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Ultra compact miniaturized microscopes to image meso-scale brain activity

English title Ultra compact miniaturized microscopes to image meso-scale brain activity
Applicant Grewe Benjamin
Number 189251
Funding scheme Project funding
Research institution Institut für Neuroinformatik Universität Zürich Irchel und ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Neurophysiology and Brain Research
Start/End 01.06.2020 - 31.05.2024
Approved amount 700'000.00
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All Disciplines (2)

Discipline
Neurophysiology and Brain Research
Other disciplines of Engineering Sciences

Keywords (6)

3D print; miniaturized microscops; mouse; calcium imaging; in vivo microscopy; fluorescence

Lay Summary (German)

Lead
Die Funktion des Gehirns zu verstehen ist eine der größten Herausforderungen unseres Jahrhunderts. Bildgebende Technologien, die es ermöglichen die Gehirnaktivität vieler Zellen sichtbar zu machen und aufzunehmen spielen dabei eine zunehmend größere Rolle. Ziel ist es dabei, die Aktivität möglichst vieler Neurone gleichzeitig im lebendenden Organismus - während dieser ‘nachdenkt‘ - aufzunehmen. Obwohl bildgebende Mikroskopieverfahren in dieser Hinsicht große Fortschritte gemacht haben, ist es zum Beispiel immer noch nicht möglich die neuronale Aktivität mehrerer Zellen in zwei unterschiedlichen Gehirnarealen (z.B. bei Labormäusen) gleichzeitig zu messen. Des Weiteren sind Messungen über einen längeren zusammenhängenden Zeitraum noch nicht möglich, da das Tier für diese Messungen sehr ruhig sein muss (Bewegung führt zu Artefakten). Neue Bildgebend Technologien, die diese Einschränkungen auflösen können, daher die Erforschung der Funktionsweise des Gehirns substantiell voranbringen.
Lay summary

Ziel dieses technischen SNSF Projektes ist es, eine neuartige, miniaturisierte Mikroskopietechnologie zu entwickeln, welche es ermöglicht neuronale Aktivität in großem Maßstab (viele Neurone) in sich frei bewegenden Tieren aufzunehmen. Dazu wird die Größe eines Fluoreszenzmikroskops drastisch (auf einige Millimeter) verkleinert. Die Entwicklung dieser ultrakompakten In-vivo Mikorskopietechnologie wird es erstmals ermöglichen, die Aktivität und Dynamik von tausenden von Neuronen in mehreren Hirnregionen (der Mesoskala) während natürlichen Verhaltens eines Tieres zu untersuchen.

Das Studium der Gehirnfunktion bei sich freibewegenden Tieren in natürlicher Umgebung ist wichtig, da nur so die gesamte Komplexität der neuronalen Funktion und des Lernens erfasst werden kann. Am wichtigsten ist, dass die neuartigen Mikroskope mehrere Stufen der hierarchischen Informationsverarbeitung im Gehirn gleichzeitig erfassen können - von der kognitiven Berechnung sensorischer Eingangssignale bis hin zur Verhaltenssteuerung.

Durch Pionierarbeit bei der Entwicklung superkleiner, chronisch implantierbarer, mikrooptischer Bildgebungsverfahren soll dieses SNSF Projekt die Grundlagen für die nächsten konzeptionellen Durchbrüche beim Verständnis der Funktionsweise des Gehirns ermöglichen.

Direct link to Lay Summary Last update: 20.05.2020

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
173721 Temporal Information Integration in Neural Networks 01.06.2018 Sinergia

Abstract

In the framework of this technical/engineering project, I aim to advance in vivo imaging of large-scale neuronal activity in freely-behaving animals by drastically reducing the size of current miniaturized fluorescence microscopes to a few millimeters. Developing such an ultra-compact in vivo calcium imaging technology (the µCam) will address a long-standing challenge in neuroscience, because it will enable researchers for the first time to investigate brain dynamics of thousands of neurons across several brain areas (the meso-scale) in a natural behavioral setting. Studying brain function and animal behavior in natural environments is important because it allows capturing the full complexity of real-world neural computation and learning. Most importantly, the novel µCam devices will be able to simultaneously visualize multiple stages of hierarchical information processing - from the cognitive computation to behavioral output. By pioneering the development of super-small, chronically-implanted, micro-optic imaging devices, I aim to lay out the groundwork for addressing the next set of conceptual breakthroughs in understanding large-scale, multi-site brain dynamics. To develop such a tiny, ultra-flat fluorescence microscope, I will explore a radically new micro-optic manufacturing and assembly approach that makes use of a new 3D-micro-optic glass printing technology. My lab is uniquely positioned to pioneer the miniaturization of next-generation brain imaging devices because it combines both engineering expertise in optics with a deep understanding and know-how regarding in vivo calcium imaging and related neuroscience topics. Within this project, I pursue three consecutive aims. First, I will pioneer novel micro-optic in silico design and 3D-glass-printing approaches to overcome current technical limitations that so far have hindered a further downscaling of miniaturized microscope optics. While a novel manufacturing approach - 3D optic glass-printing - will allow rapid prototyping, a super-flat stacking and a sub-micron-precise alignment of all optical components, the combination with in silico (in software) systems engineering will facilitate the exploration of the µCam optical design (i.e., size) and optical performance limits (i.e., resolution). In the second phase, I will use the new optics manufacturing approach to construct two different µCam prototypes, validate their optical performance and test their applicability in an in vivo imaging experiment in mice. The major advantage of the new, super-flat µCam optical design (height ~ 4-5 mm) is that it is easily scalable in the lateral dimension to match different imaging sensors - from a very small 2x2 mm to a large field-of-view (FOV) imaging sensor. The first µCam prototype, will be designed for a large imaging sensor (FOV ~4x3 mm) while the second µCam prototype will be designed as a pin-sized microscope with a total size of ~2x2x4 mm and a FOV of ~0.8x0.8 mm. In the third phase of the project, I then aim to find strong applications that showcase the pioneering design of the new µCam technology. By selecting a set of research projects employing the new µCams, I aim to demonstrate how the new technology allows addressing a broad range of novel, exciting and fundamental neuroscience questions. Disseminating the first µCam prototypes to seven collaborating labs and integrating their feedback will then allow me to further improve the microscope design and usability. Overall, the project will result in the design and construction of two types of µCam microscopes (large FOV and pin-sized) that will premiere the true investigation of meso-scale brain dynamics in freely-behaving animals with many new exciting possibilities and applications. For example, the new approach will allow to image thousands of superficial Layer 2/3 neurons across multiple cortical sensory areas (e.g., mouse V1, A1, S1) using the 12 mm2 FOV µCam or to record from multiple deep and superficial brain areas simultaneously (e.g., mPFC, MEC and HC) using multiple pin-sized µCams on the same mouse. Finally, I anticipate that the open-source dissemination of the new µCam technology to a broader neuroscience community will bring the European and Swiss research back on the global map when it comes to cutting-edge mobile imaging technology in rodents and other species.To summarize, using cutting-edge 3D optic glass-printing technology I propose a radically new micro-optic design and manufacturing approach that allows down-scaling miniaturized microscopes to the technically possible limit. Using this approach, I aim to construct two different µCam prototypes that will provide me and the broader research community with the missing link to characterize the interaction of multiple hierarchical network levels during animal behavior - a key challenge in neurosciences today.
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