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Multi electrode array (MEA) systems have evolved from custom-made experimental tools, exploited for neural research, into commercially available systems that are used throughout non-invasive electrophysiological study. MEA systems are used in conjunction with cells and tissues from a number of differing organisms (e.g. mice, monkeys, chickens, plants). The development of MEA systems has been incremental over the past 30 years due to constantly changing specific bioscientific requirements in research. As the application of MEA systems continues to diversify contemporary commercial systems are requiring increased levels of sophistication and greater throughput capabilities.

The retina contains neural circuits that carry out computations as complex as object motion sensing, pattern recognition, and position anticipation. Models of some of these circuits have been recently discovered. A remarkable outcome of these efforts is that all such models can be constructed out of a limited set of components such as linear filters, instantaneous nonlinearities, and feedback loops. The present study explores the consequences of assuming that these components can be used to construct models for all retinal circuits. I recorded extracellularly from several retinal ganglion cells while stimulating the photoreceptors with a movie rich in temporal and spatial frequencies. Then I wrote a computer program to fit their responses by searching through large spaces of anatomically reasonable models built from a small set of circuit components. The program considers the input and output of the retinal circuit and learns its behavior without over-fitting, as verified by running the final model against previously unseen data. In other words, the program learns how to imitate the behavior of a live neural circuit and predicts its responses to new stimuli. This technique resulted in new models of retinal circuits that outperform all existing ones when run on complex spatially structured stimuli. The fitted models demonstrate, for example, that for most cells the center--surround structure is achieved in two stages, and that for some cells feedback is more accurately described by two feedback loops rather than one. Moreover, the models are able to make predictions about the behavior of cells buried deep within the retina, and such predictions were verified by independent sharp-electrode recordings. I will present these results, together with a brief collection of ideas and methods for furthering these modeling efforts in the future. / Physics

D-Serine is regarded as an obligatory co-agonist required for the activation of NMDA-type glutamate receptors (NMDARs). In the retina D-serine and a second NMDAR coagonist, glycine, are present at similar concentration and the cells that produce and release them are in close apposition. This arrangement allows for an abundant supply of coagonists and under certain conditions the NMDAR coagonist binding site could be saturated. There is also evidence suggesting that D-serine can act in an inhibitory manner at AMPA/kainate-type glutamate receptors (GluRs). Glutamate receptor activation can lead to direct and indirect elevation of intracellular calcium (Ca2+) concentration ([Ca2+]i). Therefore, in this thesis, I predominantly used Ca2+ imaging techniques to study the effect of D-serine on GluR activation in the mammalian retina. I first describe a novel method I developed to load retinal cells with Ca2+ indicator dye using electroporation and show that retinas remain viable and responsive following electroporation. This technique was used to explore the excitatory role of D-serine at NMDARs and its potential inhibition of AMPA/kainate receptors using cultured retinal ganglion cells (RGCs) and isolated retina preparations. Using cultured RGCs I demonstrated that D-serine and glycine enhance NMDAR-mediated Ca2+ responses in a concentration-dependent manner and are equally effective as coagonists. In isolated retinas I showed that D-serine application enhanced NMDA-induced responses consistent with sub-saturating endogenous coagonist concentration. Degradation of endogenous D-serine reduced NMDAR-mediated Ca2+ responses supporting the contribution of this coagonist to NMDAR activation in the retina. Using imaging and two different electrophysiological approaches, I found that D-serine reduced AMPA/kainate receptor-mediated responses in cultured RGCs and isolated retinas at concentrations that are saturating at NMDARs. Antagonist experiments suggest that the majority of inhibition is due to D-serine acting on AMPA receptor activity. Degradation of endogenous D-serine enhanced AMPA/kainate-induced responses of some cells in isolated retina suggesting that, under these conditions, D-serine concentration may be sufficient to inhibit AMPA receptor activity. Overall, the work in this thesis illustrates the utility of electroporation as a method to load Ca2+-sensitive fluorescent dyes into retinal cells and highlights the potential role for D-serine as a modulator of ionotropic GluRs in the CNS.

Die vorliegende Arbeit befasst sich mit der Anwendbarkeit von transparenter Elektronik basierend auf oxidischen Halbleitern in Multielektrodenarrays zur Messung von neuronalen Signalen. Im ersten experimentellen Kapitel werden auf Zinkoxid basierende Bauelemente untersucht. Verschiedene Varianten von Feldeffekttransistoren (FETs) werden charakterisiert und ihre Eignung zur Detektion von Zellsignalen überprüft. Die Anwendbarkeit physikalischer Modelle zur Beschreibung von ZnO-basierten Metal-Halbleiter-FETs (MESFETs) wird behandelt. Weiterhin wird die Eignung von einfachen Inverterschaltungen zur Spannungsverstärkung diskutiert. Das zweite Kapitel thematisiert Rauschmessungen an unterschiedlichen ZnO-basierten Proben, darunter Dünnfilme, Mikronadeln, MESFETs und Inverter. Darauf aufbauend wird die Auswirkung des gemessenen Stromrauschens auf die Sensitivität der Bauelemente nachvollzogen und theoretisch modelliert. Im dritten Kapitel wird das Verhalten der Bauelemente im Kontakt mit Elektolyt beschrieben. Die Signalübertragung von Spannungsänderungen im Elektrolyt auf die Chipelektronik wird mit verschiedenen Messmethoden charakterisiert. Dabei kommt teilweise ein selbstgebauter Vorverstärker zum Einsatz, dessen Aufbau ebenfalls beschrieben wird. Die Stabilität der verwendeten Materialien in physiologischen Salzlösungen und ihre Biokompatibilität wird überprüft. Darüber hinaus werden FETs mit Elektrolytgate und Zinkzinnoxid-Kanal vorgestellt.

There is an increasing need for tuneable spectrally pure semiconductor laser sources as well as broadband and polarization insensitive semiconductor optical amplifiers based on the InGaASP/InP material system, to be monolithically integrated with other active and passive components in a photonic integrated circuit. This thesis aims to contribute to finding a solution through modelling, experimental characterization and design improvements. In this thesis we have analyzed laterally-coupled distributed feedback (LC-DFB) lasers. These lasers have the gratings etched directly out of the ridge sidewalls thus lowering the cost associated with the re-growth process required if the gratings were otherwise embedded above the active region. The performance characteristics are analyzed for the LC-DFB lasers partitioned into 1-, 2-, and 3-, electrodes with individual bias control at various operating temperatures. The laser exhibits a stable single mode emission at 1560 nm with a current tuning rate of ~14 pm/mA for a tuning of 2.25 nm. The side modes are highly suppressed with a maximum side-mode suppression ratio of 58 dB. The light-current characteristics show a minimum 40 mA threshold current, and power saturation occurring at higher injection currents. The linewidth characteristics show a minimum Lorentzian linewidth of 210 kHz under free-running and further linewidth reduction under feedback operation. The multi-electrode LC-DFB laser devices under appropriate and selective driving conditions exhibit a flat frequency modulation response from 0 to above 300 MHz. The multi-electrode configuration can thus be further exploited for certain requirements. Simulation results and design improvements are also presented. The experimental characterization of semiconductor optical amplifier (SOA) and Fabry-Perot (FP) laser operating in the E-band are also presented. For the SOA, the linear vertical and horizontal states of polarization corresponding to the transverse electric (TE) and transverse magnetic (TM) modes were considered. For various input power and bias, performance characteristics shows a peak gain of 21 dBm at 1360 nm, gain bandwidth of 60 nm and polarization sensitivity of under 3 dB obtained for the entire wavelength range analyzed from 1340 to 1440 nm. The analysis presented in this thesis show good results with room for improvement in future designs.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22335号 / 医博第4576号 / 新制||医||1041(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 山下 潤, 教授 岩田 想, 教授 木村 剛 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

The purpose of this study is to find out that if antibiotic streptomycin decreases neuronal network activity or affects the pharmacological responses. The experiments in this study were conducted via MEA (multi-electrode array) technology which records neuronal activity from devices that have multiple small electrodes, serve as neural interfaces connecting neurons to electronic circuitry. The result of this study shows that streptomycin lowered the spike production of neuronal network, and also, sensitization was seen when neuronal network pre-exposed to streptomycin.

The human body is dynamic and understanding such complexity for accurate diagnostics and therapies remains a challenge due to lack of minimally-invasive biotechnologies capable of long-term measurements of various biochemical and bioelectrical signals simultaneously from single cells to cell networks. Biocompatibility is a major challenge but recent advancements in micro- and nano-fabrication has shown that patterned protruding pillars from surfaces at the micro- and nano-scale can mimic intrinsic biological structural cues to trigger strong cell adhesion, engulfment, and growth, providing a means by which to engineer the biocompatibility for controlled cell-device bio-interfaces. Here, we sought to leverage the unique biocompatibility of engineered three-dimensional (3D) features with integrated biochemical and bioelectrical sensor arrays to create a multi-modal platform for complex systems biological research. For the biochemical sensor, we introduced a tunable optical nanoantenna that is driven wirelessly by incident laser light (photons) to create a highly localized electric field capable of enhancing the photon scattering rate of nearby chemical bonds, a unique signature that provides a means to fingerprint the local biomolecular ensembles depending on the color of detected scattered photons. By a novel scalable fabrication technique, we merged such nano-sensors with 3D micropillar electrode arrays to create a device with hybrid biophotonic and bioelectronic functionality. We revealed the unique optical properties by micro-reflectance measurements and numerical simulations and verified by spectroscopic measurements a million-fold enhancement to the scattered photon signature from a standard chemical monolayer. We showed favorable bioelectrical properties by electrochemical impedance spectroscopy and cyclic voltammetry, revealing a stable electrochemical interface and reduced resistance due to 3D geometry enabling improved transduction of electrical signals, useful for higher signal to noise ratios in bioelectrical measurements. Overall, we demonstrated the scalable fabrication and unique optical and electrical properties suitable for next generation multi-modal bio-interfacing platforms. / This work was supported by US AFOSR Young Investigator Award FA9550-18-1-0328, US AFOSR DURIP Award FA9550-19-1-0287, US NIST grant 70NANB18H201, and US NIST grant 70NANB19H163. / Master of Science / The human body is dynamic and understanding such complexity for accurate diagnostics and therapies remains a challenge due to lack of minimally-invasive biotechnologies capable of long-term measurements of various biochemical and bioelectrical signals simultaneously from single cells to cell networks. Biocompatibility is a major challenge but recent advancements in micro- and nano-fabrication has shown that patterned protruding pillars from surfaces at the micro- and nano-scale can mimic intrinsic biological structural cues to trigger strong cell adhesion, engulfment, and growth, providing a means by which to engineer the biocompatibility for controlled cell-device bio-interfaces. Here, we sought to leverage the unique biocompatibility of engineered three-dimensional (3D) features with integrated biochemical and bioelectrical sensor arrays to create a multi-modal platform for complex systems biological research. For the biochemical sensor, we introduced a tunable optical nanoantenna that is driven wirelessly by incident laser light (photons) to create a highly localized electric field capable of enhancing the photon scattering rate of nearby chemical bonds, a unique signature that provides a means to fingerprint the local biomolecular ensembles depending on the color of detected scattered photons. By a novel scalable fabrication technique, we merged such nano-sensors with 3D micropillar electrode arrays to create a device with hybrid biophotonic and bioelectronic functionality. We revealed the unique optical properties by micro-reflectance measurements and numerical simulations and verified by spectroscopic measurements a million-fold enhancement to the scattered photon signature from a standard chemical monolayer. We showed favorable bioelectrical properties by electrochemical impedance spectroscopy and cyclic voltammetry, revealing a stable electrochemical interface and reduced resistance due to 3D geometry enabling improved transduction of electrical signals, useful for higher signal to noise ratios in bioelectrical measurements. Overall, we demonstrated the scalable fabrication and unique optical and electrical properties suitable for next generation multi-modal bio-interfacing platforms.

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