A Tonically Active Network in the Neostriatum

描述(申请人提供)：人类帕金森氏病研究的最新进展和该疾病的实验动物模型已将注意力集中在基底节的振荡电活动上。在贝塔范围(13-30赫兹)的低频振荡已被证明在帕金森氏症中被夸大，当运动被抑制时正常发生。这种振荡是用粗大的电极作为场电位来测量的，因此它们的细胞起源尚不清楚，但它们部分是在纹状体产生的。因为场电位是一种群体测量，所以它们必须反映神经元群中的同步活动。对猴子实验性帕金森综合征的研究表明，与低频振荡有节奏地放电的神经元都是紧张性活跃的纹状体中间神经元。即使在动物不动的时候，这些细胞也会保持它们的背景放电。相比之下，纹状体的主细胞、棘神经元和研究最深入的中间神经元(快速尖峰中间神经元)与运动有关时会时断时续地发出信号，否则大多是沉默的。因此，与运动迟缓相关的低频振荡的纹状体生成器可能正在调谐地激发中间神经元。以往的研究认为，纹状体中所有强直活动的中间神经元都是胆碱能中间神经元。最近，人们已经清楚地发现，纹状体中有两种调频活动的中间神经元(即在没有其他刺激的情况下活动)。它们是胆碱能中间神经元和低阈值放电中间神经元。这两种类型的神经元共同构成了纹状体中的自发活动网络，即使在没有输入的情况下，该网络也会产生持续的振荡活动。自发活动网络从纹状体传入接受较稀疏的突触输入，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进行神经调节控制而与时相纹状体细胞相互作用。本实验将确定自发活动中间神经元网络的连通性和动力学特性。他们将确定由音调活跃的纹状体中间神经元组成的网络的固有共振特性是否适合在β频段产生振荡。我们将确定LTS细胞自发振荡的机制，以及它们之间的突触连接是促进还是反对同步活动。我们还将研究6-羟基多巴胺慢性耗竭后固有振荡和同步性的变化。这两种自主活跃的细胞类型可以很容易地在切片上识别出来，并成为研究的目标。这些实验将揭示促进同步化的机制，这些机制可能是多巴胺能耗竭的作用点，也可能是未来抗帕金森病治疗的靶点。 公共卫生相关性：虽然帕金森病是由黑质多巴胺能神经元的丢失引起的，但帕金森病的实际症状是由基底节完整神经元的异常放电模式引起的，我们所看到的疾病是神经元活动动力学的变化。神经元动力学中最显著的变化是基底节β带同步节律的夸大。这些研究的目标是发现纹状体中这些节律的起源，希望了解脑深部刺激和其他当前治疗的作用机制，并确定能够进行下一代治疗的治疗靶点。

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. PUBLIC HEALTH RELEVANCE: Although Parkinson's disease is caused by the loss of dopaminergic neurons in the substantia nigra, the actual symptoms of PD are caused by abnormal firing patterns of the intact neurons in the basal ganglia, and the disease as we see it is a change in the dynamics of neuronal activity. The most prominent change in neuronal dynamics is the exaggeration of beta band synchronous rhythms in the basal ganglia. The goal of these studies is to discover the origin of those rhythms in the striatum, in the hope of understanding the mechanism of action of deep brain stimulation and other current treatments, and identifying a therapeutic target that would allow a next generation treatment.