Optogenetic control of striatal dopamine in Huntington's disease

亨廷顿病纹状体多巴胺的光遗传学控制

• 批准号: 8284759
• 负责人: Michael S. Levine
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8284759
• 关键词: Axon; Basal Ganglia; Behavior; Behavioral; Cerebral cortex; Corpus striatum structure; Data; Disease; Dopamine; Dopamine D1 Receptor; Equilibrium; Functional disorder; Genetic; Glutamates; Goals; Halorhodopsins; Hereditary Disease; Huntington Disease; Impaired cognition; Length; Light; Locomotion; Mediating; Motor; Movement; Mus; Mutation; Nature; Neurodegenerative Disorders; Neurons; Output; Pathway interactions; Patients; Population; Publishing; Rhodopsin; Severities; Staging; Symptoms; Synapses; Synaptic Transmission; Testing; Tetrabenazine; Time; Transgenic Mice; Work; dopaminergic neuron; effective therapy; gamma-Aminobutyric Acid; illness length; mouse model; neuron loss; neurotransmission; novel; novel strategies; optogenetics; transmission process

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a genetic autosomal neurodegenerative disorder that is always fatal and for which there are no effective treatments or cures. Patients carrying the mutation display motor dysfunction, cognitive impairment and psychiatric disturbances. Neuropathologically, HD is characterized by neuronal loss in the striatum and cortex and a progressive disconnection between cortex and striatum, interrupting the flow of information from the cortex to the basal ganglia. We have shown that imbalances in synaptic activity in the direct and indirect striatal output pathways differ during early and late stages of the disease and contribute to motor symptoms in two full-length transgenic mouse models of HD. In early stage HD, there is increased glutamate and GABA release onto direct pathway medium-sized spiny neurons (MSNs) while GABA release is increased in the late stage but only onto indirect pathway MSNs. Changes in synaptic activity are associated with increased repetitive behaviors in early stage HD mice and with decreased locomotion in late stage mice. Early stage changes may be mediated by elevated striatal dopamine (DA), because depletion of endogenous DA reduced repetitive behaviors and reversed some of the electrophysiological alterations. In contrast, decreased locomotion in late stage HD might be mediated by decreased DA function. The goal of this application is to employ novel optogenetic approaches, using light stimulation to activate and/or inhibit DA terminals in a mouse model of HD, to better understand the electrophysiological and behavioral dysfunctions. In Aim 1 we will selectively inhibit DA release in the striatum in early stage HD, using optogenetics by expressing halorhodopsin (which inhibits firing when activated by yellow light) in DA neurons. In Aim 2 we will selectively increase DA release in the striatum in late stage HD using optogenetics by expressing channel rhodopsin (which increases firing when activated with blue light). We hypothesize that reducing striatal DA release in early stage HD will restore synaptic activity of MSNs and will have beneficial effects on abnormal repetitive movements. In late stage HD, increasing DA release will restore some of the balance in MSN activity and will alleviate motor symptoms. PUBLIC HEALTH RELEVANCE: In Huntington's disease, abnormal striatal dopamine transmission induces time-dependent alterations in excitatory and inhibitory synaptic transmission that contribute to imbalances in activity of the direct and indirect striatal output pathways leading to motor and cognitive disturbances. In order to modify the differential symptoms in early and late stages of Huntington's disease, this application will alter dopamine release using novel optogenetic approaches to uncover new targets to alleviate symptoms and slow the progression of this devastating genetic disorder.

描述（由申请人提供）：亨廷顿病（HD）是一种遗传性常染色体神经退行性疾病，通常是致命的，并且没有有效的治疗或治愈方法。携带突变的患者表现出运动功能障碍、认​​知障碍和精神障碍。从神经病理学角度来说，HD 的特点是纹状体和皮质中的神经元丢失，以及皮质和纹状体之间的进行性断开，从而中断了从皮质到基底神经节的信息流。我们已经表明，直接和间接纹状体输出途径中突触活动的不平衡在疾病的早期和晚期阶段有所不同，并导致两种全长 HD 转基因小鼠模型的运动症状。在 HD 早期，直接通路中型多棘神经元 (MSN) 上的谷氨酸和 GABA 释放增加，而在后期，GABA 释放增加，但仅在间接通路 MSN 上增加。 突触活动的变化与早期 HD 小鼠的重复行为增加有关，而与晚期小鼠的运动减少有关。早期变化可能是由纹状体多巴胺 (DA) 升高介导的，因为内源性 DA 的消耗减少了重复行为并逆转了一些电生理改变。相反，HD 晚期运动能力下降可能是由 DA 功能下降介导的。本申请的目标是采用新颖的光遗传学方法，利用光刺激激活和/或抑制 HD 小鼠模型中的 DA 末端，以更好地了解电生理和行为功能障碍。在目标 1 中，我们将利用光遗传学，通过在 DA 神经元中表达盐视紫红质（在被黄光激活时抑制放电）来选择性抑制 HD 早期纹状体中的 DA 释放。在目标 2 中，我们将使用光遗传学通过表达通道视紫红质（在蓝光激活时增加放电）选择性地增加 HD 晚期纹状体中 DA 的释放。我们假设减少 HD 早期纹状体 DA 的释放将恢复 MSN 的突触活性，并对异常的重复运动产生有益的影响。在 HD 晚期，增加 DA 释放将恢复 MSN 活动的部分平衡，并缓解运动症状。 公共健康相关性：在亨廷顿病中，异常的纹状体多巴胺传递会引起兴奋性和抑制性突触传递的时间依赖性改变，从而导致直接和间接纹状体输出途径的活动失衡，从而导致运动和认知障碍。为了改变亨廷顿病早期和晚期的不同症状，该应用将使用新型光遗传学方法改变​​多巴胺的释放，以发现新的靶点来减轻症状并减缓这种破坏性遗传疾病的进展。