Optogenetic control of striatal dopamine in Huntington's disease

描述(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，总是致命的，没有有效的治疗方法或治疗方法。携带该突变的患者表现为运动功能障碍、认知障碍和精神障碍。在神经病理学上，HD的特点是纹状体和皮质中的神经元丢失，皮质和纹状体之间逐渐断开，中断了从皮质到基底节的信息流。我们已经证明，在疾病的早期和晚期，直接和间接纹状体输出通路中突触活动的失衡是不同的，并导致两个全长转基因HD小鼠模型的运动症状。在HD早期，直接通路中型棘神经元(MSN)上谷氨酸和GABA的释放增加，而在晚期，GABA的释放增加，但仅在间接通路MSN上。突触活性的变化与早期HD小鼠重复行为的增加和晚期小鼠运动能力的减少有关。早期的变化可能是由纹状体多巴胺(DA)升高所介导的，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变化。相反，HD晚期运动量减少可能是DA功能降低所致。本应用的目的是使用新的光遗传学方法，使用光刺激来激活和/或抑制HD小鼠模型中的DA终末，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神经元中表达卤视紫质(当被黄光激活时抑制放电)，选择性地抑制早期HD纹状体中DA的释放。在目标2中，我们将利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)来选择性地增加晚期HD患者纹状体中DA的释放。我们推测，在HD早期减少纹状体DA的释放将恢复MSN的突触活动，并将对异常重复运动产生有益的影响。在HD晚期，增加DA释放将恢复MSN活动的部分平衡，并将缓解运动症状。 公共卫生相关性：在亨廷顿病中，纹状体多巴胺传输异常导致兴奋性和抑制性突触传输的时间依赖性改变，导致直接和间接纹状体输出通路活动失衡，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，这一应用程序将使用新的光遗传学方法改变多巴胺的释放，以发现新的靶点来缓解症状和减缓这种毁灭性的遗传疾病的进展。

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.