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  • Neocortical excitation/inhibition balance in information processing and social dysfunction NATURE Yizhar, O., Fenno, L. E., Prigge, M., Schneider, F., Davidson, T. J., O'Shea, D. J., Sohal, V. S., Goshen, I., Finkelstein, J., Paz, J. T., Stehfest, K., Fudim, R., Ramakrishnan, C., Huguenard, J. R., Hegemann, P., Deisseroth, K. 2011; 477 (7363): 171-178

    Abstract

    Severe behavioural deficits in psychiatric diseases such as autism and schizophrenia have been hypothesized to arise from elevations in the cellular balance of excitation and inhibition (E/I balance) within neural microcircuitry. This hypothesis could unify diverse streams of pathophysiological and genetic evidence, but has not been susceptible to direct testing. Here we design and use several novel optogenetic tools to causally investigate the cellular E/I balance hypothesis in freely moving mammals, and explore the associated circuit physiology. Elevation, but not reduction, of cellular E/I balance within the mouse medial prefrontal cortex was found to elicit a profound impairment in cellular information processing, associated with specific behavioural impairments and increased high-frequency power in the 30-80?Hz range, which have both been observed in clinical conditions in humans. Consistent with the E/I balance hypothesis, compensatory elevation of inhibitory cell excitability partially rescued social deficits caused by E/I balance elevation. These results provide support for the elevated cellular E/I balance hypothesis of severe neuropsychiatric disease-related symptoms.

    View details for DOI 10.1038/nature10360

    View details for Web of Science ID 000294603900027

    View details for PubMedID 21796121

  • The Development and Application of Optogenetics ANNUAL REVIEW OF NEUROSCIENCE, VOL 34 Fenno, L., Yizhar, O., Deisseroth, K. 2011; 34: 389-412

    Abstract

    Genetically encoded, single-component optogenetic tools have made a significant impact on neuroscience, enabling specific modulation of selected cells within complex neural tissues. As the optogenetic toolbox contents grow and diversify, the opportunities for neuroscience continue to grow. In this review, we outline the development of currently available single-component optogenetic tools and summarize the application of various optogenetic tools in diverse model organisms.

    View details for DOI 10.1146/annurev-neuro-061010-113817

    View details for Web of Science ID 000293772100017

    View details for PubMedID 21692661

  • 193?Optogenetic stimulation of motor cortex neurons promotes functional recovery after stroke. Neurosurgery Cheng, M., Woodson, W. J., Wang, E., Wang, S., Sun, G., Lee, A. G., Arac, A., Fenno, L., Deisseroth, K., Steinberg, G. K. 2013; 60 Suppl 1: 184

    Abstract

    Functional recovery after stroke has been observed in both animal and human studies and is currently attributed to both brain remodeling and plasticity. Brain stimulation techniques such as electrical stimulation and transcranial magnetic stimulation have been used successfully to enhance recovery. However, what mediates this recovery is not well understood. Elucidating the mechanism(s) is difficult because these stimulation techniques non-specifically activate all cell types near the stimulation site. Here we use optogenetic techniques to specifically stimulate layer V pyramidal neurons in the ipsilesional motor cortex at day 5 post-stroke, and investigate the effects on functional recovery as well as underlying mechanisms.Thy-1-ChR2-YFP line-18 transgenic male mice were used. Mice underwent stereotaxic surgery to implant a fiber cannula in the ipsilesional M1. All mice were then subjected to an intraluminal middle cerebral artery suture occlusion (30 minutes). Optogenetic stimulation began at day 5 post-stroke and continued until day 14 post-stroke. Sensorimotor behavior tests were used to assess their behavioral recovery at day 0, 2, 7, 10 and 14 post-stroke. Changes in cerebral blood flow following stimulation were measured at day 14 post-stroke using the Laser Doppler Flowmetry.Rotating beam test revealed that stimulated mice recovered significantly faster than non-stimulated control mice at day 10 and 14 after stroke (P < .05). Stimulated mice also performed significantly better in the adhesive tape test at day 14, with a shorter tape removal time on the contralesional limb (P < .05). Cerebral blood flow measurements revealed that stimulated mice exhibited significantly larger increase in cerebral blood flow following stimulation at day 14 post-stroke (P < .05-.01).These data indicate that optogenetic stimulation of motor cortex neurons can promote behavioral recovery in mice after stroke. Current studies examine the mechanisms underlying this recovery, including genes related to neurotrophic factors after stimulation.

    View details for PubMedID 23839460

  • Principles for applying optogenetic tools derived from direct comparative analysis of microbial opsins. Nature methods Mattis, J., Tye, K. M., Ferenczi, E. A., Ramakrishnan, C., O'Shea, D. J., Prakash, R., Gunaydin, L. A., Hyun, M., Fenno, L. E., Gradinaru, V., Yizhar, O., Deisseroth, K. 2012; 9 (2): 159-172

    Abstract

    Diverse optogenetic tools have allowed versatile control over neural activity. Many depolarizing and hyperpolarizing tools have now been developed in multiple laboratories and tested across different preparations, presenting opportunities but also making it difficult to draw direct comparisons. This challenge has been compounded by the dependence of performance on parameters such as vector, promoter, expression time, illumination, cell type and many other variables. As a result, it has become increasingly complicated for end users to select the optimal reagents for their experimental needs. For a rapidly growing field, critical figures of merit should be formalized both to establish a framework for further development and so that end users can readily understand how these standardized parameters translate into performance. Here we systematically compared microbial opsins under matched experimental conditions to extract essential principles and identify key parameters for the conduct, design and interpretation of experiments involving optogenetic techniques.

    View details for DOI 10.1038/nmeth.1808

    View details for PubMedID 22179551

  • The Microbial Opsin Family of Optogenetic Tools CELL Zhang, F., Vierock, J., Yizhar, O., Fenno, L. E., Tsunoda, S., Kianianmomeni, A., Prigge, M., Berndt, A., Cushman, J., Polle, J., Magnuson, J., Hegemann, P., Deisseroth, K. 2011; 147 (7): 1446-1457

    Abstract

    The capture and utilization of light is an exquisitely evolved process. The single-component microbial opsins, although more limited than multicomponent cascades in processing, display unparalleled compactness and speed. Recent advances in understanding microbial opsins have been driven by molecular engineering for optogenetics and by comparative genomics. Here we provide a Primer on these light-activated ion channels and pumps, describe a group of opsins bridging prior categories, and explore the convergence of molecular engineering and genomic discovery for the utilization and understanding of these remarkable molecular machines.

    View details for DOI 10.1016/j.cell.2011.12.004

    View details for Web of Science ID 000298403400011

    View details for PubMedID 22196724

  • SNCA Triplication Parkinson's Patient's iPSC-derived DA Neurons Accumulate alpha-Synuclein and Are Susceptible to Oxidative Stress PLOS ONE Byers, B., Cord, B., Ha Nam Nguyen, H. N., Schuele, B., Fenno, L., Lee, P. C., Deisseroth, K., Langston, J. W., Pera, R. R., Palmer, T. D. 2011; 6 (11)

    Abstract

    Parkinson's disease (PD) is an incurable age-related neurodegenerative disorder affecting both the central and peripheral nervous systems. Although common, the etiology of PD remains poorly understood. Genetic studies infer that the disease results from a complex interaction between genetics and environment and there is growing evidence that PD may represent a constellation of diseases with overlapping yet distinct underlying mechanisms. Novel clinical approaches will require a better understanding of the mechanisms at work within an individual as well as methods to identify the specific array of mechanisms that have contributed to the disease. Induced pluripotent stem cell (iPSC) strategies provide an opportunity to directly study the affected neuronal subtypes in a given patient. Here we report the generation of iPSC-derived midbrain dopaminergic neurons from a patient with a triplication in the ?-synuclein gene (SNCA). We observed that the iPSCs readily differentiated into functional neurons. Importantly, the PD-affected line exhibited disease-related phenotypes in culture: accumulation of ?-synuclein, inherent overexpression of markers of oxidative stress, and sensitivity to peroxide induced oxidative stress. These findings show that the dominantly-acting PD mutation is intrinsically capable of perturbing normal cell function in culture and confirm that these features reflect, at least in part, a cell autonomous disease process that is independent of exposure to the entire complexity of the diseased brain.

    View details for DOI 10.1371/journal.pone.0026159

    View details for Web of Science ID 000297555400007

    View details for PubMedID 22110584

  • A new mode of corticothalamic transmission revealed in the Gria4(-/-) model of absence epilepsy NATURE NEUROSCIENCE Paz, J. T., Bryant, A. S., Peng, K., Fenno, L., Yizhar, O., Frankel, W. N., Deisseroth, K., Huguenard, J. R. 2011; 14 (9): 1167-U225

    Abstract

    Cortico-thalamo-cortical circuits mediate sensation and generate neural network oscillations associated with slow-wave sleep and various epilepsies. Cortical input to sensory thalamus is thought to mainly evoke feed-forward synaptic inhibition of thalamocortical (TC) cells via reticular thalamic nucleus (nRT) neurons, especially during oscillations. This relies on a stronger synaptic strength in the cortico-nRT pathway than in the cortico-TC pathway, allowing the feed-forward inhibition of TC cells to overcome direct cortico-TC excitation. We found a systemic and specific reduction in strength in GluA4-deficient (Gria4(-/-)) mice of one excitatory synapse of the rhythmogenic cortico-thalamo-cortical system, the cortico-nRT projection, and observed that the oscillations could still be initiated by cortical inputs via the cortico-TC-nRT-TC pathway. These results reveal a previously unknown mode of cortico-thalamo-cortical transmission, bypassing direct cortico-nRT excitation, and describe a mechanism for pathological oscillation generation. This mode could be active under other circumstances, representing a previously unknown channel of cortico-thalamo-cortical information processing.

    View details for DOI 10.1038/nn.2896

    View details for Web of Science ID 000294284900017

    View details for PubMedID 21857658

  • Optogenetics in Neural Systems NEURON Yizhar, O., Fenno, L. E., Davidson, T. J., Mogri, M., Deisseroth, K. 2011; 71 (1): 9-34

    Abstract

    Both observational and perturbational technologies are essential for advancing the understanding of brain function and dysfunction. But while observational techniques have greatly advanced in the last century, techniques for perturbation that are matched to the speed and heterogeneity of neural systems have lagged behind. The technology of optogenetics represents a step toward addressing this disparity. Reliable and targetable single-component tools (which encompass both light sensation and effector function within a single protein) have enabled versatile new classes of investigation in the study of neural systems. Here we provide a primer on the application of optogenetics in neuroscience, focusing on the single-component tools and highlighting important problems, challenges, and technical considerations.

    View details for DOI 10.1016/j.neuron.2011.06.004

    View details for Web of Science ID 000292806200004

    View details for PubMedID 21745635

  • Amygdala circuitry mediating reversible and bidirectional control of anxiety NATURE Tye, K. M., Prakash, R., Kim, S., Fenno, L. E., Grosenick, L., Zarabi, H., Thompson, K. R., Gradinaru, V., Ramakrishnan, C., Deisseroth, K. 2011; 471 (7338): 358-362

    Abstract

    Anxiety--a sustained state of heightened apprehension in the absence of immediate threat--becomes severely debilitating in disease states. Anxiety disorders represent the most common of psychiatric diseases (28% lifetime prevalence) and contribute to the aetiology of major depression and substance abuse. Although it has been proposed that the amygdala, a brain region important for emotional processing, has a role in anxiety, the neural mechanisms that control anxiety remain unclear. Here we explore the neural circuits underlying anxiety-related behaviours by using optogenetics with two-photon microscopy, anxiety assays in freely moving mice, and electrophysiology. With the capability of optogenetics to control not only cell types but also specific connections between cells, we observed that temporally precise optogenetic stimulation of basolateral amygdala (BLA) terminals in the central nucleus of the amygdala (CeA)--achieved by viral transduction of the BLA with a codon-optimized channelrhodopsin followed by restricted illumination in the downstream CeA--exerted an acute, reversible anxiolytic effect. Conversely, selective optogenetic inhibition of the same projection with a third-generation halorhodopsin (eNpHR3.0) increased anxiety-related behaviours. Importantly, these effects were not observed with direct optogenetic control of BLA somata, possibly owing to recruitment of antagonistic downstream structures. Together, these results implicate specific BLA-CeA projections as critical circuit elements for acute anxiety control in the mammalian brain, and demonstrate the importance of optogenetically targeting defined projections, beyond simply targeting cell types, in the study of circuit function relevant to neuropsychiatric disease.

    View details for DOI 10.1038/nature09820

    View details for Web of Science ID 000288444000041

    View details for PubMedID 21389985

  • Microbial opsins: a family of single-component tools for optical control of neural activity. Cold Spring Harbor protocols Yizhar, O., Fenno, L., Zhang, F., Hegemann, P., Diesseroth, K. 2011; 2011 (3): top102-?

    View details for DOI 10.1101/pdb.top102

    View details for PubMedID 21363959

  • An Implantable Optical Stimulation Delivery System for Actuating an Excitable Biosubstrate IEEE JOURNAL OF SOLID-STATE CIRCUITS Paralikar K, Peng Cong, Ofer Yizhar, Lief Ericsson Fenno, Wesley Santa, Chris Nielsen, David Dinsmoor, Bob Hocken, Gordon O. Munns, Jon Giftakis, Karl Deisseroth, Timothy Denison 2011; 46 (1): 321-32
  • Global and local fMRI signals driven by neurons defined optogenetically by type and wiring NATURE Lee, J. H., Durand, R., Gradinaru, V., Zhang, F., Goshen, I., Kim, D., Fenno, L. E., Ramakrishnan, C., Deisseroth, K. 2010; 465 (7299): 788-792

    Abstract

    Despite a rapidly-growing scientific and clinical brain imaging literature based on functional magnetic resonance imaging (fMRI) using blood oxygenation level-dependent (BOLD) signals, it remains controversial whether BOLD signals in a particular region can be caused by activation of local excitatory neurons. This difficult question is central to the interpretation and utility of BOLD, with major significance for fMRI studies in basic research and clinical applications. Using a novel integrated technology unifying optogenetic control of inputs with high-field fMRI signal readouts, we show here that specific stimulation of local CaMKIIalpha-expressing excitatory neurons, either in the neocortex or thalamus, elicits positive BOLD signals at the stimulus location with classical kinetics. We also show that optogenetic fMRI (of MRI) allows visualization of the causal effects of specific cell types defined not only by genetic identity and cell body location, but also by axonal projection target. Finally, we show that of MRI within the living and intact mammalian brain reveals BOLD signals in downstream targets distant from the stimulus, indicating that this approach can be used to map the global effects of controlling a local cell population. In this respect, unlike both conventional fMRI studies based on correlations and fMRI with electrical stimulation that will also directly drive afferent and nearby axons, this of MRI approach provides causal information about the global circuits recruited by defined local neuronal activity patterns. Together these findings provide an empirical foundation for the widely-used fMRI BOLD signal, and the features of of MRI define a potent tool that may be suitable for functional circuit analysis as well as global phenotyping of dysfunctional circuitry.

    View details for DOI 10.1038/nature09108

    View details for Web of Science ID 000278551800047

    View details for PubMedID 20473285

  • Temporally precise in vivo control of intracellular signalling NATURE Airan, R. D., Thompson, K. R., Fenno, L. E., Bernstein, H., Deisseroth, K. 2009; 458 (7241): 1025-1029

    Abstract

    In the study of complex mammalian behaviours, technological limitations have prevented spatiotemporally precise control over intracellular signalling processes. Here we report the development of a versatile family of genetically encoded optical tools ('optoXRs') that leverage common structure-function relationships among G-protein-coupled receptors (GPCRs) to recruit and control, with high spatiotemporal precision, receptor-initiated biochemical signalling pathways. In particular, we have developed and characterized two optoXRs that selectively recruit distinct, targeted signalling pathways in response to light. The two optoXRs exerted opposing effects on spike firing in nucleus accumbens in vivo, and precisely timed optoXR photostimulation in nucleus accumbens by itself sufficed to drive conditioned place preference in freely moving mice. The optoXR approach allows testing of hypotheses regarding the causal impact of biochemical signalling in behaving mammals, in a targetable and temporally precise manner.

    View details for DOI 10.1038/nature07926

    View details for Web of Science ID 000265412900042

    View details for PubMedID 19295515

  • Human embryonic stem cells: emerging technologies and practical applications CURRENT OPINION IN GENETICS & DEVELOPMENT Fenno, L. E., Ptaszek, L. M., Cowan, C. A. 2008; 18 (4): 324-329

    Abstract

    Human embryonic stem cells possess the unique ability to differentiate into any adult cell type. Recent advances in the understanding of stem cell biology make new applications possible for stem cell based technology. Of note, it is now possible to reprogram terminally differentiated human somatic cells into pluripotent cells that are functionally equivalent to embryonic stem cells. These induced pluripotent cells may become the substrate for future disease models and cell-based therapies. In addition, novel techniques for genetic manipulation have increased the ease with which genes can be modified into stem cells. In this review, we describe these novel technologies as well as developments in the understanding of basic biology of stem cell pluripotency and differentiation.

    View details for DOI 10.1016/j.gde.2008.06.004

    View details for Web of Science ID 000260700500007

    View details for PubMedID 18625311

  • Adult Stem Cells, in Chemical and Functional Genomic Approaches to Stem Cell Biology and Regenerative Medicine Fenno LE, Cowan CA 2007

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