Optogenetic neural probes for the study of neurodegenerative disorders

推进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，人类大脑是一个高度复杂的系统，有超过1011个神经元，每个神经元有100到1000个连接。通过识别动物模型中的某些神经回路，并采用光遗传学等基因靶向技术，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，作为光开关（通过特定波长的光照明打开或关闭神经活动），并可以通过基因表达技术或病毒针对特定的细胞类型。它让我们对阿尔茨海默氏症、帕金森症和癫痫等疾病有了更深入的了解，并带来了新的治疗策略。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地方）。此外，理想情况下，这种光传输将与监测电生理反应的记录电极相结合，从而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硅探针，它可以穿透老鼠的大脑，通过一组植入的微型led在细胞尺度上传递光。然而，III-V半导体材料的最新进展使得新的微型led器件能够在新的波长下发射，我们有能力通过称为微转移印刷的过程将其与我们的神经探针集成。这有望带来新的光电探针，具有三色光遗传学控制（蓝色，绿色和红色），允许在大脑回路中不同的神经元群体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，允许对自由行为的动物进行电生理记录。这有望激活/抑制大脑深层的神经元，同时监测它们的活动。该项目与H2020资助的欧盟项目deep项目相关联，该项目汇集了来自欧洲各地的一些领先技术专家、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相结合，并将其用于领先的神经科学实验室，以进一步了解我们的大脑。斯特拉斯克莱德大学由物理学家、工程师和神经科学家组成的强大团队加强了这些国际联系。Mathieson教授和Sakata博士已经在神经技术方面建立了一个联合研究小组，以确保神经探针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使用已经在Strathclyde基准测试的先进技术。该学生将开发先进的纤维测光系统，该系统利用微制造的微型led探针与锥形纤维技术相结合。我们最近投资了一个50万英镑的激光光刻系统，该系统能够实现窄至300纳米的电迹连接，这意味着我们可以在微创针状探针上安装多个微型led。该技术将是最先进的，当与deep联盟开发的新光遗传视蛋白相结合时，将有机会在该项目期间实现高影响力的出版物。除了deep项目外，该奖学金还与皇家工程院新兴技术主席基金保持一致，该基金支持更广泛的团队，并与斯特拉斯克莱德博士培训中心相关联。这使得斯特拉斯克莱德大学的一个技术-神经科学小组拥有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.