WorldCat Identities

Deisseroth, Karl

Works: 32 works in 33 publications in 1 language and 49 library holdings
Roles: Thesis advisor, Author, Editor
Publication Timeline
Most widely held works by Karl Deisseroth
Communication between synapse and nucleus by Karl Deisseroth( )

2 editions published in 1998 in English and held by 3 WorldCat member libraries worldwide

Optogenetic studies of brain disease : engineering light delivery into biological tissue by Murtaza Mogri( )

1 edition published in 2011 in English and held by 2 WorldCat member libraries worldwide

Optogenetic neuromodulation is giving scientists an unprecedented ability to modulate neural circuits, providing specificity with regards to location, cell type, as well as neuromodulatory effect. On the other hand, electrical stimulation and lesions, methods commonly used to study neural circuits, are lacking in specificity, often affecting both local cells and passing axons, as well as multiple cell types. Our laboratory has been at the forefront of the field of optogenetics, having developed, for use in mammalian systems, Channelrhodopsin-2 (ChR2), an algal light-activated cation channel that depolarizes neurons in response to blue light, and Natronomonas pharaonis halorhodopsin (eNpHR), a chloride pump that hyperpolarizes neurons in response to amber light. These proteins can control neuronal activity with millisecond timescale precision, and through promoters, they can be targeted to specific cell-types in heterogeneous tissue. Along with its specificity, light stimulation with optogenetic tools often allows the recording of neural activity without the artifact that obfuscates recordings with electrical stimulation. The advantages provided by optogenetics allowed us to make a breakthrough in determining the therapeutic mechanism of deep brain stimulation, a robust treatment for Parkinson's disease in which stimulating electrodes are implanted deep in the brain. Using optogenetics, we replicated the effect of deep brain stimulation by modulating cortical inputs into the region where the stimulating electrode is normally placed. Combined with other corroborating publications, a hypothesis is emerging that electrical stimulation deep in the brain actually produces its effect by modulating cortical projections to the deep brain region. Based on this concept, several clinical studies are being done to better understand the cortical role in Parkinson's disease and determine whether cortical stimulation (potentially non-invasive), could be an alternative to the invasive implants currently used. In order to perform these experiments, we studied the transmission of visible light in brain tissue to estimate the volume of activation produced by optogenetic stimulation and developed a device to measure fluorescence in awake, behaving animals, allowing the quantification of virally transfected gene expression over time, as well as the localization of expression along axon bundles. The knowledge gained from these experiments will have a significant impact on future experiments in the broader field of optogenetics
Optogenetic dissection of amygdala and extended amygdala circuits in the anxious state by Sung-Yon Kim( )

1 edition published in 2013 in English and held by 2 WorldCat member libraries worldwide

Anxiety, a sustained state of apprehension in the absence of a specific and imminent threat, is critical for an organism to survive in an environment with unpredictable risks. In disease states, however, anxiety becomes severely debilitating; anxiety disorders represent the most common psychiatric diseases (28% lifetime prevalence). Despite the high prevalence of anxiety disorders, current treatments are often ineffective and have severe side-effects, such as addiction, pointing to the need for a deeper understanding of anxiety circuits. The amygdala and extended amygdala have long been hypothesized to play a central role in anxiety, but the function of the intra- and inter-connections of the amygdala and extended amygdala circuits are unclear, largely due to the lack of appropriate tools. With the advent of optogenetics, which was pioneered in the Deisseroth lab, and with the evolution of virus- or promoter-based targeting strategies, it is now possible to manipulate a specific circuit element with unprecedented precision and to identify its function in behavior. The first part of this thesis illustrates the application of optogenetics to identify an intra-amygdala circuit element that decreases anxiety. The second part explores the functional circuitry of the bed nucleus of the stria terminalis (BNST), a key component of the extended amygdala. We studied the roles of its input from the amygdala and outputs to the hypothalamus and brainstem areas in the anxious state. Here, the term 'anxious state' is used to emphasize that anxiety is a behavioral state consisting of distinct features, such as behavioral risk-avoidance and changes in respiration rate. We sought to find circuit elements mediating each distinct feature of the anxious state. The data provided by this thesis furthers our understanding of the function and dysfunction of anxiety circuitry. The approach that we employed here for functional circuit mapping may be applicable to the dissection of other behavioral states, such as fear and aggression
Combining light restriction and optogenetics to dissect the neural circuitry underlying behavior by Rohit Prakash( )

1 edition published in 2012 in English and held by 2 WorldCat member libraries worldwide

Aberrant states in the nervous system, both acute and chronic are the cause of mental health diseases that affect more than a quarter of Americans over the age of 18. The mechanisms underlying mental health diseases such as Parkinsons, schizophrenia, anxiety, and depression are poorly understood, and thus current treatment approaches are often ineffective or carry with them significant side effects. In order to improve our understanding of these diseases and others, new tools must be developed that take into account the complex dynamics and diversity of circuit elements that make up the neural substrates from which these behaviors arise from. Our lab has pioneered the use of light activated microbial opsins in mammalian neurons in order that we can manipulate neural circuits with cell- type specificity, millisecond temporal precision, and millimeter spatial resolution -- termed 'Optogenetics" . These genetically encoded elements include two broad classes, excitatory channels such as Channelrhodopsin - 2 (ChR2) and inhibitory pumps such as Halorhodopsin (NpHR). The use of these tools allow for bidirectional control ove r cell types and connections that make up the neural circuits that underlie behavior within normal and diseased mental health states using simple gene and light targeting approaches. But, the nervous system's structural complexity -- both in the geometrical arrangement of neurons and connections between neurons - requires more than these basic approaches to dissect its function. T o address this extra layer of complexity, the spatial control of light excitation itself could be a versatile method in combination with optogenetic approaches to dissect neural circuitry. The studies herein look to build upon current optogenetic technology by utilizing light restriction in order to control and dissect neural circuits with high precision. There are two approaches used to accomplish this: (1) in vivo and ex vivo one photon light restriction that utilize simple light restrictive optical elements to more precisely stimulate and inhibit both genetically targeted cells or connections between close brain areas and (2) in vivo and ex vivo two photon techniques that allow for fast excitation, inhibition, and bi- stable modulation at the level of a single - cell, multiple single - cells, or in some cases, sub-cellularly . The tools developed here can be used in a variety of systems and allows for the dissection of neural circuitry using optogenetics to a new level of precision that was otherwise unapproachable via any technique available to researchers. As these tools are further developed, a bridge between the individual cellular contributions to neural circuit function and behavioral neuroscience will hopefully emerge
Optogenetic reverse-engineering of brain sleep/wake circuitry by Matthew Evan Carter( )

1 edition published in 2011 in English and held by 2 WorldCat member libraries worldwide

The neural control of sleep and wakefulness depends upon a complex and partially defined balance between subcortical excitatory and inhibitory populations in the brain. Wake-active neurons include hypocretin (Hcrt)-containing neurons in the lateral hypothalamus and noradrenergic neurons that make up the brainstem locus coeruleus (LC). Experimentally determining a causal role for these neurons in promoting and maintaining wakefulness has remained elusive using traditional pharmacological and electrical techniques due to their small size, unique morphology, and proximity to heterogeneous neuronal and non-neuronal cell types. The recent development of optogenetic technology provides a toolkit of genetically-encodable, millisecond timescale, stimulation and inhibition probes that can be targeted to specific cell types with no toxicity to the cells under investigation. This dissertation discusses the application of optogenetic tools to questions about sleep/wake circuitry and uses these tools to study Hcrt and LC neurons, both individually and in combination
Illuminating the function of dopaminergic neurons in reward by Hsing-Chen Tsai( )

1 edition published in 2010 in English and held by 2 WorldCat member libraries worldwide

This thesis examines a neural substrate (i.e. dopaminergic signaling) of reward, by integrating techniques designed to manipulate and quantify changes in behavior, neural activity, and neurotransmitter release in freely-moving animals. Dopaminergic signaling is essential to the brain's reward system. The majority of dopaminergic neurons reside in the ventral tegmental area (VTA) and project to diverse brain regions including the nucleus accumbens (NAc), one of the major integrative hubs of reward signals. Dopaminergic neurons are known to fire in two distinct modes (phasic,> 15Hz; tonic, <10Hz) under different behavioral conditions. Both firing modes are known to be involved in multiple reward-related behaviors in normal and neuropsychiatric conditions. However, the casual role of dopaminergic neuron activity in reward-related behaviors remains unclear, largely due to a lack of technologies to selectively control dopaminergic neuron signaling in freely-moving animals during reward-related behavioral tasks. To solve this problem, we first developed a set of optogenetic technologies to selectively control dopaminergic neuron activity in vivo. By targeting a light-sensitive microbial opsin, channelrhodopsin-2 (ChR2), to the VTA dopaminergic neurons we were able to modulate dopaminergic neuron activity in freely-moving mice during behavioral tasks. We accomplished this using a thin optical fiber to deliver precisely-timed trains of light flashes directly into the VTA. We found that phasic and not tonic firing evoked by light in dopaminergic neurons is sufficient to mediate a strong conditioned place preference in rodents in the absence of other reward. Similarly, phasic dopaminergic neuron firing reinforces the lever-pressing behavior during an operant conditioning task. Phasic firing also induced substantial transient dopamine release in NAcc, as measured by fast scan cyclic Voltammetry (FSCV). Together, our behavioral and electrochemical data demonstrate a causal role of phasic dopaminergic neuron firing in behavioral conditioning. The integration of cell-specific targeting techniques with electrophysiological, behavioral, and biochemical readout methods proves to be a powerful approach to studying the role of dopaminergic signaling in the brain reward system and is likely to prove effective in the study of neuropsychiatric disorders such as depression and addiction
Inhibitory projection neurons in olfactory information processing by Liang Liang( )

1 edition published in 2013 in English and held by 2 WorldCat member libraries worldwide

Inhibition occurs throughout the nervous system and impacts diverse neuronal processes. In this dissertation, I focus on an inhibitory circuit motif in the Drosophila olfactory system, parallel inhibition, which differs from the classical feed-forward or feedback inhibition. The Drosophila excitatory and GABAergic inhibitory projection neurons (ePNs and iPNs) each receive input from antennal lobe glomeruli and send parallel output to the lateral horn, a higher-order brain center implicated in regulating innate olfactory behavior. By incorporating in vivo two-photon calcium imaging, advanced fly genetics and optogenetic methods to manipulate and record neuronal activity, we find that iPNs selectively suppress food-related odorant responses but spare signals from pheromone channel stimulation when using specific lateral horn neurons as an olfactory readout. Co-applying food odorant does not affect pheromone signal transmission, suggesting that the differential effects likely result from connection specificity of iPNs, rather than a generalized inhibitory tone. Calcium responses in the ePN axon terminals show no detectable suppression by iPNs, arguing against presynaptic inhibition as a primary mechanism. The parallel inhibition motif may provide specificity in inhibition to funnel specific olfactory information, such as food and pheromone, into distinct downstream circuits
Optogenetic tool development and interrogation of frequency-dependent signaling in the hippocamposeptal pathway by Joanna Hochberg Mattis( )

1 edition published in 2013 in English and held by 2 WorldCat member libraries worldwide

Hippocampal oscillations are critical for information processing, and are strongly influenced by inputs from the medial septum. Hippocamposeptal neurons provide direct inhibitory feedback from the hippocampus onto septal cells, and are therefore likely to also play an important role in the circuit; these neurons fire at either low or high frequency, reflecting hippocampal network activity during theta oscillations or ripple events, respectively. Since the hippocamposeptal projection is sparse and long-range, the impact of high or low frequency hippocampal input on septal physiology has not been addressable with classical electrophysiological or pharmacological techniques. In order to understand the contribution of defined neuronal subtypes, such as hippocamposeptal neurons, to brain function, our laboratory has developed a technique termed optogenetics, which integrates genetic targeting and optical stimulation to achieve temporally precise manipulation of genetically and spatially defined cell types in intact tissue. Optogenetics employs light sensitive microbial proteins, including ion pumps and channels that can elicit or inhibit action potentials. Optogenetics has already proved invaluable to neuroscience, but several key limitations to its application have become apparent: First, increasingly diverse optogenetic tools allow more versatile control over neural activity, but since new tools have been developed in multiple laboratories and tested across different preparations it is difficult to draw direct comparisons between them. As a result, it has become increasingly challenging for end users to select the optimal reagents for their experimental needs. Second, as the power of genetically encoded interventional and observational tools for neuroscience expands, the boundary of experimental design is increasingly defined by limits in selectively expressing these tools in specific cell types. To date, cell-type has primarily referred to genetic specificity, achieved with promoter-driven expression either in transgenic animals or in viruses. This approach is limited in its ability to define a 'cell type': cells may be targeted based on only a single parameter, and genetic targeting does not take into account anatomic connectivity, in many cases the most salient feature of a target population. The aim of this thesis is thus three-fold: 1) To interrogate frequency-dependent signaling in the hippocamposeptal pathway, using optogenetics to gain cell-type specific, temporally-precise control over hippocamposeptal fibers, 2) To systematically compare 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, and 3) To develop new viral and molecular strategies to target cells of interest based on both genetic and topological parameters. The investigation of the hippocamposeptal projection will increase our understanding of the larger circuit of which it is a part, and will also illustrate the importance of firing frequency in neuronal signaling. The tool development described will be useful for future work investigating the hippocamposeptal pathway in particular, and more generally for a broad variety of applications of optogenetics to neuroscience
Optical techniques for integrated control and recording of neural activity by Raag Dar Airan( )

1 edition published in 2010 in English and held by 2 WorldCat member libraries worldwide

A long-standing objective of psychiatry has been the ability to both control and record the activity of precisely-defined populations of brain cells on the millisecond timescale most relevant for neural computation. Recent advances bring that goal increasingly near by leveraging the genetically-precise techniques of molecular biology with the high-speed, multiplexed command afforded by optical technologies to introduce and utilize light-sensitive neural activity control integrated with fast neural circuit imaging. In this thesis, I present exemplars of these technological advances and demonstrate their utility in illuminating the neural circuit basis of behaviors relevant to understanding psychiatric disease. I first show how fast neural circuit imaging may be integrated with optical neural control tools to develop insight into the role of genetically, developmentally, or projection defined populations of brain cells in mediating circuit-level physiological changes. I then demonstrate computational methods to analyze the resultant imaging data and apply fast circuit imaging to delineate links between hippocampal physiology and behavior in an animal model of depression. Finally, I present the development of a novel class of optically-activated, genetically-targetable control tools that permit optical control of G-protein coupled intracellular signaling; and the use of these molecular devices to determine causal roles of neuromodulatory inputs in reward processing. The development of these and similar optical modalities further improves the precision of questions addressable by the neuroscientist, and potentially the extent of disease treatable by the clinician
Functional neural imaging of signals triggered by topologically- and genetically-specified neurons in the mammalian brain by Remy Durand( )

1 edition published in 2012 in English and held by 2 WorldCat member libraries worldwide

Functional brain imaging techniques such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) have emerged over the last several decades as powerful methods for understanding brain function and neuropsychiatric disorders. However, due to an inability to precisely and distinctly control the heterogeneous population of circuit elements in the brain, understanding the fundamental physiological mechanisms of these imaging modalities and realizing their potential for functional brain mapping has been limited. Optogenetics is a novel technique that allows for cell-type specific, reversible focal control within the mammalian brain with millisecond-timescale precision. In this thesis, I have utilized the unique cell-type specific neuromodulatory capacity of optogenetics to demonstrate and characterize, for the first time, the effect of direct stimulation of a subclass of excitatory neurons on the in vivo functional hemodynamic response of a rodent brain as measured with functional magnetic resonance imaging (fMRI). I have then used this technique, which we have called ofMRI, to perform large-scale functional mapping of distinct neural circuits that are specified by cell-type, cell-body location, and projection topology. To complement ofMRI studies, I have also developed the use of PET imaging and the radiotracer [18F]-fluorodeoxyglucose (FDG) to further characterize the metabolic and hemodynamic response resulting from activation of genetically-specified neurons in the mammalian brain. Additionally, I have constructed an automated, parallelized all-optical ex vivo system for modulation and recording of distinct neural circuits relevant to neuropsychiatric disorders using voltage sensitive dye imaging (VSDI). Combining the highly specific and rapid control of optogenetics with the biological process sensitivity of PET, the spatial and temporal resolution of BOLD fMRI, and the neural circuit analysis capabilities of optical imaging has the potential to vastly increase our understanding of the roles of neural circuits in both normal and diseased brain states
Optical microendoscopy for imaging cells lying deep within live tissue by Robert Juson Barretto( )

1 edition published in 2010 in English and held by 2 WorldCat member libraries worldwide

Optical microendoscopy is an emerging modality for imaging in live subjects. Using gradient refractive index (GRIN) microlenses, microendoscopy enables subcellular-resolution imaging in deep tissues that are inaccessible by traditional imaging techniques. We present a platform of methods and technologies that build upon GRIN microendoscopy: 1) miniaturized microscopes for imaging in awake, behaving animals, 2) methods for imaging contractile dynamics in the muscles of animal and human subjects, 3) chronic brain preparations that allow for longitudinal examinations of subcellular neuronal features and disease progression, and 4) novel microendoscope probes whose imaging capabilities approach that of standard water-immersion microscope objectives. When combined with the broad sets of available fluorescent reporters, and minimally invasive surgical preparations, the work described in this dissertation enables sophisticated experimental designs for probing how cellular char- acteristics may underlie or explain behavior, in models of both healthy and diseased states
Optogenetic tool development and application to dissecting dopaminergic circuitry in social behavior by Lisa Aila Gunaydin( )

1 edition published in 2012 in English and held by 2 WorldCat member libraries worldwide

Social interaction is an essential and highly integrative behavioral task that is impaired in major psychiatric disorders such as autism, schizophrenia, social anxiety disorder, and depression. Current treatments for many of these disorders are based on pharmacological approaches that have been used for decades even though their mechanisms of action are poorly understood and carry many side effects. In particular, treatment of the asocial symptoms of these disorders has remained elusive due to a generally poor understanding of the neural circuitry underlying normal social behavior. In order to move toward a deeper circuit-level understanding of these complex neural processes, our lab has pioneered the use of two light-activated microbial opsins, Channelrhodopsin-2 (ChR2) and Halorhodopsin (NpHR), to achieve precise bidirectional optogenetic control of specific cell types in behaving animals. However, it has become clear that the complexity of the circuitry involved in psychiatric behaviors will require new classes of optogenetic tools to modulate cells in a more refined manner based on characteristics such as projection profile, receptor expression, and endogenous firing patterns. The purpose of this study was thus two-fold: 1) to develop novel optogenetic tools for more physiologically relevant stimulation of different cell types on different timescales, and 2) to apply these tools to define in socializing animals the real-time causal role not only of a specific brain region and cell type, but also of distinct subpopulations defined by projections to different downstream brain regions and distinct downstream cell types. The engineered opsins we develop here will be generalizable to dissect other neural circuits in health and disease, enabling new domains of optogenetic investigation that have thus far been inaccessible, and enhancing the precision of optical neural control in a broad variety of settings
Oxytocin enhances signal-to-noise in hippocampal feed-forward transmission by selective action on targeted interneuron subtypes by Scott Fraser Owen( )

1 edition published in 2012 in English and held by 2 WorldCat member libraries worldwide

Neural circuits throughout the brain are under the continuous influence of neuromodulators which shape network activity in accordance with behavioral context. Oxytocin is a key neuromodulator that has been linked to social memory and maternal behavior in animals, as well as to autism spectrum disorders, trust, emotion recognition and parenting in humans. Here we show that activation of oxytocin receptors sharpens the responses of the hippocampal circuit, increasing the signal of spike transmission through the network while simultaneously suppressing the noise of background spontaneous activity. Both of these actions are mediated through a depolarization of the fast-spiking interneurons. The resulting increase in inhibitory tone serves to silence spontaneous activity in the CA1 pyramidal cells, while a use-dependent depression of the inhibitory synapses permits enhanced feed-forward spike transmission. Furthermore, we show that oxytocin potently modulates spontaneous hippocampal Sharp-Wave Ripple oscillations in a slice preparation. These results elucidate the action of oxytocin in the hippocampus, while simultaneously shedding light on a novel mechanism by which modulation of fast-spiking interneurons can modify hippocampal circuit activity
Optical deconstruction of fully-assembled biological systems by Karl Deisseroth( Visual )

1 edition published in 2014 in English and held by 2 WorldCat member libraries worldwide

Mechanisms of deep brain stimulation revealed by optogenetic deconstruction of diseased brain circuitry by Viviana Gradinaru( )

1 edition published in 2010 in English and held by 2 WorldCat member libraries worldwide

Deep brain stimulation (DBS) is a powerful therapeutic option for intractable movement and affective disorders (Parkinson's disease or PD, tremor, dystonia, Tourette syndrome, chronic pain, obsessive compulsive disorder, depression, bipolar). The benefits of DBS are immediate and dramatic, manifested as instantaneous improvements in motor function in the case of PD patients. However, due to the nonspecificity of electrical stimulation, DBS has variable efficacy and can lead to serious side effects. The mechanisms behind the effects of DBS are still highly controversial and there is tremendous interest from both neuroscience and clinical communities to understand and improve DBS. We have developed a novel technology based on two microbial opsins, Channelrhodopsin (ChR2) and Halorhodopsin (NpHR), that allows to directly and specifically control the activity of distinct cell-types with high temporal precision in well defined brain regions, therefore allowing us to overcome the lack of specificity of electrical DBS. This study provides the first investigation of the role of specific cell types in ameliorating PD symptoms addressed by effective DBS treatment. The focus of the thesis was twofold: (1) to develop and optimize optogenetic technologies (molecular and hardware) for safe and effective use in behaving mammals; and (2) to employ the above developed optogenetic toolkit to deconstructing diseased brain circuitry, with focus on Parkinson's disease. The framework and technological toolbox presented here can be employed across many brain circuits to selectively control individual components and therefore systematically deconstruct intact and disordered brain processes
Novel approaches to the visualization of cell specific gene expression patterns by Chuba Benson Odimegwu Oyolu( )

1 edition published in 2011 in English and held by 2 WorldCat member libraries worldwide

The fate of a cell is largely determined by the unique patterns of gene expression found within it. Complex biological machinery exists within each cell to manipulate chromatin state, and ultimately control gene expression. Developmental processes such as cellular differentiation require very specific chemical signals and environmental conditions. These serve as triggers to put the chromatin modification schemes that produce the resultant patterns of differential gene expression into action, leading to the formation of the cell type of interest. My thesis work is an in depth study of the link between chromatin modification, gene expression, and the unique genetic signatures that characterize distinct cells on unicellular and multi-cellular levels. On the multi-cellular level, I have examined histone modification patterns for their effects on gene activation and repression during human embryonic stem cell differentiation. On the unicellular level, I have worked with a variety of cell types to ascertain the degree of individuality that exists between single members of relatively homogenous cell groups while simultaneously looking for housekeeping gene expression signatures that can be used to classify each cell type into a unique group. To further elucidate the patterns of gene expression found within cell groups and the single cells that comprise them, I have worked to develop new computational methods that produce visual aids to elucidate gene expression signatures of single cells and cell groups
Coded computational illumination and detection for three-dimensional fluorescence microscopy by Samuel J Yang( )

1 edition published in 2016 in English and held by 1 WorldCat member library worldwide

In vivo calcium imaging enables the optical monitoring of neural activity at the level of individual neurons in real time, necessitating the development of high speed, three-dimensional (3D) fluorescence microscopy techniques with at least single-neuron spatial resolution. Because a typical widefield microscope intrinsically produces only two-dimensional images, various illumination and detection coding strategies have been implemented to address the challenge of 3D fluorescence microscopy, utilizing either precisely structured and temporally scanned illumination patterns, such as in two-photon laser scanning microscopy or coding of the emission, as in light field microscopy, respectively. However, many single-focal illumination coding strategies have limited acquisition speeds, while detection-coding-only strategies requiring computational reconstruction of the 3D volume are limited by optical aberrations of the tissue. We present a 3D calcium imaging approach utilizing both multifocal scanned two-photon laser excitation for illumination coding and detection coding with the light field microscopy approach suitable for in vivo mammalian calcium imaging. A holographic 3D multifocal illumination pattern is targeted only towards pre-localized neurons avoiding the unnecessary illumination of other regions. The resulting fluorescence emission is coded and detected on an image sensor and deconvolution is used to recover the neural activity at each site. We present the design and optimization of such an imaging strategy, and validate the approach with experimental measurements. Finally, we demonstrate the application of this approach to in vivo mouse calcium imaging. The design and implementation of another technique, frame-projected independent fiber photometry, enabling the optical recording and control of neural activity in freely moving mammals with region-level spatial resolution, is presented in a dedicated chapter as well, including simultaneous recording from multiple brain regions in a mouse during social behavior, two-color activity recording, and optical optogenetic stimulation eliciting dynamics matching naturally observed patterns
Imaging a dopaminergic reward-seeking state and its modulation by prefrontal cortex using optogenetic functional magnetic resonance imaging by Emily Anne Ferenczi( )

1 edition published in 2015 in English and held by 1 WorldCat member library worldwide

The anticipation and experience of reward drives many behaviors across the animal kingdom and is an important determinant of mental health in humans. The loss of the capacity to experience reward or enjoyment is termed anhedonia, a symptom that is manifest in a number of psychiatric diseases, including depression and schizophrenia. We optimized optogenetic functional MRI (ofMRI) to manipulate and image dopaminergic reward circuits in awake rodents and determine the contribution of dopamine to reward-related neuroimaging signals commonly observed in humans. We also sought to investigate the role of the medial prefrontal cortex in modulating dopaminergic signaling and reward-seeking behavior. The influence of phasic midbrain dopamine firing on brainwide BOLD activity was assessed by expressing a Cre-dependent channelrhodopsin (ChR2) in the dopaminergic midbrain of transgenic tyrosine hydroxylase (TH-cre) rats. Phasic stimulation of the midbrain with blue light supported self-stimulation in an operant chamber. During fMRI scanning, this phasic stimulation generated robust increases in BOLD activity, particularly in the striatum (in a manner that correlated with individual rats' self-stimulation behavior), as well as other regions including the retrosplenial cortex and thalamus. The BOLD activity increases were sensitive to post-synaptic dopamine (D1 and D2) receptor antagonists. In addition, we directly visualized the impact of suppressing dopaminergic neuron firing on BOLD activity using the inhibitory optogenetic tool, halorhodopsin (eNpHR3.0). We next assessed whether focal excitability changes in medial prefrontal cortex (mPFC) could modulate reward-seeking, using optogenetically-triggered shifts in mPFC excitability with a stable step-function opsin (SSFO, expressed in predominantly glutamatergic neurons) during natural appetitive behaviors. Notably, we observed a suppression of typical reward-seeking behavior (a preference for sucrose-containing water and social interaction with a same-sex juvenile) in optogenetically-stimulated rats compared to controls. In the fMRI scanner, elevated mPFC excitability provoked changes in spatiotemporal correlations in BOLD activity across a number of brain regions, and the strength of correlations between specific regions was associated with the observed reduction in sucrose preference at the individual level. To directly test the hypothesis that elevated mPFC excitability negatively influences subcortical responses to reward, we expressed a red-shifted channelrhodopsin variant, C1V1, in midbrain dopaminergic neurons and SSFO in mPFC glutamatergic neurons of TH-Cre rats. Phasic C1V1 stimulation of dopamine neurons generated robust striatal BOLD activity in the fMRI scanner, however in the presence of superimposed SSFO activation of mPFC, this striatal BOLD activity was suppressed. Behaviorally, the tendency for rats to seek out a location in which they received C1V1 stimulation was abolished in the presence of mPFC activation by SSFO. These findings inform theories about how specific neurochemical projections interact to promote or modulate reward processing and neuroimaging signals, with a direct bridge between animal and human research. This may help further our understanding of cortical-subcortical interactions in the diagnosis, pharmacology and treatment of symptoms related to altered reward processing in neuropsychiatric disorders
Optogenetics : development and application by Karl Deisseroth( Visual )

1 edition published in 2012 in English and held by 1 WorldCat member library worldwide

(CIT): Dr. Deisseroth's lab has developed and applied optogenetic methods based on microbial opsin genes, to achieve gain- or loss-of-function of well-defined events within specific cells of living tissue, including freely moving mammals. This talk will cover their recent efforts on optogenetics, including the crystal structure of channelrhodopsin, recent genomic and molecular engineering work to expand the microbial opsin toolkit, the development of novel optogenetic hardware and techniques (based on optical imaging, of MRI, electrophysiology, and behavior) for control and readout of neural activity, and a number of optogenetic applications relevant to neuropsychiatric disease, spanning anxiety, social behavior dysfunction, fear memory recall, drug abuse, and depression
Development of optogenetics for motor systems neuroscience in non-human primates by Werapong Goo( )

1 edition published in 2014 in English and held by 1 WorldCat member library worldwide

Voluntary movement is such an integral part of common tasks that the loss of this ability is detrimental to quality of life. Effective functional restoration for patients with a limited ability to move requires deep understanding of movement control. However, despite decades of motor system research, the mechanism by which motor cortex controls movement is still unclear. Although technological advances such as electrical microstimulation have been used to investigate this mechanism, its limitations in simultaneous recording and perturbation have prevented us from obtaining more informative measurements. To address this challenge, a multidisciplinary approach was taken to further examine the underlying mechanism of motor control. Specifically, we used optogenetics along with the analytical framework of dynamical systems theory to probe the dynamics of motor preparation. Three major results are presented in this work. Firstly, we characterized and assessed the functionality of optogenetics electrophysiologically and histologically in non-human primates. Although optogenetics has been used extensively in rodents, it is still in a developmental state in primates. Hence, the efficiency of virus transfection, the reliability of neural responses to optical stimulation, the pattern of opsin expression and the safety to animals were investigated to minimize any potential risk and to aid future experimental designs. We also discovered that, in contrast to electrical microstimulation, optical stimulation in cortical motor and premotor areas did not evoke overt skeletal movements. Secondly, we continued the characterization process by injecting a red-shifted opsin, C1V1(TT), in dorsal premotor cortex (PMd) and optically perturbed the neural activity while the animals were actively engaged in an instructed-delay reach task. We found that the optical perturbation in PMd resulted in increased reach reaction times. Moreover, using the dynamical systems perspective, we discovered that, post-perturbation, the neural state did not return to its pre-perturbed state. Instead, it proceeded directly to re-join the normal neural trajectory path to execute the movement. We also observed that optical stimulation did not obliterate task-related activity in light-responsive neurons. In fact, the relationship between task-related and optically-evoked activities appeared to be linearly additive. Lastly, we developed a decoding algorithm to extract kinematics information from optogenetically-perturbed data. We trained a Kalman filter based on a mixture of perturbed and unperturbed data, and found that it provided us with an effective decoder. This decoding performance was achieved despite the fact that the decoder made no attempt to detect whether or not the neural activity was perturbed
moreShow More Titles
fewerShow Fewer Titles
Audience Level
Audience Level
  Kids General Special  
Audience level: 0.78 (from 0.71 for Optical de ... to 0.96 for Optogeneti ...)

Alternative Names
Karl Deisseroth Amerikaans psychiater

Karl Deisseroth US-amerikanischer Psychiater, Neurobiologe und Bioingenieur

Дейссерот, Карл

קרל דייסרות'

كارل ديسيروث

کارل دایسرات



English (21)