Synaptic integration and intrinsic firing properties of basal ganglia neurons

我们实验室的工作集中在中脑多巴胺系统神经元的兴奋性和整合的细胞和亚细胞原则。该实验室的一个主要兴趣是识别中脑多巴胺神经元的功能独特的亚群，并了解这些神经元是如何由基底神经节回路控制的，以及最终它们如何对行为做出贡献。体内实验表明，黑质多巴胺能神经元（SNc）的一个子集表现出反弹活动在一个令人厌恶的刺激终止。然而，这种行为背后的局部神经回路目前尚不清楚。我们先前检查了多巴胺神经元的内在特性，并鉴定了腹侧SNc中表现出不同的反弹放电特性的细胞亚群（Evans等人，JNeurosci 2017）。我们正在继续这项研究，重点是如何抑制输入基底神经节控制SNc多巴胺能神经元。在最近的一个项目中，我们在亚细胞分辨率下对来自纹状体（纹状体和基质）、苍白球（Pvalb和Lhx6）中的四（4）个单独的遗传定义的抑制亚群的抑制投射进行了功能映射。我们发现，纹状体输入选择性抑制腹侧SNr多巴胺神经元树突。虽然孤立的SNr树突，这种连接施加强有力的控制整个细胞，并促进反弹，通过救济GABA-B受体。因此，从纹状体到SNc多巴胺神经元的抑制被最佳地放置以产生反弹放电。这项研究已经提交，目前正在印刷中（Evans等人，Cell Reports 2020）。我们目前正在进行后续研究，检查这些亚群中活动的行为后果，这些亚群与Yogita Chudasama博士（NIMH）合作，并与石楠卡梅隆博士（NIMH）单独合作。本研究的第一作者Rebekah Evans博士将于2021年1月开始在乔治敦大学担任独立终身助理教授职位。实验室的第二个方向集中在了解轴突兴奋性的调节如何影响多巴胺的释放。具体来说，我们从多巴胺能神经元轴突的切断端进行了直接记录，包括背侧纹状体内的分支轴突。我们的研究结果提供了明确的证据，GABA-A受体介导的电导的存在，我们发现去极化，但通过分流抑制传播动作电位的幅度降低。最后，我们发现这些受体对苯二氮卓类药物敏感，这突出了在考虑苯二氮卓类药物和其他靶向GABA-A受体的药理学作用时包括轴突机制的重要性。该研究已提交，最近发表在eLife上（克雷默等人，eLife 2020）。该研究是与Hoon Shin博士和Veronica Alvarez博士（NIAAA）合作进行的。在后续研究中，我们与哈佛医学院的Pascal Kaeser博士合作，研究了纹状体局部回路的输入如何控制多巴胺的释放和轴突的兴奋性。

The work in our laboratory focuses on the cellular and subcellular principles of excitability and integration of neurons in the midbrain dopamine system. A major interest of the lab is identifying functionally unique subpopulations of midbrain dopamine neurons and understanding how these neurons are controlled by basal ganglia circuits and ultimately how they contribute to behavior. In vivo experiments show that a subset of substantia nigra pars compacta (SNc) dopaminergic neurons exhibit rebound activity at the termination of an aversive stimulus. However, the local neural circuits that underly this behavior are currently unknown. We previously examined the intrinsic properties dopamine neurons and identified a subpopulation of cells in the ventral SNc that exhibits distinct rebound firing properties (Evans et al., JNeurosci 2017). We are continuing this research by focusing on how inhibitory inputs from basal ganglia control SNc dopaminergic neurons. In a recent project, we functionally mapped the inhibitory projection from four (4) separate genetically-defined inhibitory subpopulations in the striatum (striosome and matrix), globus pallidus (Pvalb and Lhx6) at subcellular resolution. We found that the striosomal inputs selectively inhibit the ventral SNr dendrite of the dopamine neurons. Although isolated to the SNr dendrite, this connection exerts strong control over the entire cell and facilitates rebounding through relief of GABA-B receptors. Therefore, inhibition from striosomes onto SNc dopamine neurons is optimally placed to produce rebound firing. This study has been submitted and is currently in press (Evans et al., Cell Reports 2020). We are currently performing follow-up studies that examine the behavioral consequences of activity in these subpopulations which are performing in collaboration with Dr. Yogita Chudasama (NIMH) and a separate collaboration with Dr. Heather Cameron (NIMH). The first author of this study, Dr. Rebekah Evans, will be moving to an independent tenure track Assistant Professor position at Georgetown University starting in Jan 2021. A second direction in the lab focuses on understanding how modulation of axonal excitability influences dopamine release. Specifically, we performed direct recordings from the cut ends of dopaminergic neuron axons, including from branching axons within the dorsal striatum. Our results provide definitive evidence for the existence of GABA-A receptor-mediated conductances, which we found were depolarizing but decreased the amplitude of a propagating action potential through shunting inhibition. Finally, we found that these receptors are sensitive to benzodiazepines, which highlights the importance of including axonal mechanisms when considering the action of benzodiazepines and other pharmacology that target GABA-A receptors. This study was submitted and has recently been published in eLife (Kramer et al. eLife 2020). The study was performed in collaboration with Dr. Hoon Shin and Dr. Veronica Alvarez (NIAAA). In follow-up studies, we have been examining how input from striatal local circuitry controls dopamine release and axonal excitability in collaboration with Dr. Pascal Kaeser at Harvard Medical School.