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: 8416342
• 负责人: Michael S. Levine
• 金额: $ 18.58万
• 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 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416342
• 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.

描述（由申请人提供）：亨廷顿氏病（HD）是一种遗传常染色体神经退行性疾病，始终是致命的，没有有效的治疗方法或治疗方法。携带突变的患者显示运动功能障碍，认知障碍和精神病患者。在神经病理学上，HD的特征是纹状体和皮质中的神经元丧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，在疾病的早期和晚期，直接和间接纹状体输出途径中突触活动的失衡有所不同，并在两个全长的HD转基因小鼠模型中导致运动症状。在早期HD中，谷氨酸和GABA释放增加到直接途径中型棘神经元（MSN），而GABA释放在后期释放增加，但仅在间接途径MSN上增加。 突触活性的变化与早期HD小鼠的重复行为增加有关，并且晚期小鼠的运动减少。早期的变化可以通过纹状体多巴胺（DA）介导，因为内源性DA的耗竭减少了重复行为并逆转了一些电生理改变。相反，晚期HD的运动降低可能是由DA功能降低介导的。该应用的目的是采用新型的光遗传学方法，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学和行为功能障碍。在AIM 1中，我们将使用光遗传学在DA神经元中使用光遗传学（通过黄光激活时抑制卤代紫红质（在激活时抑制发射），在早期阶段HD的纹状体中有选择地抑制DA释放。在AIM 2中，我们将使用光遗传学在后期HD中选择性地增加纹状体中的DA释放，通过表达通道视紫红质（用蓝光激活时，这会增加发射）。我们假设在早期HD中减少纹状体DA释放将恢复MSN的突触活动，并将对异常重复运动产生有益的影响。在晚期HD中，增加DA释放将恢复MSN活性的某些平衡，并减轻运动症状。