Optogenetic neural probes for the study of neurodegenerative disorders

提高我们对大脑功能的理解将进一步加深我们对神经退行性疾病的理解。然而，人脑是一个高度复杂的系统，每个100s到1000s的连接有超过1011个神经元。通过识别动物模型中的某些神经回路并采用基因定向技术，如光遗传学，可以降低这种复杂性。在这里，我们可以在神经元中表达光敏蛋白，这些蛋白充当光学开关(通过特定波长的光照射来开启或关闭神经活动)，并可以通过基因表达技术或病毒针对特定类型的细胞。它让我们对阿尔茨海默氏症、帕金森氏症和癫痫等疾病有了深入的了解，并导致了新的治疗策略。这种光遗传学方法的一个挑战是，以一种结构化的方式将光传递到大脑的深层区域(显微镜技术无法穿透的区域)。此外，这种光传输将理想地耦合到监测电生理反应的记录电极上，并深入了解正在研究的大脑回路中发生的神经活动。为了做到这一点，我们一直在开发微创的硅探测器，这种探测器可以穿透小鼠的大脑，并通过植入的微LED阵列在细胞规模上传递光。然而，III-V半导体材料的最新进展使新的microLED设备能够以新的波长发射，我们有能力通过一种称为微转移打印的过程将其与我们的神经探针集成在一起。这种新型光电探测器具有3种颜色的光遗传控制(蓝色、绿色和红色)，可以在大脑回路中的不同神经元群中激发和抑制神经活动。我们已经开发出一种低功耗、轻重量的电子控制系统，可以安装在老鼠身上，并结合光遗传控制来记录行为自由的动物的电生理。这承诺允许激活/抑制大脑深层的神经元，同时监控它们的活动。该项目与更深层次的项目相联系，这是一个由H2020资助的欧盟项目，汇集了来自欧洲各地的一些领先的技术专家、神经科学家和临床医生。它提供了一个平台，将该技术与最新的光遗传蛋白质结合起来，并将这些蛋白质用于领先的神经科学实验室，以进一步了解我们的大脑。斯特拉斯克莱德的一个由物理学家、工程师和神经学家组成的强大团队加强了这些国际联系。Mathieson教授和Sakata博士在神经技术方面建立了一个联合研究团队，以确保神经探测器可以立即在体内进行测试和优化，这意味着国际合作者可以获得已经在Strathclyde进行基准测试的先进技术。学生将开发先进的纤维光度测量系统，该系统利用集成了锥形光纤技术的微制造microLED探测器。我们最近投资了一套GB 500k激光光刻系统，能够实现连接窄至300 nm的电迹线，这意味着我们可以在微创针状探头上安装多个微LED。这项技术将是最先进的，当与深层次联盟内开发的新的光遗传学Opsins相结合时，将有机会在该项目期间实现高影响力的出版物。除了深层次的项目外，该项目还与皇家工程院新兴技术教席基金保持一致，该基金支持更广泛的团队，并有一个斯特拉斯克莱德中心与之相关的博士培训。这使得斯特拉斯克莱德的一个技术-神经科学小组得以成立，该小组有25名教职员工和学生。

Advancing our understanding of how the brain functions will further our understanding of neurodegenerative disorders. However, the human brain is a highly complex system with over 1011 neurons each 100s to 1000s of connections. Reducing this complexity is possible by identifying certain neural circuits in an animal model and employing genetically targeted techniques, such as optogenetics. Here we can express light-sensitive proteins in neurons that act as an optical switch (turning neural activity on or off through illumination with light of a certain wavelength) and can be targeted to specific cell types through genetic expression techniques or viruses. It is giving us insight into diseases, such Alzheimer's, Parkinson's and epilepsy and leading to novel treatment strategies.A challenge of this optogenetic approach, is to deliver light in a structured fashion to deep regions of the brain (where microscopy techniques cannot penetrate). Furthermore, this light delivery would ideally be coupled to recording electrodes that monitor the electrophysiological response and give insight in to the neural activity taking place in the brain circuit under study. To do this, we have been developing minimally invasive silicon probes that penetrate into the brain of a mouse and deliver light at the cellular scale through an array of implanted microLEDs. However, recent advances in III-V semiconductor materials have allowed new microLED devices capable of emitting at novel wavelengths that we have the capability to integrate with our neural probes through a process known a micro-transfer printing. This promises new optoelectronic probes, with 3 colour optogenetic control (blue, green and red) allowing both excitation and suppression of neural activity in different populations of neurons within a brain circuit. We have developed a low-power, light-weight electronic control system that can be mounted on a mouse and allow electrophysiological recording in freely-behaving animals combined with the optogenetic control. This promises to allow the activation/suppression of neurons within the deep layers of the brain, while monitoring their activity.The project links in with the DEEPER project, an H2020 funded EU project that draws together some of the leading technologist, neuroscientists and clinicians from across Europe. It presents a platform for the technology to be combined with the latest optogenetic proteins and for these to be used in leading neuroscience laboratories to further our understanding of the brain. These international connections are reinforced by a strong team of physicists, engineers and neuroscientists at Strathclyde. Prof. Mathieson and Dr. Sakata have developed a joint research team in neurotechnology to ensure that the neural probes can be tested in vivo immediately and optimised, meaning that the international collaborators have access to advanced technology already benchmarked at Strathclyde.The student will develop advanced fibre photometry systems that utilise microfabricated microLED probes integrated with tapered fibre technologies. We have recently invested in a £500k laser lithography system capable of realising connecting electrical traces as narrow as 300nm, meaning we can have multiple microLEDs on minimally invasive needle-like probes. The technology would be the state-of-the-art and when combined with the new optogenetic opsins developed within the DEEPER consortium, gives the opportunity for high-impact publications to be realised during this project.In addition to the DEEPER project the studentship aligns with the Royal Academy of Engineering Chair in Emerging Technology grant that is supporting the wider team and has a Strathclyde Centre for Doctoral Training associated with it. This has enabled a technology-neuroscience grouping at Strathclyde that numbers 25 staff and students.