Tarfa Rahilla A, Evans Rebekah C, Khaliq Zayd M
Department of Neuroscience, Brown University, Providence, Rhode Island 02906 and.
Cellular Neurophysiology Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892.
J Neurosci. 2017 Mar 22;37(12):3311-3330. doi: 10.1523/JNEUROSCI.2969-16.2017. Epub 2017 Feb 20.
Midbrain dopamine neurons recorded pause their firing in response to reward omission and aversive stimuli. While the initiation of pauses typically involves synaptic or modulatory input, intrinsic membrane properties may also enhance or limit hyperpolarization, raising the question of how intrinsic conductances shape pauses in dopamine neurons. Using retrograde labeling and electrophysiological techniques combined with computational modeling, we examined the intrinsic conductances that shape pauses evoked by current injections and synaptic stimulation in subpopulations of dopamine neurons grouped according to their axonal projections to the nucleus accumbens or dorsal striatum in mice. Testing across a range of conditions and pulse durations, we found that mesoaccumbal and nigrostriatal neurons differ substantially in rebound properties with mesoaccumbal neurons displaying significantly longer delays to spiking following hyperpolarization. The underlying mechanism involves an inactivating potassium (I) current with decay time constants of up to 225 ms, and small-amplitude hyperpolarization-activated currents (I), characteristics that were most often observed in mesoaccumbal neurons. Pharmacological block of I completely abolished rebound delays and, importantly, shortened synaptically evoked inhibitory pauses, thereby demonstrating the involvement of A-type potassium channels in prolonging pauses evoked by GABAergic inhibition. Therefore, these results show that mesoaccumbal and nigrostriatal neurons display differential responses to hyperpolarizing inhibitory stimuli that favors a higher sensitivity to inhibition in mesoaccumbal neurons. These findings may explain, in part, observations from experiments that ventral tegmental area neurons tend to exhibit longer aversive pauses relative to SNc neurons. Our study examines rebound, postburst, and synaptically evoked inhibitory pauses in subpopulations of midbrain dopamine neurons. We show that pauses in dopamine neuron firing, evoked by either stimulation of GABAergic inputs or hyperpolarizing current injections, are enhanced by a subclass of potassium conductances that are recruited at voltages below spike threshold. Importantly, A-type potassium currents recorded in mesoaccumbal neurons displayed substantially slower inactivation kinetics, which, combined with weaker expression of hyperpolarization-activated currents, lengthened hyperpolarization-induced delays in spiking relative to nigrostriatal neurons. These results suggest that input integration differs among dopamine neurons favoring higher sensitivity to inhibition in mesoaccumbal neurons and may partially explain observations that ventral tegmental area neurons exhibit longer aversive pauses relative to SNc neurons.
记录到的中脑多巴胺神经元会因奖励缺失和厌恶刺激而停止放电。虽然放电暂停的起始通常涉及突触或调制输入，但内在膜特性也可能增强或限制超极化，这就引发了一个问题，即内在电导如何塑造多巴胺神经元的放电暂停。我们使用逆行标记和电生理技术，并结合计算模型，研究了在根据轴突投射到小鼠伏隔核或背侧纹状体进行分组的多巴胺神经元亚群中，由电流注入和突触刺激诱发的放电暂停所涉及的内在电导。在一系列条件和脉冲持续时间下进行测试，我们发现中脑伏隔核神经元和黑质纹状体神经元在反弹特性上有很大差异，中脑伏隔核神经元在超极化后出现动作电位的延迟明显更长。其潜在机制涉及一种失活钾电流（I），其衰减时间常数可达225毫秒，以及小幅度超极化激活电流（I），这些特性在中脑伏隔核神经元中最常被观察到。对I的药理学阻断完全消除了反弹延迟，重要的是，缩短了突触诱发的抑制性放电暂停，从而证明了A 型钾通道参与延长由GABA能抑制诱发的放电暂停。因此，这些结果表明，中脑伏隔核神经元和黑质纹状体神经元对超极化抑制性刺激表现出不同的反应，这使得中脑伏隔核神经元对抑制具有更高的敏感性。这些发现可能部分解释了实验观察结果，即腹侧被盖区神经元相对于黑质致密部神经元往往表现出更长的厌恶放电暂停。我们的研究考察了中脑多巴胺神经元亚群中的反弹、爆发后和突触诱发的抑制性放电暂停。我们表明，由GABA能输入刺激或超极化电流注入诱发的多巴胺神经元放电暂停，会被一类在低于动作电位阈值的电压下被激活的钾电导增强。重要的是，在中脑伏隔核神经元中记录到的A 型钾电流显示出明显更慢的失活动力学，这与超极化激活电流的较弱表达相结合，相对于黑质纹状体神经元延长了超极化诱导的动作电位延迟。这些结果表明，多巴胺神经元之间的输入整合存在差异，这使得中脑伏隔核神经元对抑制具有更高的敏感性，并且可能部分解释了腹侧被盖区神经元相对于黑质致密部神经元表现出更长的厌恶放电暂停这一观察结果。
