Synaptic integration and intrinsic firing properties of basal ganglia neurons

我们实验室的工作重点是中脑多巴胺系统中神经元的兴奋性和整合的细胞和亚细胞原理。实验室的主要兴趣是识别功能独特的中脑多巴胺神经元亚群，并了解这些神经元是如何由基底神经节回路控制的，以及它们最终是如何影响行为的。体内实验表明，黑质致密部（SNc）多巴胺能神经元的一个子集在厌恶刺激终止时表现出反弹活动。然而，这种行为背后的局部神经回路目前尚不清楚。我们之前研究了多巴胺神经元的内在特性，并在腹侧SNc中发现了一个细胞亚群，其表现出明显的反弹放电特性（Evans等人，JNeurosci 2017）。我们将继续研究基底神经节的抑制性输入如何控制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纹状体（纹状体和基质）、苍白球（Pvalb和Lhx6）中四个独立的基因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地抑制了多巴胺神经元的腹侧SNr树突。虽然孤立于SNr树突，但这种连接对整个细胞具有很强的控制作用，并通过释放GABA-B受体促进反弹。因此，纹状体对SNc多巴胺神经元的抑制是产生反跳放电的最佳位置。这项研究已经提交，目前正在出版中（Evans et al., Cell Reports 2020）。我们目前正在与Yogita Chudasama博士（NIMH）和Heather Cameron博士（NIMH）合作进行后续研究，以检查这些亚人群中活动的行为后果。这项研究的第一作者丽贝卡·埃文斯博士将于2021年1月开始在乔治城大学担任独立的终身教授助理。实验室的第二个方向是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割端进行了直接记录，包括从背纹状体的分支轴突。我们的结果为GABA-A受体介导的电导的存在提供了明确的证据，我们发现它是去极化的，但通过分流抑制降低了传播动作电位的振幅。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。该研究已提交并于近期发表在eLife上（Kramer et al. 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，我们一直在与哈佛医学院的Pascal Kaeser博士合作，研究纹状体局部电路的输入如何控制多巴胺释放和轴突兴奋性。

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.