Miniature, Integrated Fluorescence Microscopes for In Vivo Brain Imaging

描述（由申请人提供）：神经回路在神经精神疾病中的作用越来越受到重视。然而，对于神经活动的正常模式以及这些模式在疾病中是如何出错的，我们仍然缺乏关键的知识。尽管大脑研究人员已经建立了许多人类大脑疾病的小鼠模型，但目前还没有技术可以可视化观察行为小鼠大脑中大量个体的活动，这些神经元的基因类型是确定的——最好是在多个小鼠中并行进行。

DESCRIPTION (provided by applicant): There is a rising emphasis today on the role of neural circuitry in neuropsychiatric disease. However we still lack crucial knowledge of both normal patterns of neural activity and how these patterns go awry in disease. Although brain researchers have already created mouse models of many human brain diseases, presently there is no technology that can visualize the activity of large numbers of individual, neurons of genetically identified types in the brains of behaving mice - ideally in multiple mice in parallel. The capacity to obtain such large-scale data sets is important towards identifying neurophysiologic signatures of brain disease and is a prerequisite for developing therapeutic means of re-tuning aberrant activity patterns. Fluorescence microscopy has key advantages for tracking neural activity. However, while conventional fluorescence microscopes offer the spatiotemporal resolution needed for imaging the brain's cellular dynamics, they neither permit studies in freely behaving mice nor are scalable for studies of large numbers of animal subjects. If fluorescence microscopes could be made small, portable, and cheap, then in principle large numbers of behaving mice could be studied in parallel. Inscopix, Inc. has spun-out of Stanford University to commercialize miniature, integrated fluorescence microscopes - imaging technology that helps neuroscientists visualize neural circuit dynamics in awake behaving mice and rats. Prototype microscopes at Stanford are already enabling imaging of cerebellar microcirculation and permitting visualization of Ca2+ dynamics within hundreds of individual neurons (over weeks in some experiments) as the animal behaves freely in a naturalistic manner. The core miniature, integrated microscope technological innovation and its promise for studying the brain and its diseases was recently featured in Nature, MIT Technology Review, and several media outlets. In Phase I Inscopix aims to develop and test a new set of prototype microscopes that are significantly higher-performing, robust and part of a user-friendly end-to-end solution for in vivo brain imaging in freely behaving rodents. Specifically, we will: (1) Desig and create a new version of our miniaturized, integrated microscope. We will further develop the core technology and incorporate several improvements to significantly enhance imaging performance and extend the capabilities for in vivo brain imaging, including: (a) Attaining spatial resolution finer than 1 ¿m over fields-of-view up to 1 mm2; (b) Developing a digital, high-speed rotary commutator enabling unsupervised, imaging studies of brain activity; (c) Creating a robust and reliable microscope housing suitable for low-cost manufacturing in large volumes. (2) Develop accompanying hardware and software for data acquisition and processing. We will create a compact and user-friendly USB-compatible box for image acquisition and microscope control along with an easy-to-use Graphical User Interface (GUI). (3) Fabricate and test 10 new miniature microscopes with accompanying peripherals. We will fabricate and internally test our new designs before distributing 10 prototypes to carefully chosen beta labs for in vivo testing and validation. By the end of Phase I we expect to have received considerable in vivo usage feedback from beta labs, laying the foundation for volume production and roll-out of a market-ready product in Phase II.