Pharmacology And Physiology Of The Substantia Nigra And Basal Ganglia
黑质和基底神经节的药理学和生理学
基本信息
- 批准号:8149623
- 负责人:
- 金额:$ 115.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Current focus in the Neurophysiological Pharmacology Section is on mechanisms underlying the ability of dopamine-containing neurons to affect information processing in the basal ganglia and associated areas. The Sections on-going neurophysiological studies in several different rat preparations - locally anaesthetized, immobilized and artificially respired rats, freely moving rats and systemically anesthetized rats - have provided evidence that normal levels of dopamine receptor stimulation act to prevent emergence of inappropriately synchronized and oscillatory neuronal firing activity in basal ganglia networks, while significant increases and decreases in dopamine receptor stimulation enhance the expression of these dysfunctional patterns.
In the past year, we have been exploring the specifics of dysfunctional alterations in basal ganglia output in animal models of Parkinsons disease. In particular, we have focused on beta range (12 35 Hz) activity which appears enhanced in the subthalamic nucleus of parkinsonian patients and has been hypothesized to be antikinetic in nature. Studies in the current review period have also used the 1 Hz rhythm dominant in the cortex of the anesthetized rat to develop hypotheses about how loss of dopamine can lead to entrainment of basal ganglia output to cortical rhythms. The data from the anesthetized rat studies suggest that loss of dopamine affects the ability of the striatum to properly filter input from the cortex, and promotes entrainment of the basal ganglia to cortical rhythms.
To further examine this hypothesis, we have developed an awake behaving rat model of Parkinsons disease which allows us to investigate changes in basal ganglia activity after loss of dopamine in conjunction with changes in gait. The goal was to determine whether increases in synchronized and oscillatory activity in the beta range would be evident in a rodent preparation and correlated with loss of dopamine and motor dysfunction. Such a model would allow us to explore a number of questions related to the source of the exaggerated beta activity expressed in the basal ganglia in Parkinsons disease, and the extent to which this activity is responsible for motor dysfunction in parkinsonian patients.
Rats were trained to walk in a novel rotary treadmill while EMG activity in shoulder muscle and neuronal activity in basal ganglia output were recorded. After unilateral loss of dopamine, rats made progress walking counterclockwise on the rotary treadmill, but tended to freeze during clockwise walking as this required the affected side to make more demanding adjustments of gait and posture.
Our first studies in the awake behaving rats focused on the effect of dopamine cell lesion on firing rate and pattern in the SNpr during epochs of treadmill walking and inattentive rest. We hypothesized that we would see elevations in beta range activity in the lesioned hemisphere, relative to the intact hemisphere, as predicted by observations of prominent beta activity in the subthalamic nucleus in Parkinson patients. Substantia nigra pars reticulata (SNpr) was chosen as our initial target for these studies because changes in basal ganglia output are critical to the ultimate impact of basal ganglia dysfunction on downstream sites, and data from the anesthetized preparation predicted that SNpr activity would be entrained by increased synchronization in basal ganglia circuits.
Recordings began seven days after surgery for unilateral dopamine cell lesion and electrode bundle implantation, in order to allow the rat time to recover from those procedures. Epochs identified as inattentive rest showed that SNpr local field potential (LFP) power in the low beta range (relatively concentrated around the 1218 Hz) was significantly greater in the dopamine-depleted hemisphere than in non-lesioned (opposite to the lesioned) or control (brains with no lesions) hemispheres. At the end of the rest epoch, a buzzer sounded, and the investigator adjusted the rat in the treadmill and turned it on. During this adjustment period, as rats became alert and began to move, low beta power was reduced in the SNpr in both intact and lesioned hemispheres and, strikingly, activity in the high beta range (25-40 Hz, technically high beta/low gamma) became quite prominent in the lesioned hemisphere only. During treadmill walking, this high beta band was consistently expressed in the lesioned hemisphere, centered around 33 Hz. Thus, in the hemiparkinson rat, dopamine loss is associated with increases in the synchronization of SNpr activity, with apparent differences in the peak frequency depending on the behavior expressed by the rat.
To further examine factors modulating the expression of high beta oscillatory activity in the basal ganglia under conditions of dopamine cell loss, single neurons and LFPs in SNpr were simultaneously recorded from lesioned and non-lesioned hemispheres in the hemiparkinsonian rats during a range of behaviors including alert rest, grooming, REM sleep, and while under light anesthesia (urethane) with sensory stimulation, in addition to walking and inattentive rest. SNpr LFP high beta oscillations remained consistently elevated from 1 week to 8 weeks post lesion in the lesioned hemisphere during ipsiversive treadmill walking, with mean SNpr power in lesioned hemisphere 5 fold greater than in the non-lesioned SNpr. High beta power was greatest at walking onset and diminished during walking episodes to 2.5 fold increase by the fifth min. Results showed a subtle but significant decrease in the dominant frequency during the alert inactive state (29 Hz) relative to treadmill walking, and a further declined to approximately 21 Hz in the lightly anesthetized, lightly stimulated state. L-dopa treatment significantly reduced high beta power in the SNpr LFPs (by 80%) on the lesioned side and improved walking on the circular treadmill contraversive to the lesion. This treatment also reduced beta range activity in the lightly anesthetized state. The serotonin 1A agonist reversed L-dopas effects on SNpr high beta power during walking, consistent with evidence that serotoninergic terminals in the central nervous system are involved in conversion of L-dopa to dopamine and release of dopamine after dopamine cell death.
The correlation between beta activity and motor deficits in this animal model of Parkinsons disease support the hypothesis that increased beta range synchronization of neuronal activity in basal ganglia output plays a role in the mediating deficits in gait expressed by these rats. The range of frequencies observed in the synchronized activity in the basal ganglia over a range of behaviors in the hemiparkinsonian rat suggests that the synchronized activity is generated by complex neuronal networks, like those in the cortex, as opposed to a more limited network like that defined by the reciprocal connections between the external globus pallidus and the subthalamic nucleus. Future studies will examine the effects of local manipulation of neuronal activity at different nodes in the basal ganglia circuit to better understand how alterations in basal ganglia activity lead to motor dysfunction in Parkinsons disease.
当前在神经生理药物学部分中的重点是含多巴胺神经元影响基底神经节和相关区域信息处理能力的机制。几种不同大鼠制剂中正在进行的神经生理学研究 - 局部麻醉,固定和人为地呼吸的大鼠,自由移动大鼠和全身麻醉的大鼠 - 提供了正常水平的多巴胺受体刺激的证据,以防止出现重要的脉动,同时不适当地进行了脉动,并具有适当的脉络性神经元素的脉络性和振动性的活性及其稳定性的基础上,并具有稳定性的活性及其临床,并有稳定性的活性及其临床。在多巴胺受体刺激中,增强了这些功能失调模式的表达。
在过去的一年中,我们一直在探索帕金森氏病动物模型中基底神经节输出功能失调的细节。特别是,我们专注于β范围(12 35 Hz)活性,在帕金森患者的丘脑下核中似乎增强了活性,并且已经假设本质上是抗弱基。在当前审查期间的研究还使用了麻醉大鼠皮质中的1 Hz节律显性,以形成关于多巴胺损失如何导致基底神经节输出损失到皮质节奏的假设。 来自麻醉大鼠研究的数据表明,多巴胺的丧失会影响纹状体正确过滤皮质输入的能力,并促进基底神经节的夹带到皮质节律上。
为了进一步审查这一假设,我们开发了一种清醒的帕金森氏病大鼠模型,这使我们能够研究多巴胺丧失后基底神经节活性的变化,并结合了步态变化。目的是确定在啮齿动物制备中是否可以明显地在β范围内同步和振荡活性的增加,并且与多巴胺和运动功能障碍的丧失相关。 这样的模型将使我们能够探讨与帕金森病基底神经节中表达的夸张的β活动来源有关的许多问题,以及该活动在帕克森患者中导致运动功能障碍的程度。
训练大鼠在新型的旋转跑步机中行走,而肩部肌肉的EMG活性记录了基底神经节输出中的神经元活性。在单方面损失多巴胺后,大鼠在旋转跑步机上逆时针行走,但在顺时针行走时倾向于冻结,因为这需要受影响的一侧对步态和姿势进行更苛刻的调整。
我们在醒着的大鼠中进行的首次研究集中在多巴胺细胞病变对跑步机行走和注意力不集中的时期期间SNPR的发射速率和模式的影响。我们假设我们将看到病变半球的β范围活性升高,相对于完整的半球,帕金森氏症患者中丘脑下核中突出的β活性的预测。选择了本研究的黑质nigra pars网状(SNPR)作为这些研究的最初目标,因为基底神经节输出的变化对于基底神经节功能障碍对下游部位的最终影响至关重要,并且来自麻醉的制剂的数据预测,SNPR活性会通过增加基础神经节循环的同步来预测SNPR活性。
记录在手术后七天开始用于单侧多巴胺细胞病变和电极束植入,以便从这些过程中恢复率。 被确定为不专心的休息的时期表明,在低β范围(相对集中在1218 Hz附近)中,SNPR局部场电位(LFP)的功率在多巴胺耗尽的半球中明显大于未经损害(与病变的)或对照(无病变)半球的未渗透的半球相比。在其余时期的结尾,蜂鸣器响起,调查员调整了跑步机中的老鼠并将其打开。 在此调整期间,随着大鼠变得机敏并开始移动,SNPR的beta功率在完整和病变的半球中都降低了,并且在高β范围(25-40 Hz,技术上高的β/低伽玛)的活动中,仅在病变的半球中就非常突出。 在跑步机行走期间,这款高β频带在病变的半球中始终表达,以约33 Hz为中心。因此,在半腺大鼠中,多巴胺损失与SNPR活性同步的增加有关,峰频率的明显差异取决于大鼠表达的行为。
To further examine factors modulating the expression of high beta oscillatory activity in the basal ganglia under conditions of dopamine cell loss, single neurons and LFPs in SNpr were simultaneously recorded from lesioned and non-lesioned hemispheres in the hemiparkinsonian rats during a range of behaviors including alert rest, grooming, REM sleep, and while under light anesthesia (urethane) with sensory stimulation, in addition走路和不专心的休息。 在病变的半球病变后,SNPR LFP高β振荡在iPsiversive跑步机行走过程中始终从1周升高到8周,在病变的半球中,平均SNPR功率比非属于snpr的SNPR大。 beta发作时,高β功率最大,在步行情节中减少到第五分钟的增加到2.5倍。结果表明,相对于跑步机行走,在警报状态(29 Hz)期间,显性频率的微妙但显着降低,在轻度麻醉,轻微刺激的状态下进一步下降了约21 Hz。 L-DOPA处理可显着降低SNPR LFP的高β功率(80%),并改善了在圆形跑步机上行走的病变。这种处理还降低了轻度麻醉状态的β范围活性。 5-羟色胺1A激动剂在步行过程中逆转了L-DOPA对SNPR高β功率的影响,这与证据相一致,证明中枢神经系统中的5-羟色胺能末端与L-DOPA转化为多巴胺以及多巴胺细胞死亡后多巴胺的释放。
在这种帕金森氏病动物模型中,β活性与运动缺陷之间的相关性支持以下假设:基底神经节输出中神经元活性同步的假设在这些大鼠表达的步态中的介导缺陷中起作用。在偏半蛋白大鼠的一系列行为中,基础神经节中同步活性中观察到的频率范围表明,同步活性是由复杂的神经元网络产生的,就像皮层中的复杂神经元网络一样,与外部全球pallus pallip pallymicus sucthamic sucthamic cuttion nections the Cortex一样,与更有限的网络相反。未来的研究将研究基底神经节回路中不同节点神经元活动的局部操纵的影响,以更好地了解基底神经节活动的改变如何导致帕金森病的运动功能障碍。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JUDITH RICHMOND WALTERS其他文献
JUDITH RICHMOND WALTERS的其他文献
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{{ truncateString('JUDITH RICHMOND WALTERS', 18)}}的其他基金
PHARMACOLOGY AND PHYSIOLOGY OF THE SUBSTANTIA NIGRA AND BASAL GANGLIA
黑质和基底神经节的药理学和生理学
- 批准号:
6290613 - 财政年份:
- 资助金额:
$ 115.33万 - 项目类别:
Pharmacology And Physiology Of The Substantia Nigra And Basal Ganglia
黑质和基底神经节的药理学和生理学
- 批准号:
8940031 - 财政年份:
- 资助金额:
$ 115.33万 - 项目类别:
Thalamo-Cortical Plasticity: Pain, Executive Function and Loss of Dopamine
丘脑皮质可塑性:疼痛、执行功能和多巴胺丧失
- 批准号:
9563157 - 财政年份:
- 资助金额:
$ 115.33万 - 项目类别:
Pharmacology And Physiology Of The Substantia Nigra And
黑质的药理学和生理学
- 批准号:
7143804 - 财政年份:
- 资助金额:
$ 115.33万 - 项目类别:
Pharmacology And Physiology Of The Substantia Nigra And Basal Ganglia
黑质和基底神经节的药理学和生理学
- 批准号:
7594641 - 财政年份:
- 资助金额:
$ 115.33万 - 项目类别:
Thalamo-Cortical Plasticity: Sensory Denervation and Loss of Dopamine
丘脑皮质可塑性:感觉神经支配和多巴胺丧失
- 批准号:
8158248 - 财政年份:
- 资助金额:
$ 115.33万 - 项目类别:
Pharmacology And Physiology Of The Substantia Nigra And Basal Ganglia
黑质和基底神经节的药理学和生理学
- 批准号:
7969508 - 财政年份:
- 资助金额:
$ 115.33万 - 项目类别:
Pharmacology And Physiology Of The Substantia Nigra And Basal Ganglia
黑质和基底神经节的药理学和生理学
- 批准号:
7735246 - 财政年份:
- 资助金额:
$ 115.33万 - 项目类别:
Thalamo-Cortical Plasticity: Sensory Denervation and Loss of Dopamine
丘脑皮质可塑性:感觉神经支配和多巴胺丧失
- 批准号:
8940110 - 财政年份:
- 资助金额:
$ 115.33万 - 项目类别:
Pharmacology And Physiology Of The Substantia Nigra And Basal Ganglia
黑质和基底神经节的药理学和生理学
- 批准号:
9358528 - 财政年份:
- 资助金额:
$ 115.33万 - 项目类别:
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