Medical Research Council Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX1 3TH, United Kingdom
Medical Research Council Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX1 3TH, United Kingdom.
J Neurosci. 2021 Dec 15;41(50):10382-10404. doi: 10.1523/JNEUROSCI.1753-21.2021. Epub 2021 Nov 9.
The cerebral cortex, basal ganglia and motor thalamus form circuits important for purposeful movement. In Parkinsonism, basal ganglia neurons often exhibit dysrhythmic activity during, and with respect to, the slow (∼1 Hz) and beta-band (15-30 Hz) oscillations that emerge in cortex in a brain state-dependent manner. There remains, however, a pressing need to elucidate the extent to which motor thalamus activity becomes similarly dysrhythmic after dopamine depletion relevant to Parkinsonism. To address this, we recorded single-neuron and ensemble outputs in the basal ganglia-recipient zone (BZ) and cerebellar-recipient zone (CZ) of motor thalamus in anesthetized male dopamine-intact rats and 6-OHDA-lesioned rats during two brain states, respectively defined by cortical slow-wave activity and activation. Two forms of thalamic input zone-selective dysrhythmia manifested after dopamine depletion: (1) BZ neurons, but not CZ neurons, exhibited abnormal phase-shifted firing with respect to cortical slow oscillations prevalent during slow-wave activity; and (2) BZ neurons, but not CZ neurons, inappropriately synchronized their firing and engaged with the exaggerated cortical beta oscillations arising in activated states. These dysrhythmias were not accompanied by the thalamic hypoactivity predicted by canonical firing rate-based models of circuit organization in Parkinsonism. Complementary recordings of neurons in substantia nigra pars reticulata suggested that their altered activity dynamics could underpin the BZ dysrhythmias. Finally, pharmacological perturbations demonstrated that ongoing activity in the motor thalamus bolsters exaggerated beta oscillations in motor cortex. We conclude that BZ neurons are selectively primed to mediate the detrimental influences of abnormal slow and beta-band rhythms on circuit information processing in Parkinsonism. Motor thalamus neurons mediate the influences of basal ganglia and cerebellum on the cerebral cortex to govern movement. Chronic depletion of dopamine from the basal ganglia causes some symptoms of Parkinson's disease. Here, we elucidate how dopamine depletion alters the ways motor thalamus neurons engage with two distinct oscillations emerging in cortico-basal ganglia circuits We discovered that, after dopamine depletion, neurons in the thalamic zone receiving basal ganglia inputs are particularly prone to becoming dysrhythmic, changing the phases and/or synchronization (but not rate) of their action potential firing. This bolsters cortical dysrhythmia. Our results provide important new insights into how aberrant rhythmicity in select parts of motor thalamus could detrimentally affect neural circuit dynamics and behavior in Parkinsonism.
大脑皮层、基底神经节和运动丘脑形成了对有目的运动很重要的回路。在帕金森病中，基底神经节神经元在皮层慢波（∼1 Hz）和β波段（15-30 Hz）振荡出现时通常表现出节律紊乱的活动，而且这种活动与大脑状态有关。然而，仍然迫切需要阐明在与帕金森病相关的多巴胺耗竭后，运动丘脑活动在多大程度上变得同样节律紊乱。为了解决这个问题，我们在麻醉雄性多巴胺完整大鼠和 6-OHDA 损伤大鼠的两个脑状态下，分别在基底神经节接受区（BZ）和小脑接受区（CZ）记录了单个神经元和神经元集群的输出。多巴胺耗竭后表现出两种形式的丘脑传入区选择性节律紊乱：（1）BZ 神经元，但不是 CZ 神经元，表现出与皮层慢波活动期间流行的皮层慢振荡异常的相位偏移放电；（2）BZ 神经元，但不是 CZ 神经元，不恰当地同步其放电，并与在激活状态下产生的过度皮层β振荡结合。这些节律紊乱并不伴有帕金森病中基于经典放电率的电路组织模型预测的丘脑活动减少。对黑质网状部神经元的补充记录表明，它们的活动动力学改变可能是 BZ 节律紊乱的基础。最后，药理学干扰表明，运动丘脑的持续活动增强了运动皮层中过度的β振荡。我们得出结论，BZ 神经元被选择性地启动，以介导异常慢波和β波段节律对帕金森病中电路信息处理的有害影响。运动丘脑神经元介导基底神经节和小脑对大脑皮层的影响，以控制运动。从基底神经节慢性耗竭多巴胺会导致一些帕金森病的症状。在这里，我们阐明了多巴胺耗竭如何改变运动丘脑神经元与皮质基底节回路中出现的两种不同振荡的参与方式。我们发现，多巴胺耗竭后，接收基底神经节输入的丘脑区域的神经元特别容易出现节律紊乱，改变其动作电位放电的相位和/或同步性（但不是频率）。这增强了皮层节律紊乱。我们的研究结果为理解选择的运动丘脑部分的异常节律性如何对帕金森病中的神经回路动力学和行为产生有害影响提供了重要的新见解。
