Advancement and Application of a Novel Basal Ganglia Thalamocortical Circuitry Model in Dystonia Rats

新型肌张力障碍大鼠基底节丘脑皮质环路模型的进展及应用

• 批准号: 10084214
• 负责人: Mark S Baron
• 金额: --
• 依托单位: VA VETERANS ADMINISTRATION HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084214
• 关键词: Anatomy; Animal Model; Area; Bacteria; Basal Ganglia; Beds; Brain; Brain region; Cell Nucleus; Cells; Cerebral Palsy; Chemicals; Color; Computer Models; Craniocerebral Trauma; Custom; Diffuse; Disinhibition; Dorsal; Dystonia; Electromyography; Exhibits; Eye; Failure; Frequencies; Functional disorder; Genetic; Globus Pallidus; Goals; Health; Human; Icterus; Incidence; Investigation; Label; Lead; Lesion; Light; Manuals; Mediating; Medical; Methodology; Methods; Modeling; Modernization; Motor; Motor Cortex; Movement; Movement Disorders; Muscle; Neurons; Operative Surgical Procedures; Opsin; Output; Pacemakers; Parkinsonian Disorders; Pathologic; Pattern; Pharmaceutical Preparations; Pharmacology; Post-Traumatic Stress Disorders; Posture; Property; Proteins; Rattus; Recombinants; Refractory; Regulation; Research Proposals; Resistance; Rest; Risk; Rodent; Rodent Model; Role; Secondary Dystonia; Signal Transduction; Site; Soldier; Stroke; Structure; Surface; Synapses; Techniques; Testing; Thalamic structure; Therapeutic; Transgenic Organisms; Translating; Trauma; Traumatic Brain Injury; Vesicular stomatitis Indiana virus; Veterans; Viral; base; behavioral response; brain abnormalities; brain cell; design; experimental study; extracellular; improved; insight; microorganism; neurophysiology; neurotoxic; novel; novel therapeutic intervention; optogenetics; physiologic model; prevent; programs; real time monitoring; receptor; response; side effect; simulation

Dystonia is a devastating condition characterized by ineffective, twisting movements and contorted postures. While surgical treatments are effective for those with many genetic or undetermined causes, treatments for secondary forms due to such as trauma, strokes and cerebral palsy are poorly responsive to current medical and surgical therapies. Because of the high incidence of dystonia from head trauma, our soldiers are particularly susceptible to developing secondary dystonia. Despite its impact on human health, the underlying abnormalities in the brain had not prior to our recent studies been well investigated in animal models. Our investigations in rodent models of dystonia are revealing remarkable insight into how abnormal signals originating in the basal ganglia, located in a deep region of the brain, are causing another deep brain region, the thalamus, to send abnormal signals onto the motor cortex at the surface of the brain. The abnormal brains signals thus generated in the motor cortex ultimately lead to erroneous signals being sent to the muscles, causing the devastating motor features of this condition. We discovered that the neuronal (brain cell) activity in a specific part of the basal ganglia, the globus pallidus externa (GPe) was grossly silent in rodents with experiment dystonia from being jaundiced in their brain. This led us to pursue destructive chemical lesions in GPe in other rodents to further test if silencing the GPe would indeed produce dystonia. After affirming this, we developed a second much improved focused rodent model which will be invaluable for our ongoing studies. In the new studies, we will utilize a modern technique, which takes advantage of the properties of opsins, which are light-sensitive proteins contained in microorganisms, including bacteria. Opsins, like the light receptors in the human eye, are important for producing actions in these microorganisms, such as movement, in response to light. By incorporating viral-opsin constructs directly into select brain cells and then passing a light probe through the brain near these cells, different colored light frequencies can be used to stimulate or inhibit the ‘infected’ brain cells with very high precision. These opsins will be used here to program the abnormal brain cell activity in previously defined pathological brain regions, including in different nuclei (regions) of the basal ganglia and the thalamus. Our intent is to program the brain cells in these regions to approach more natural patterned activity, with the hope of reversing the dystonia in the rodents. Additional methods will involve introducing a pharmacological agent into the thalamus to turn off electrical burst properties of these brain cells to determine the role of bursting of these brain cells in programming of normal and pathological movement. Brain cells in the thalamus exist in two states: a tonic firing mode and a burst firing mode and the importance of each has been debated. Our studies are showing that the burst mode is the main mode in the thalamus for motor actions and that the specific fine details of the bursts precisely influence movement activity. Since the details of the burst signaling are highly abnormal in dystonia, we will attempt to normalize this activity by stimulating opsins injected directly into the thalamus, as well as introduced into regions connecting to and influencing the thalamus. We will additionally extensively incorporate computational neuronal simulations to further test our physiological modeling and to guide our neurophysiological studies. Our comprehensive approach is anticipated to lead to refinement of our novel evolving normal and pathological basal ganglia- thalamocortical circuitry model. Ultimately, the hope is that the findings here will translate to new treatments for a condition which is often refractory to current therapies.

肌张力障碍是一种破坏性的条件，其特征是无效的，扭曲的运动和扭曲 姿势虽然手术治疗对那些有许多遗传或不确定性的人有效， 由于创伤、中风和脑瘫等继发性疾病的治疗效果很差， 对当前的内科和外科治疗有反应。由于肌张力障碍的高发病率， 头部创伤，我们的士兵特别容易发展为继发性肌张力障碍。尽管 对人类健康的影响，大脑中潜在的异常在我们最近的研究之前还没有 在动物模型中得到了很好的研究。 我们对啮齿动物肌张力障碍模型的研究揭示了对如何 起源于位于大脑深部的基底神经节的异常信号， 另一个脑深部区域，丘脑，将异常信号发送到运动皮层， 大脑的表面。运动皮层中产生的异常大脑信号最终导致 错误的信号被发送到肌肉，导致破坏性的运动功能， 条件我们发现基底神经节特定部位的神经元（脑细胞）活动， 在实验性肌张力障碍的啮齿动物中，苍白球外（GPe）明显沉默， 在他们的大脑中产生了黄疸。这促使我们在其他啮齿动物的GPe中寻找破坏性的化学损伤， 进一步测试沉默GPe是否真的会产生肌张力障碍。在肯定了这一点之后，我们制定了一个 第二个大大改进的重点啮齿动物模型，这将是非常宝贵的，我们正在进行的研究。 在新的研究中，我们将利用一种现代技术， 视蛋白是包含在微生物（包括细菌）中的光敏蛋白质。视蛋白， 就像人眼中的光受体一样，对于产生这些动作很重要。 微生物，如运动，响应于光。通过整合病毒视蛋白构建体 直接进入选定的脑细胞，然后将光探针穿过这些细胞附近的大脑， 不同颜色的光频率可以用来刺激或抑制“感染”的脑细胞， 高精度这些视蛋白将在这里被用来编程异常的脑细胞活动， 先前定义的病理性脑区域，包括基底节的不同核团（区域） 神经节和丘脑。我们的目的是对这些区域的脑细胞进行编程， 自然模式的活动，希望能逆转啮齿动物的肌张力障碍。另外的方法 将包括将药物引入丘脑以关闭电脉冲 这些脑细胞的特性，以确定这些脑细胞的爆裂在编程中的作用， 正常和病理性运动。丘脑中的脑细胞以两种状态存在： 和突发点火模式以及每一种模式的重要性一直存在争议。我们的研究表明， 突发模式是丘脑中用于运动动作的主要模式， 这些爆发精确地影响运动活动。由于突发信号的细节非常复杂， 在肌张力障碍中，我们将尝试通过刺激直接注射的视蛋白来使这种活动正常化。 进入丘脑，以及被引入到连接和影响丘脑的区域。我们 此外，还将广泛采用计算神经元模拟，以进一步测试我们的 生理建模和指导我们的神经生理学研究。我们的综合方法是 预期会导致我们的新进化的正常和病理基底神经节的细化- 丘脑皮层电路模型最终，希望这里的发现将转化为新的 通常对当前疗法难以治疗的病症的治疗。