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      In vivo optical modulation of neural signals using monolithically integrated two-dimensional neural probe arrays

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          Abstract

          Integration of stimulation modalities ( e.g. electrical, optical, and chemical) on a large array of neural probes can enable an investigation of important underlying mechanisms of brain disorders that is not possible through neural recordings alone. Furthermore, it is important to achieve this integration of multiple functionalities in a compact structure to utilize a large number of the mouse models. Here we present a successful optical modulation of in vivo neural signals of a transgenic mouse through our compact 2D MEMS neural array (optrodes). Using a novel fabrication method that embeds a lower cladding layer in a silicon substrate, we achieved a thin silicon 2D optrode array that is capable of delivering light to multiple sites using SU-8 as a waveguide core. Without additional modification to the microelectrodes, the measured impedance of the multiple microelectrodes was below 1 MΩ at 1 kHz. In addition, with a low background noise level (±25 μV), neural spikes from different individual neurons were recorded on each microelectrode. Lastly, we successfully used our optrodes to modulate the neural activity of a transgenic mouse through optical stimulation. These results demonstrate the functionality of the 2D optrode array and its potential as a next-generation tool for optogenetic applications.

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          Most cited references18

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          Neural substrates of awakening probed with optogenetic control of hypocretin neurons.

          The neural underpinnings of sleep involve interactions between sleep-promoting areas such as the anterior hypothalamus, and arousal systems located in the posterior hypothalamus, the basal forebrain and the brainstem. Hypocretin (Hcrt, also known as orexin)-producing neurons in the lateral hypothalamus are important for arousal stability, and loss of Hcrt function has been linked to narcolepsy. However, it is unknown whether electrical activity arising from Hcrt neurons is sufficient to drive awakening from sleep states or is simply correlated with it. Here we directly probed the impact of Hcrt neuron activity on sleep state transitions with in vivo neural photostimulation, genetically targeting channelrhodopsin-2 to Hcrt cells and using an optical fibre to deliver light deep in the brain, directly into the lateral hypothalamus, of freely moving mice. We found that direct, selective, optogenetic photostimulation of Hcrt neurons increased the probability of transition to wakefulness from either slow wave sleep or rapid eye movement sleep. Notably, photostimulation using 5-30 Hz light pulse trains reduced latency to wakefulness, whereas 1 Hz trains did not. This study establishes a causal relationship between frequency-dependent activity of a genetically defined neural cell type and a specific mammalian behaviour central to clinical conditions and neurobehavioural physiology.
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            GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease.

            In Alzheimer's disease (AD), memory impairment is the most prominent feature that afflicts patients and their families. Although reactive astrocytes have been observed around amyloid plaques since the disease was first described, their role in memory impairment has been poorly understood. Here, we show that reactive astrocytes aberrantly and abundantly produce the inhibitory gliotransmitter GABA by monoamine oxidase-B (Maob) and abnormally release GABA through the bestrophin 1 channel. In the dentate gyrus of mouse models of AD, the released GABA reduces spike probability of granule cells by acting on presynaptic GABA receptors. Suppressing GABA production or release from reactive astrocytes fully restores the impaired spike probability, synaptic plasticity, and learning and memory in the mice. In the postmortem brain of individuals with AD, astrocytic GABA and MAOB are significantly upregulated. We propose that selective inhibition of astrocytic GABA synthesis or release may serve as an effective therapeutic strategy for treating memory impairment in AD.
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              Mechanisms of gamma oscillations in the hippocampus of the behaving rat.

              Gamma frequency oscillations (30-100 Hz) have been suggested to underlie various cognitive and motor functions. Here, we examine the generation of gamma oscillation currents in the hippocampus, using two-dimensional, 96-site silicon probes. Two gamma generators were identified, one in the dentate gyrus and another in the CA3-CA1 regions. The coupling strength between the two oscillators varied during both theta and nontheta states. Both pyramidal cells and interneurons were phase-locked to gamma waves. Anatomical connectivity, rather than physical distance, determined the coupling strength of the oscillating neurons. CA3 pyramidal neurons discharged CA3 and CA1 interneurons at latencies indicative of monosynaptic connections. Intrahippocampal gamma oscillation emerges in the CA3 recurrent system, which entrains the CA1 region via its interneurons.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                23 October 2015
                2015
                : 5
                : 15466
                Affiliations
                [1 ]Centre for BioMicrosystems, Brain Science Institute, Korea Institute of Science and Technology (KIST) , 5 Hwarang-ro 14-gil 5, Seongbuk-gu, Seoul, 136-791, Korea
                [2 ]Department of Electrical Engineering, Korea University , 145 Anam-ro, Seongbuk-gu, Seoul, 136-701, Korea
                [3 ]School of Electrical Engineering, Korea Advanced Institute of Science and Technology (KAIST) , 291 Daehak-ro, Yuseong-gu, Daejeon, 305-701, Korea
                [4 ]Centre for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology (KIST) , 5 Hwarang-ro 14-gil 5, Seongbuk-gu, Seoul, 136-791, Korea
                [5 ]Department of Electrical Engineering and Computer Science, University of Michigan , 1301 Beal Avenue, Ann Arbor, Michigan, 48105, USA
                [6 ]Department of Biomedical Engineering, Korea University of Science and Technology (UST) , 217 Gajeong-ro, Yuseong-gu, Daejeon, 305-350, Korea
                Author notes
                [*]

                These authors contributed equally to this work.

                Article
                srep15466
                10.1038/srep15466
                4616027
                26494437
                657d69c0-776a-484e-8311-8122130e796d
                Copyright © 2015, Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 05 January 2015
                : 17 September 2015
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