苍白球外侧部在异常不自主运动产生中的作用研究
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摘要
基底神经节(Basal Ganglia)是一群重要的皮质下灰质核团,一般认为包括五部分：新纹状体(包括尾状核和壳核)、苍白球外侧部(External Globus Pallidus,GPe)、苍白球内侧部(Internal Globus Pallidus, GPi)—黑质网状部(Substantia Nigra pars reticulate, SNr)复合体、黑质致密部(substantia nigra pars compacta, SNc)及丘脑底核(Subthalamic nucleus, STn)。基底神经节对于运动控制的神经环路机制一直不是非常清楚。目前人们对于基底神经节环路的认识主要集中在直接通路与间接通路模型。然而直接通路与间接通路模型并不能涵盖基底神经节环路的所有方面,不能解释所有基底神经节参与的运动障碍疾病的神经环路机制。对于基底神经节在异常行为与运动障碍中的作用,有待于进一步的研究。
GPi是基底神经节的主要输出结构。大部分运动障碍疾病与之功能异常相关,目前临床上应用高频电刺激GPi可以改善部分帕金森病、肌张力障碍、舞蹈病患者的运动症状。而GPe的作用尚不是很清楚,其能否成为部分运动障碍疾病治疗的靶核团有待于进一步研究。目前认为GPe是基底神经节间接通路中的一个重要核团,其主要接受新纹状体中脑啡肽(enkephalin, ENK)阳性的γ-氨基丁酸(GABA)能神经元的抑制性投射以及STn的谷氨酸能神经元的兴奋性投射。亨廷顿舞蹈病(Huntington disease, HD)早期特征性的病理改变为新纹状体中ENK阳性的GABA能神经元的丢失。这部分抑制GPe的GABA能神经元的丢失,将会增加GPe的放电节律。GPe放电节律的增加可能是HD舞蹈样症状产生的重要神经基础。有实验在猴子的GPe局部注射GABA受体拮抗剂,增加GPe核团的活性使猴子对侧肢体产生不自主运动及异常行为(包括活动过多、注意力缺陷等)。总之GPe的活性增加可能与异常不自主运动(abnormal involuntary movements)和异常行为的产生相关。对GPe的功能进行进一步研究,有可能为其成为另一个潜在的运动障碍疾病治疗的靶核团提供实验依据。
传统的研究脑功能的手段包括：建立实验动物损伤模型、神经影像学(如PET、 fMRI)检查、电刺激核团和核团内局部注射药物等方法。这些方法具有各自的优缺点,但均很难特异性地实时控制特定核团特定类型神经元的活动,因此难以建立神经元活性与运动症状之间的直接因果关系。近几年,随着一项新型的技术-光遗传学(optogenetics)技术的出现,使人们看到了突破这一瓶颈的曙光。光遗传学技术是将来自海藻或古生物的光敏感的离子通道蛋白(如对细胞起兴奋作用的光敏感阳离子通道蛋白channelrhodopsin-2, ChR2;或对细胞起抑制作用的光敏感阴离子通道蛋白natronomonas pharaonis halorhodopsins, NpHR)基因通过特定转基因技术手段(如病毒转导或构建转基因小鼠等)特异性地表达在特定类型的神经元中,以便通过光刺激改变该神经元的兴奋性,从而研究其在神经环路及特定行为中的作用。我们可以通过光遗传学技术特异性地兴奋GPe的GABA能神经元,从而研究其对运动行为的影响,并分析其参与的神经环路机制。这将提供比以往更为确凿的关于GPe的功能的证据。
因此,本课题中我们利用新的光遗传学技术,特异性兴奋GPe的GABA神经元,进一步研究其在不自主运动与异常行为产生中的作用,及其在基底神经节环路中的作用。
第一部分光刺激直接兴奋小鼠GPe的GABA能神经元对小鼠运动行为的影响
GPe的神经元类型主要为GABA能神经元。VGAT-ChR2-EYFP转基因小鼠是一种特异性在GABA能神经元上表达ChR2的转基因鼠。将光纤植入该小鼠的右侧GPe,在其自由活动时,给予蓝光刺激,发现小鼠在光刺激过程中出现头颈部扭转、对侧前肢异常姿势等肌张力障碍样改变,同时伴有咀嚼与伸舌等不自主运动以及旋转行为,光刺激结束后上述不自主运动与异常行为消失。同步脑电图记录,排除刺激过程中癫痫发作可能。我们第一次通过光遗传学手段非常直观地观察到了直接兴奋GPe的GABA能神经元可使小鼠产生异常不自主运动。以c-Fos表达作为神经元兴奋的标记,检测小鼠皮质-基底神经节-皮质环路中主要核团(运动皮质M1、GPe、GPi、STn)的c-Fos表达情况,进一步提示了这种异常不自主运动产生的神经环路基础,与GPe活性增加、GPi活性下降、M1活性增加相关。
第二部分光刺激兴奋GPe的兴奋性输入纤维对小鼠运动行为的影响
GPe主要接受纹状体的抑制性输入与STn的兴奋性输入。Thyl-ChR2-EYFP转基因小鼠是一种在兴奋性投射神经元中表达ChR2的转基因鼠。我们通过免疫组化证实,在该小鼠内ChR2不表达在GPe的神经元胞体上,而是表达在GPe的兴奋性输入纤维上。将光纤植入该小鼠的GPe,同样在其自由活动时,给予蓝光刺激,发现小鼠在光刺激过程中出现与之前VGAT-ChR2-YFP转基因小鼠类似的头颈部扭转,左前肢痉挛等不自主运动以及旋转行为。同步脑电图记录,排除癫痫发作可能。c-Fos的表达结果证实了光刺激兴奋GPe的兴奋性输入从而增加了GPe的GABA能神经元的兴奋性。结果提示通过光遗传学手段兴奋GPe的兴奋性输入,同样能产生肌张力障碍样改变及其它不自主运动。说明GPe的兴奋性输入增加可能是GPe活性增加的原因,某些运动障碍疾病产生的神经环路机制可能与GPe的兴奋性输入增加有关。同时也进一步说明了GPe的活性增加是异常不自主运动产生的关键。
第三部分光刺激特异性兴奋STn投射至GPe的谷氨酸能神经元轴突末梢对小鼠运动行为的影响
由于GPe接受的兴奋性输入主要来源于STn。之前对Thy1-ChR2-EYFP转基因小鼠GPe的光刺激可能就是兴奋了STn对GPe的投射纤维。为进一步验证STn对GPe的兴奋性投射这条通路,我们通过对小鼠STn局部注射AAV病毒AAV-CaMKIIα-ChR2-mCherry,使STn谷氨酸能神经元特异性地表达ChR2。通过对该小鼠大脑切片观察,发现GPe与GPi内均有来源于STn的表达ChR2的谷氨酸能神经元的投射纤维,这与已知的STn向GPe与GPi的解剖投射关系相符。将光纤植入该小鼠的GPe处,在其自由活动时,给予蓝光刺激,发现小鼠在光刺激过程中出现头颈部扭转及旋转行为等不自主运动。从而特异性地证明了：增加STn投射至GPe这条通路的神经兴奋性,可产生异常不自主运动。提示GPe的活性增加可能与STn投射至GPe这条通路的神经活性增加有关,并推测STn投射至GPe的这条神经通路的活性增加可能与某些运动障碍疾病有关。通过检测c-Fos的表达情况,再次证实了GPe的GABA能神经元活性增加在异常不自主运动产生中的关键作用。
总之,本课题首次应用光遗传学技术,通过直接兴奋GPe的GABA能神经元或兴奋GPe的兴奋性输入纤维或特异性地兴奋STn投射至GPe的谷氨酸能神经元投射这条神经通路,均使小鼠产生了异常不自主运动。从而明确了GPe的GABA能神经元活性增加可产生异常不自主运动,这可能是一些与异常不自主运动相关的运动障碍疾病的神经基础。另外我们的研究结果提示GPe的活性增加的原因之一可以是STn投射至GPe的谷氨酸能神经元这条通路的活性增加,STn投射至GPe的谷氨酸能神经元投射这条神经通路的活性增加可能与某些运动障碍疾病有关。通过对皮质-基底神经节-皮质环路中主要核团(M1、GPe、GPi、STn)的c-Fos表达检测发现：GPe的GABA能神经元活性增加、GPi的活性下降、M1的活性增加可能是异常不自主运动产生的神经环路机制。这些结果为进一步理解与异常不自主运动相关的运动障碍疾病的神经环路机制提供了有价值的线索,为GPe有可能成为治疗这类运动障碍疾病的靶核团提供了实验依据。
The basal ganglia are a group of subcortical nuclei. The main components of the basal ganglia are the striatum (caudate nucleus and putamen), external globus pallidus (GPe), internal globus pallidus (GPi)-substantia nigra pars reticulate (SNr), substantia nigra pars compacta (SNc) and the subthalamic nucleus (STn). The role of the basal ganglia in motor control is debated. A considerable advance was made in understanding the role of the basal ganglia with the development of what has come to be commonly called the direct pathway and indirect pathway model of basal ganglia. However, the direct pathway and indirect pathway models of basal ganglia are still incapable to explain all the neural circuitry of all the movement disorders which are associated with the basal ganglia dysfunction. The role of the specific neuron subtype of the basal ganglia in movement disorders needs to be further studied.
GPi is the primary output nuclei of the BG. Most of the movement disorders are associated with the dysfunction of GPi. The recent literature confirms the efficacy of high-frequency electrical stimulation of the GPi for parkinson disease, primary dystonia, huntington disease. But the function of GPe is not clear. The GPe is a component of the indirect pathway. The GPe receives massive GABAergic afferent fibers from the striatum and glutamatergic afferent fibers from the STn. The chorea (hyperkinesia) characteristic of the early stage of the Huntington Disease (HD) appears to stem from preferential loss of ENK+striatal neurons. Due to loss of the inhibitory ENK positive striatal neurons projecting to the GPe, the GPe activity is increased. Excess GPe activity may be the cause of chorea in HD. Previous experiments have shown that abnormal involuntary movements could be induced by using microinjections of bicuculline into the GPe in primates. In a word, excess GPe activity may be the cause of abnormal involuntary movements. The GPe may be another good therapy target for movement disorders besides the GPi.
Traditional methods in neural circuits study include lesion animal model, functional image study, electrical stimulation, microinjection of drug. All these methods could not manipulate individual components of the brain with high-temporal resolution. Only in recent years, the emergence of optogenetics makes it possible. Neurons may be controlled by optogenetics for fast, specific excitation or inhibition in freely moving mammals. For example, Channelrhodopsins (ChR2) conduct cations and depolarize neurons upon blue light illumination, while natronomonas pharaonis halorhodopsins (NpHR) conduct chloride ions into the cytoplasm upon yellow light illumination. Here we can use the optogenetic tools to study the function of GPe GABAergic neurons in motor control and the neural circuitry of the basal ganglia.
Part1The effects of direct optical stimulation of local GPe GABAergic neurons
The majority of GPe neurons are projection neurons that contain glutamate decarboxylase (GAD). VGAT-ChR2-EYFP transgenic mice are used for precisely controlling action potential firing of GABAergic neurons using blue light. A fiber guide was inserted to the right GPe of the VGAT-ChR2-EYFP transgenic mouse. After illumination of the right GPe by blue light, the mouse developed twisted postures of the neck and the left arm abnormal posture resembling dystonia, repetitive involuntary movements (licking and chewing) and rotation. All the abnormal involuntary movements disappeared after laser off. EEG recordings from the motor cortex during the optical stimulation did not show any abnormal activity. So these involunrary movements were not caused by seizures. We first validated that stimulation of GPe GABAergic neurons could induce dystonia like behavior and involuntary movements. We examined the expression of the immediate early gene, c-Fos, a biomarker of active neurons, in the basal ganglia loop (GPe, GPi, STn, M1). Our findings suggest the neural circuitry of the abnormal involuntary movements is related with excess GPe activity, reduced GPi activity, and excess motor cortex activity.
Part2The effects of optical stimulation of excitatory afferent axons in GPe
The GPe receives massive GABAergic afferent fibers from the striatum and glutamatergic afferent fibers from the STn. The Thyl-ChR2-EYFP transgenic mice are used for precisely controlling action potential firing of excitatory projection neurons using blue light. We established that ChR2-EYFP was expressed in the excitatory afferent axons in GPe, but not cell bodies of GPe. A fiber guide was inserted to the right GPe of the Thyl-ChR2-EYFP transgenic mouse. After illumination of the right GPe by blue light, the mouse developed the similar phenotype as VGAT-ChR2-EYFP transgenic mouse in the first part, such as twisted postures of the neck and the left arm spasm resembling dystonia and rotation. EEG recordings from the motor cortex during the optical stimulation did not show any abnormal activity. So these abnormal involuntary movements were not caused by seizures. The results indicated that increasing the activity of excitatory afferent axons in GPe could also induce abnormal involuntary movements. The increase of activity of afferent axons in GPe may be the neural substrates in some movement disorders. The excess GPe activity play a critical role in producing abnormal involuntary movements.
Part3The effects of optical stimulation of specific glutamatergic afferent fibers from STn in GPe
The GPe receives glutamatergic afferent fibers from the STN. In the second part we cannot establish whether the glutamatergic afferent fibers stimulated in GPe come from the STn. In this part, we delivered AAV carrying ChR2-mCherry under the CaMKIIa promoter to the right STn of the mice. ChR2-mCherry expression was specific to STn excitatory neuron cell bodies and precesses. ChR2-mCherry was expressed in the afferent fibers in the GPe. A fiber guide was inserted to the right GPe of this mouse. After illumination of the right GPe by blue light, the mouse developed the similar phenotype as VGAT-ChR2-EYFP transgenic mouse and Thyl-ChR2-EYFP transgenic mouse in the first and second part, such as twisted postures of the neck and rotation. The results shown that optical stimulation of specific glutamatergic afferent fibers in GPe, which come from STn, would cause abnormal involuntary movements. So the abnormal activity of this specific neuron pathway (glutamatergic projection neurons from STn to GPe) may be involved in the neural circuitry mechanism of abnormal involuntary movements related movement disorders. We also emphasized the important role of excess GPe activity in producing abnormal involuntary movements.
Therefore, we first used optogenetic tools to reveal that excess GPe GABAergic neurons activity may be the cause of abnormal involuntary movements. This may be the neural substrates of abnormal involuntary movements related movement disorders. The increasing activity of specific glutamatergic afferent fibers in GPe, which come from STn, may be involved in the neural circuitry mechanism of abnormal involuntary movements related movement disorders. Excess GPe activity, reduced GPi activity and excess motor cortex activity may be the neural circuitry mechanism of the abnormal involuntary movements. The results provided an important clue to understand the neural circuitry mechanism of abnormal involuntary movements related movement disorders. GPe may be another good therapy target for abnormal involuntary movements related movement disorders.
GPi是基底神经节的主要输出结构。大部分运动障碍疾病与之功能异常相关,目前临床上应用高频电刺激GPi可以改善部分帕金森病、肌张力障碍、舞蹈病患者的运动症状。而GPe的作用尚不是很清楚,其能否成为部分运动障碍疾病治疗的靶核团有待于进一步研究。目前认为GPe是基底神经节间接通路中的一个重要核团,其主要接受新纹状体中脑啡肽(enkephalin, ENK)阳性的γ-氨基丁酸(GABA)能神经元的抑制性投射以及STn的谷氨酸能神经元的兴奋性投射。亨廷顿舞蹈病(Huntington disease, HD)早期特征性的病理改变为新纹状体中ENK阳性的GABA能神经元的丢失。这部分抑制GPe的GABA能神经元的丢失,将会增加GPe的放电节律。GPe放电节律的增加可能是HD舞蹈样症状产生的重要神经基础。有实验在猴子的GPe局部注射GABA受体拮抗剂,增加GPe核团的活性使猴子对侧肢体产生不自主运动及异常行为(包括活动过多、注意力缺陷等)。总之GPe的活性增加可能与异常不自主运动(abnormal involuntary movements)和异常行为的产生相关。对GPe的功能进行进一步研究,有可能为其成为另一个潜在的运动障碍疾病治疗的靶核团提供实验依据。
传统的研究脑功能的手段包括：建立实验动物损伤模型、神经影像学(如PET、 fMRI)检查、电刺激核团和核团内局部注射药物等方法。这些方法具有各自的优缺点,但均很难特异性地实时控制特定核团特定类型神经元的活动,因此难以建立神经元活性与运动症状之间的直接因果关系。近几年,随着一项新型的技术-光遗传学(optogenetics)技术的出现,使人们看到了突破这一瓶颈的曙光。光遗传学技术是将来自海藻或古生物的光敏感的离子通道蛋白(如对细胞起兴奋作用的光敏感阳离子通道蛋白channelrhodopsin-2, ChR2;或对细胞起抑制作用的光敏感阴离子通道蛋白natronomonas pharaonis halorhodopsins, NpHR)基因通过特定转基因技术手段(如病毒转导或构建转基因小鼠等)特异性地表达在特定类型的神经元中,以便通过光刺激改变该神经元的兴奋性,从而研究其在神经环路及特定行为中的作用。我们可以通过光遗传学技术特异性地兴奋GPe的GABA能神经元,从而研究其对运动行为的影响,并分析其参与的神经环路机制。这将提供比以往更为确凿的关于GPe的功能的证据。
因此,本课题中我们利用新的光遗传学技术,特异性兴奋GPe的GABA神经元,进一步研究其在不自主运动与异常行为产生中的作用,及其在基底神经节环路中的作用。
第一部分光刺激直接兴奋小鼠GPe的GABA能神经元对小鼠运动行为的影响
GPe的神经元类型主要为GABA能神经元。VGAT-ChR2-EYFP转基因小鼠是一种特异性在GABA能神经元上表达ChR2的转基因鼠。将光纤植入该小鼠的右侧GPe,在其自由活动时,给予蓝光刺激,发现小鼠在光刺激过程中出现头颈部扭转、对侧前肢异常姿势等肌张力障碍样改变,同时伴有咀嚼与伸舌等不自主运动以及旋转行为,光刺激结束后上述不自主运动与异常行为消失。同步脑电图记录,排除刺激过程中癫痫发作可能。我们第一次通过光遗传学手段非常直观地观察到了直接兴奋GPe的GABA能神经元可使小鼠产生异常不自主运动。以c-Fos表达作为神经元兴奋的标记,检测小鼠皮质-基底神经节-皮质环路中主要核团(运动皮质M1、GPe、GPi、STn)的c-Fos表达情况,进一步提示了这种异常不自主运动产生的神经环路基础,与GPe活性增加、GPi活性下降、M1活性增加相关。
第二部分光刺激兴奋GPe的兴奋性输入纤维对小鼠运动行为的影响
GPe主要接受纹状体的抑制性输入与STn的兴奋性输入。Thyl-ChR2-EYFP转基因小鼠是一种在兴奋性投射神经元中表达ChR2的转基因鼠。我们通过免疫组化证实,在该小鼠内ChR2不表达在GPe的神经元胞体上,而是表达在GPe的兴奋性输入纤维上。将光纤植入该小鼠的GPe,同样在其自由活动时,给予蓝光刺激,发现小鼠在光刺激过程中出现与之前VGAT-ChR2-YFP转基因小鼠类似的头颈部扭转,左前肢痉挛等不自主运动以及旋转行为。同步脑电图记录,排除癫痫发作可能。c-Fos的表达结果证实了光刺激兴奋GPe的兴奋性输入从而增加了GPe的GABA能神经元的兴奋性。结果提示通过光遗传学手段兴奋GPe的兴奋性输入,同样能产生肌张力障碍样改变及其它不自主运动。说明GPe的兴奋性输入增加可能是GPe活性增加的原因,某些运动障碍疾病产生的神经环路机制可能与GPe的兴奋性输入增加有关。同时也进一步说明了GPe的活性增加是异常不自主运动产生的关键。
第三部分光刺激特异性兴奋STn投射至GPe的谷氨酸能神经元轴突末梢对小鼠运动行为的影响
由于GPe接受的兴奋性输入主要来源于STn。之前对Thy1-ChR2-EYFP转基因小鼠GPe的光刺激可能就是兴奋了STn对GPe的投射纤维。为进一步验证STn对GPe的兴奋性投射这条通路,我们通过对小鼠STn局部注射AAV病毒AAV-CaMKIIα-ChR2-mCherry,使STn谷氨酸能神经元特异性地表达ChR2。通过对该小鼠大脑切片观察,发现GPe与GPi内均有来源于STn的表达ChR2的谷氨酸能神经元的投射纤维,这与已知的STn向GPe与GPi的解剖投射关系相符。将光纤植入该小鼠的GPe处,在其自由活动时,给予蓝光刺激,发现小鼠在光刺激过程中出现头颈部扭转及旋转行为等不自主运动。从而特异性地证明了：增加STn投射至GPe这条通路的神经兴奋性,可产生异常不自主运动。提示GPe的活性增加可能与STn投射至GPe这条通路的神经活性增加有关,并推测STn投射至GPe的这条神经通路的活性增加可能与某些运动障碍疾病有关。通过检测c-Fos的表达情况,再次证实了GPe的GABA能神经元活性增加在异常不自主运动产生中的关键作用。
总之,本课题首次应用光遗传学技术,通过直接兴奋GPe的GABA能神经元或兴奋GPe的兴奋性输入纤维或特异性地兴奋STn投射至GPe的谷氨酸能神经元投射这条神经通路,均使小鼠产生了异常不自主运动。从而明确了GPe的GABA能神经元活性增加可产生异常不自主运动,这可能是一些与异常不自主运动相关的运动障碍疾病的神经基础。另外我们的研究结果提示GPe的活性增加的原因之一可以是STn投射至GPe的谷氨酸能神经元这条通路的活性增加,STn投射至GPe的谷氨酸能神经元投射这条神经通路的活性增加可能与某些运动障碍疾病有关。通过对皮质-基底神经节-皮质环路中主要核团(M1、GPe、GPi、STn)的c-Fos表达检测发现：GPe的GABA能神经元活性增加、GPi的活性下降、M1的活性增加可能是异常不自主运动产生的神经环路机制。这些结果为进一步理解与异常不自主运动相关的运动障碍疾病的神经环路机制提供了有价值的线索,为GPe有可能成为治疗这类运动障碍疾病的靶核团提供了实验依据。
The basal ganglia are a group of subcortical nuclei. The main components of the basal ganglia are the striatum (caudate nucleus and putamen), external globus pallidus (GPe), internal globus pallidus (GPi)-substantia nigra pars reticulate (SNr), substantia nigra pars compacta (SNc) and the subthalamic nucleus (STn). The role of the basal ganglia in motor control is debated. A considerable advance was made in understanding the role of the basal ganglia with the development of what has come to be commonly called the direct pathway and indirect pathway model of basal ganglia. However, the direct pathway and indirect pathway models of basal ganglia are still incapable to explain all the neural circuitry of all the movement disorders which are associated with the basal ganglia dysfunction. The role of the specific neuron subtype of the basal ganglia in movement disorders needs to be further studied.
GPi is the primary output nuclei of the BG. Most of the movement disorders are associated with the dysfunction of GPi. The recent literature confirms the efficacy of high-frequency electrical stimulation of the GPi for parkinson disease, primary dystonia, huntington disease. But the function of GPe is not clear. The GPe is a component of the indirect pathway. The GPe receives massive GABAergic afferent fibers from the striatum and glutamatergic afferent fibers from the STn. The chorea (hyperkinesia) characteristic of the early stage of the Huntington Disease (HD) appears to stem from preferential loss of ENK+striatal neurons. Due to loss of the inhibitory ENK positive striatal neurons projecting to the GPe, the GPe activity is increased. Excess GPe activity may be the cause of chorea in HD. Previous experiments have shown that abnormal involuntary movements could be induced by using microinjections of bicuculline into the GPe in primates. In a word, excess GPe activity may be the cause of abnormal involuntary movements. The GPe may be another good therapy target for movement disorders besides the GPi.
Traditional methods in neural circuits study include lesion animal model, functional image study, electrical stimulation, microinjection of drug. All these methods could not manipulate individual components of the brain with high-temporal resolution. Only in recent years, the emergence of optogenetics makes it possible. Neurons may be controlled by optogenetics for fast, specific excitation or inhibition in freely moving mammals. For example, Channelrhodopsins (ChR2) conduct cations and depolarize neurons upon blue light illumination, while natronomonas pharaonis halorhodopsins (NpHR) conduct chloride ions into the cytoplasm upon yellow light illumination. Here we can use the optogenetic tools to study the function of GPe GABAergic neurons in motor control and the neural circuitry of the basal ganglia.
Part1The effects of direct optical stimulation of local GPe GABAergic neurons
The majority of GPe neurons are projection neurons that contain glutamate decarboxylase (GAD). VGAT-ChR2-EYFP transgenic mice are used for precisely controlling action potential firing of GABAergic neurons using blue light. A fiber guide was inserted to the right GPe of the VGAT-ChR2-EYFP transgenic mouse. After illumination of the right GPe by blue light, the mouse developed twisted postures of the neck and the left arm abnormal posture resembling dystonia, repetitive involuntary movements (licking and chewing) and rotation. All the abnormal involuntary movements disappeared after laser off. EEG recordings from the motor cortex during the optical stimulation did not show any abnormal activity. So these involunrary movements were not caused by seizures. We first validated that stimulation of GPe GABAergic neurons could induce dystonia like behavior and involuntary movements. We examined the expression of the immediate early gene, c-Fos, a biomarker of active neurons, in the basal ganglia loop (GPe, GPi, STn, M1). Our findings suggest the neural circuitry of the abnormal involuntary movements is related with excess GPe activity, reduced GPi activity, and excess motor cortex activity.
Part2The effects of optical stimulation of excitatory afferent axons in GPe
The GPe receives massive GABAergic afferent fibers from the striatum and glutamatergic afferent fibers from the STn. The Thyl-ChR2-EYFP transgenic mice are used for precisely controlling action potential firing of excitatory projection neurons using blue light. We established that ChR2-EYFP was expressed in the excitatory afferent axons in GPe, but not cell bodies of GPe. A fiber guide was inserted to the right GPe of the Thyl-ChR2-EYFP transgenic mouse. After illumination of the right GPe by blue light, the mouse developed the similar phenotype as VGAT-ChR2-EYFP transgenic mouse in the first part, such as twisted postures of the neck and the left arm spasm resembling dystonia and rotation. EEG recordings from the motor cortex during the optical stimulation did not show any abnormal activity. So these abnormal involuntary movements were not caused by seizures. The results indicated that increasing the activity of excitatory afferent axons in GPe could also induce abnormal involuntary movements. The increase of activity of afferent axons in GPe may be the neural substrates in some movement disorders. The excess GPe activity play a critical role in producing abnormal involuntary movements.
Part3The effects of optical stimulation of specific glutamatergic afferent fibers from STn in GPe
The GPe receives glutamatergic afferent fibers from the STN. In the second part we cannot establish whether the glutamatergic afferent fibers stimulated in GPe come from the STn. In this part, we delivered AAV carrying ChR2-mCherry under the CaMKIIa promoter to the right STn of the mice. ChR2-mCherry expression was specific to STn excitatory neuron cell bodies and precesses. ChR2-mCherry was expressed in the afferent fibers in the GPe. A fiber guide was inserted to the right GPe of this mouse. After illumination of the right GPe by blue light, the mouse developed the similar phenotype as VGAT-ChR2-EYFP transgenic mouse and Thyl-ChR2-EYFP transgenic mouse in the first and second part, such as twisted postures of the neck and rotation. The results shown that optical stimulation of specific glutamatergic afferent fibers in GPe, which come from STn, would cause abnormal involuntary movements. So the abnormal activity of this specific neuron pathway (glutamatergic projection neurons from STn to GPe) may be involved in the neural circuitry mechanism of abnormal involuntary movements related movement disorders. We also emphasized the important role of excess GPe activity in producing abnormal involuntary movements.
Therefore, we first used optogenetic tools to reveal that excess GPe GABAergic neurons activity may be the cause of abnormal involuntary movements. This may be the neural substrates of abnormal involuntary movements related movement disorders. The increasing activity of specific glutamatergic afferent fibers in GPe, which come from STn, may be involved in the neural circuitry mechanism of abnormal involuntary movements related movement disorders. Excess GPe activity, reduced GPi activity and excess motor cortex activity may be the neural circuitry mechanism of the abnormal involuntary movements. The results provided an important clue to understand the neural circuitry mechanism of abnormal involuntary movements related movement disorders. GPe may be another good therapy target for abnormal involuntary movements related movement disorders.
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