A Tonically Active Network in the Neostriatum

描述（由申请人提供）：人类帕金森病和该疾病的实验动物模型研究的最新进展已经将注意力转向基底神经节中的振荡电活动。β范围（13-30 Hz）的低频振荡已被证明在帕金森氏病中被夸大，并且在运动被抑制时正常发生。这些振荡是用总电极测量的场电位，因此它们的细胞起源尚不清楚，但它们部分是在纹状体中产生的。因为场电位是一种群体测量，它们必须反映神经元组的同步活动。对猴子实验性帕金森综合征的研究表明，与低频振荡节律性放电的神经元都是具有紧张性活性的纹状体中间神经元。这些细胞保持它们的背景放电，即使动物不动。相比之下，纹状体的主要细胞、多刺神经元和研究最多的中间神经元（快速尖峰中间神经元）在运动时会偶尔放电，而在其他情况下则大多沉默。因此，与运动迟缓相关的低频振荡的纹状体发生器可能是紧张性放电的中间神经元。以前认为纹状体中所有紧张性活性中间神经元都是胆碱能中间神经元。最近，已经清楚的是，在纹状体中有两种紧张性活跃的中间神经元（即在没有来自其他地方的兴奋的情况下活跃）。它们是胆碱能中间神经元和LTS（低阈值尖峰）爆发中间神经元。这两种类型的神经元共同组成了纹状体中的自发活动网络，即使在没有输入的情况下，也会产生连续的振荡活动。自发活动网络接收来自纹状体传入的稀疏突触输入，并主要通过乙酰胆碱、一氧化氮、生长抑素和神经肽Y对兴奋性和突触可塑性的神经调节控制与相位纹状体细胞相互作用。这里提出的实验将确定自发活动的中间神经元网络的连通性和动态特性。他们将确定由紧张性活性纹状体中间神经元组成的网络的固有共振特性是否适合于在β频带中产生振荡。我们将确定LTS细胞中自发振荡的机制，以及它们之间的突触连接是否促进或反对同步活动。我们还将研究6-羟基多巴胺慢性多巴胺耗竭后内在振荡和同步化的变化。这两种自主活动的细胞类型可以很容易地在切片中识别，并作为研究的目标。这些实验将揭示促进同步的机制，可能是多巴胺能耗竭的作用点和未来抗帕金森病治疗的可能靶点。

DESCRIPTION (provided by applicant): Recent advances in the study of human Parkinson's disease and experimental animal models of the disease have directed attention to oscillatory electrical activity in the basal ganglia. Low frequency oscillations in the beta range (13-30 Hz) have been shown to be exaggerated in Parkinson's disease, and to occur normally when movements are inhibited. The oscillations are measured as field potentials using gross electrodes, so their cellular origins are not known, but they are in part generated in the striatum. Because field potentials are a population measure, they must reflect synchronous activity in groups of neurons. Studies of experimental parkinsonism in monkeys have shown that neurons firing in rhythm with the low frequency oscillation are all tonically active striatal interneurons. These cells maintain their background firing, even when animals are not moving. In contrast, the principal cells of the striatum, the spiny neurons, and the best-studied interneurons (the fast-spiking interneurons) fire episodically in relation to movement and are mostly silent otherwise. Thus, the striatal generator for the low frequency oscillations associated with bradykinesia is probably tonically firing interneurons. It has previously been thought that all tonically active interneurons in the striatum are cholinergic interneurons. Recently, it has become clear that there are two kinds of tonically active interneurons in the striatum (i.e. active in the absence of excitation from elsewhere). They are the cholinergic interneuron and the LTS (low-threshold spike) bursting interneuron. Together, these two neuron types comprise a spontaneously active network in the striatum that generates continuous oscillatory activity, even in the absence of input. The spontaneously active network receives sparser synaptic input from striatal afferents, and interacts with the phasic striatal cells primarily by way of neuromodulatory control of excitability and synaptic plasticity via acetylcholine, nitric oxide, somatostatin, and neuropeptide Y. The experiments proposed here will determine the connectivity and dynamic properties of the network of spontaneously-active interneurons. They will determine whether the intrinsic resonant properties of the network consisting of tonically active striatal interneurons are appropriate for generation of oscillations in the beta frequency band. We will determine the mechanism of spontaneous oscillations in LTS cells, and whether synaptic connections between them act to promote or oppose synchronous activity. We will also examine the changes in the intrinsic oscillations and synchronization that follow chronic dopamine depletion with 6- hydroxydopamine. The two autonomously active cell types can be readily identified in slices, and targeted for study. These experiments will reveal mechanisms promoting synchronization that may be points of action of dopaminergic depletion and possible targets for future anti-parkinsonian therapies.