发现，虽然NALCN有助于黑质神经元的放电，但NALCN的贡献在内侧多巴胺能神经元中要强得多，特别是投射到内侧核的那些。这项研究已提交出版，目前正在修订中。

Research in the Cellular Neurophysiology Section focuses on the principles of excitability and integration of neurons in the midbrain dopamine system. Recently our laboratory has undergone major efforts to understand how dopamine signaling in the striatum is shaped by ligand-gated receptors that are present on the dopaminergic axon terminals. Although the role of the axons of dopaminergic neurons is to transmit somatic information, their terminals also receive local input directly from acetylcholine-releasing neurons that may influence striatal dopamine release. How this communication occurs between cells that bypasses dendrites is an open question. In a recent published study from our laboratory (Kramer et al, Neuron 2022), we addressed this question using direct electrophysiological patch recording techniques to measure the subthreshold membrane voltage from the dopaminergic neuron axons within the striatum of adult mice. Although anatomical studies have shown that dopaminergic axons largely lack classic synapses, our data show that signaling onto axons of dopaminergic neurons was functionally similar to signaling at traditional dendritic synapse. In addition, we examined integration of spontaneous cholinergic inputs onto axons. We found that the spontaneous cholinergic inputs in some cases can initiate spontaneous action potentials generated locally in axons. In a related collaborative study with the laboratory of Dr. Pascal Kaeser at Harvard Medical School, our laboratory also contributed perforated patch data from dopaminergic axons demonstrating that activation of axonal nicotinic receptors by synchronous optical stimulation of cholinergic interneurons can result in locally-generated axonal action potentials that may underlie striatal dopamine release (Liu et al., Science 2022). Together, these observations go against the classical notion of unidirectional flow of information in the nervous system. Instead, they demonstrate that similar to dendrites and soma, the axons may be important sites for the integration and generation of dopamine signaling. Thus, these studies establish framework for understanding the flow of information in the dopaminergic neurons pointing to possible new targets for treating substance use disorders and Parkinsons Disease. In a separate study, we have been investigating the role of the sodium leak conductance, NALCN, to slow spontaneous firing called pacemaking in different dopamine neuron subpopulations. We have found that while NALCN contributes to firing in substantia nigra neurons, the contribution of NALCN is much stronger in medial dopaminergic neurons, particularly those that project to medial nucleus accumbens. This study has been submitted for publication and is currently in revisions.