Dopaminergic and serotonergic neurons modulate and control processes ranging from reward signaling to regulation of motor outputs. Further, we find that melanin-concentrating hormone signalling (which is involved in mammalian sleep) also regulates propagating wave sleep signatures and the overall amount of sleep in zebrafish, probably via activation of ependymal cells. Optogenetics offers the ability to selectively manipulate individual neural circuit elements that underlie disease-relevant behaviors and is currently accelerating the pace of preclinical research into neurobiological mechanisms of disease. A Genetically Defined Compartmentalized Striatal Direct Pathway for Negative Reinforcement. Human pluripotent stem cell tools for cardiac optogenetics. An amendment to this paper has been published and can be accessed via a link at the top of the paper. View details for DOI 10.1088/1741-2560/9/1/016001, View details for Web of Science ID 000300618700003, View details for Web of Science ID 000300029600026. Via directed differentiation, we created channelrhodopsin-expressing cardiomyocytes, which we subjected to optical stimulation. View details for DOI 10.1016/j.celrep.2020.108094. Neuregulin 1 (NRG1) and its interneuron-specific receptor ERBB4 are critical genes for interneuron maturation. The 2015 Lurie Prize in Biomedical Sciences "for leading the development of optogenetics, a technology for controlling cells with light to determine function, as well as for CLARITY, a method for transforming intact organs into transparent polymer gels to allow visualization of biological structures with high resolution and detail". Chen, R. n., Gore, F. n., Nguyen, Q. Targeting cells with single vectors using multiple-feature Boolean logic. A major long-term goal of systems neuroscience is to identify the different roles of neural subtypes in brain circuit function. Using focal illumination of the cerebral cortex and olfactory bulb, we demonstrate a highly reproducible, light-dependent activation of neurons and precise control of firing frequency in vivo. We previously demonstrated, in vitro, the dual capability (optical delivery and electrical recording) while testing a novel hybrid device (optrode-MEA), which incorporates a tapered coaxial optical electrode (optrode) and a 100 element microelectrode array (MEA). [39] For example, HTC variants now enable improved anchoring and amplification of RNA, reversible size changes (contraction or expansion), and in situ sequencing (reviewed in[39]). View details for DOI 10.1016/j.cell.2015.11.038. Although further engineering of step-function channelrhodopsin variants with higher photoconductances will be required to employ this approach at the nanoscale, our findings provide a framework to guide future development of this technique. View details for DOI 10.1038/nprot.2009.226, View details for Web of Science ID 000275234900006. View details for Web of Science ID 000312488200056. No. Christensen, A. J., Iyer, S. M., Franois, A., Vyas, S., Ramakrishnan, C., Vesuna, S., Deisseroth, K., Scherrer, G., Delp, S. L. Locus coeruleus and dopaminergic consolidation of everyday memory. Mateo, C., Avermann, M., Gentet, L. J., Zhang, F., Deisseroth, K., Petersen, C. C. Multiscale Computational Models for Optogenetic Control of Cardiac Function. Information processing in the striatum is critical for basal ganglia function and strongly influenced by neuromodulators (e.g., dopamine). Optogenetic methods have emerged as powerful tools for dissecting neural circuit connectivity, function and dysfunction. View details for DOI 10.1016/j.neuron.2020.04.023. Dopamine D2 receptors (D2Rs) play a major role in the function of the prefrontal cortex (PFC), and may contribute to prefrontal dysfunction in conditions such as schizophrenia. We are interested both in natural behaviorally-relevant neural circuit dynamics, and in pathological dynamics underlying neuropsychiatric disease symptomatology and treatment. Over the last sixteen years, his laboratory created and developed optogenetics, hydrogel-tissue chemistry (beginning with CLARITY), and a broad range of enabling methods. View details for Web of Science ID 000172848800107, View details for PubMedCentralID PMC65031. Both transcription and three-dimensional (3D) architecture of the mammalian genome play critical roles in neurodevelopment and its disorders. Although the impact of this temporal versatility and cellular specificity has been greater for basic science than clinical research, it is natural to ask whether the dynamic patterns of neural circuit activity discovered to be causal in adaptive or maladaptive behaviors could become targets for treatment of neuropsychiatric diseases. Here, we present novel methods to study the functional influence of PV cells on layer 5 PYRs using optogenetics combined with laser-scanning photostimulation (LSPS). Multiple neuron types and brain regions are involved in reward processing, posing fascinating scientific questions, and major experimental challenges. This learning occurs when the sensory cues are paired with an aversive event occurring in close temporal proximity. Here, we used in vivo fast-scan cyclic voltammetry to record transients evoked by cocaine and raclopride in nucleus accumbens (NAc) of urethane-anesthetized rats. Subsequent dual whole-cell patch-clamp recordings of connected pairs of striatal neurons revealed that only lateral inhibition between MSNs is negatively modulated, whereas feedforward inhibition from fast-spiking GABAergic interneurons onto MSNs is unaffected by histamine. 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. As such, BF-PV neurons may represent a novel target for pharmacotherapy in disorders such as schizophrenia which involve aberrant increases in cortical broadband gamma activity. [citation needed] He serves as an attending physician at Stanford Hospital and Clinics and has been affiliated with the Howard Hughes Medical Institute (HHMI) since 2009. Synaptic interactions between excitatory and inhibitory neocortical neurons are important for mammalian sensory perception. Here we show that optogenetic activation of the PFC produces strong antinociceptive effects in a rat model (spared nerve injury model) of persistent neuropathic pain. Our findings strongly support the hypothesis that CREB regulates memory allocation by modulating neuronal excitability. Here we describe a cation-conducting channelrhodopsin (VChR1) from Volvox carteri that can drive spiking at 589 nm, with excitation maximum red-shifted approximately 70 nm compared with ChR2. We report the potential efficacy of gene therapy in focal neocortical epilepsy using a rodent model in which epilepsy is induced by tetanus toxin injection in the motor cortex. Through this mechanism, D2Rs might enhance outputs to subcortical structures, contribute to reward-related persistent firing, or increase the level of noise in prefrontal circuits. Ca(2+)-dependent movement of calmodulin (CaM) to the nucleus is highly responsive to Ca(2+) entry through L-type channels and promotes activation of the transcription factor CREB (cAMP-responsive element binding protein) through phosphorylation by CaM-sensitive kinases. Our data suggest a model of brain region evolution by duplication and divergence of entire cell-type sets. How rich is Stephen Baldwin All About Wendy from Red Velvet: Age, Family, Heig What happened to JOJI? Here we describe bi-stable channelrhodopsins that convert a brief pulse of light into a stable step in membrane potential. Cells in living organisms may be recruited to construct synthetic materials or structures if treated as anatomically defined compartments for specific chemistry, harnessing biology for the assembly of complex functional structures. These findings indicate that intracranial light delivery in eNpHR3.0 rats disrupts endogenous dorsal mPFC neural activity that plays a role in stress-induced relapse to food seeking in female rats. While changes in gene expression are critical for many brain functions, including long-term memory, little is known about the cellular processes that mediate stimulus-transcription coupling at central synapses. Before launching large-scale primate studies, the method needs to be further characterized and adapted for use in the primate brain. Using a similar approach, optogenetic activation of local hippocampal PV ([Formula: see text]) neurons generated trains of [Formula: see text]-mediated IPSCs in CA1 pyramidal neurons. Gao, C., Leng, Y., Ma, J., Rooke, V., Rodriguez-Gonzalez, S., Ramakrishnan, C., Deisseroth, K., Penzo, M. A. A., Deisseroth, K. n., Zeineh, M. n. Stretchable and Fully Degradable Semiconductors for Transient Electronics. It is unknown, however, how extinction learning-induced changes in mPFC activity are relayed to target structures in the amygdala, resulting in diminished fear responses. New probe architectures and materials, nanoparticles, dyes, and designer genetically encoded proteins push the limits of recording and stimulation lifetime, localization, and specificity, blurring the boundary between living tissue and engineered tools. Here, we demonstrate the potential of optogenetic control in cardiac cells using a hybrid experimental/computational technique. Retrieving high-content gene-expression information while retaining 3D positional anatomy at cellular resolution has been difficult, limiting integrative understanding of structure and function in complex biological tissues. Previous observations were limited to a single spot or the cell boundary, while movement across the entire neuron during the action potential remained unclear. CaV3.2 T-type calcium channels, encoded by CACNA1H, are expressed throughout the brain, yet their general function remains unclear. Finally, we show that CLARITY enables fine structural analysis of clinical samples, including non-sectioned human tissue from a neuropsychiatric-disease setting, establishing a path for the transmutation of human tissue into a stable, intact and accessible form suitable for probing structural and molecular underpinnings of physiological function and disease. Gaspari, S., Papachatzaki, M. M., Koo, J. W., Carr, F. B., Tsimpanouli, M., Stergiou, E., Bagot, R. C., Ferguson, D., Mouzon, E., Chakravarty, S., Deisseroth, K., Lobo, M. K., Zachariou, V. Natural neural projection dynamics underlying social behavior. Stimulation-based mapping of prefrontal D1 neuron projections implicates the medial basolateral amygdala (mBLA) as a downstream target of these afferents. Functional maturation of the differentiated hiNSCs within fetal ECM-enriched cultures was confirmed by calcium signaling and spectral/cluster analysis. Here, we delineate behavioral and computational models for the role of circuit homeostasis in enabling neuron insertion to modulate hippocampal function adaptively, and we describe molecular and cellular mechanisms for implementing this circuit-level adaptive regulation of hippocampal activity. The resolution and dimensionality with which biologists can characterize cell types have expanded dramatically in recent years, and intersectional consideration of such features (e.g., multiple gene expression and anatomical parameters) is increasingly understood to be essential. The present study uses a combination of optogenetic stimulation with viral and transgenic approaches, coupled with neural activity mapping and brain transparency visualization to demonstrate the following: (i) selective activation of Arc POMC neurons inhibits food consumption rapidly in unsated animals; (ii) activation of Arc neurons arising from POMC-expressing progenitors, including POMC and a subset of AgRP neurons, triggers robust feeding behavior, even in the face of satiety signals from POMC neurons; (iii) the opposing effects on food intake are associated with distinct neuronal projection and activation patterns of adult hypothalamic POMC neurons versus Arc neurons derived from POMC-expressing lineages; and (iv) the increased food intake following the activation of orexigenic neurons derived from POMC-expressing progenitors engages an extensive neural network that involves the endogenous opioid system. CLARITY also enables intact-tissue in situ hybridization, immunohistochemistry with multiple rounds of staining and de-staining in non-sectioned tissue, and antibody labelling throughout the intact adult mouse brain. View details for DOI 10.1038/s41467-019-13374-0. Accordingly, we performed voltage-clamp experiments to compare the currents carried by L-type channels during depolarizing waveforms that approximated APs or dendritic EPSPs. However, VTA dopamine neurons make connections with diverse brain regions, and the specific efferent target(s) that mediate the ability of dopamine neuron activation to support ICSS have not been definitively demonstrated. An important problem is to understand how these signals regulate the functioning of the neostriatum. We applied the method to optically map synaptic circuits in mouse neocortical brain slices and to activate small dendritic regions and individual spines. Although the recently solved crystal structure of a chimeric ChR, C1C2, provided the structural basis for ChR, our understanding of the molecular mechanism of ChR still remains limited. If you think Karl Deisseroth's age is not correct, please leave a comment about Karl Deisseroth's real age and Karl Deisseroth's actual birthday below. The development of optogenetics provides increased precision in the control of neuronal activity that can be used to address the temporal nature of the modulation of memory consolidation. Photostimulation of ChR2-positive axons in DH(Cre/0) mouse brain slices produced EPSCs in 71% of tested DMV preganglionic neurons (PGNs) but no IPSCs. Next-generation probes, particles, and proteins for neural interfacing. A., Motelow, J. E., Meng, J., Ma, C., Buchanan, G. F., Witten, I. Despite their importance, the role of cholecystokinin (CCK)-expressing inhibitory cells remains unknown. Neither context nor tone freezing behavior was altered by this manipulation during the same retrieval test. Both synapse types exhibited short-term depression (STD) of IPSCs. Elucidating the roles of these neurons has been greatly facilitated by bacterial artificial chromosome (BAC) transgenic mouse lines expressing channelrhodopsin to readily enable cell-type specific activation. Simultaneous deletion of Dlx5 and 6 results in exencephaly of the anterior brain; despite this defect, prenatal basal ganglia differentiation appeared largely intact, while tangential migration of Lhx6(+) and Mafb(+) interneurons to the cortex was reduced and disordered. 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. Motivation for reward drives adaptive behaviors, whereas impairment of reward perception and experience (anhedonia) can contribute to psychiatric diseases, including depression and schizophrenia. Recent advances in understanding microbial opsins have been driven by molecular engineering for optogenetics and by comparative genomics. These temporal characteristics define a framework for uncovering cellular transitions between fixed and flexible behaviors, and corresponding disturbances in pathologies. However, the mechanisms which can result in increased broadband gamma power and the pathophysiological implications for cognition and behavior are poorly understood. However, direct evidence--in real time--linking dopamine neuron phasic firing in promoting the susceptible (depression-like) phenotype is lacking. The reinforcing and rewarding properties of cocaine are attributed to its ability to increase dopaminergic transmission in nucleus accumbens (NAc). Its been truly a blessing to work on this journey, together elucidating a holy grail of optogenetics, with https://t.co/Cayg5mePTl, Recalling the profound impact ~25 yrs ago of seeing the 1st K channel structure of MacKinnon & team. View details for Web of Science ID 000284395900011, View details for PubMedCentralID PMC2988875. These investigations have revealed that control of projection-specific dynamics is well suited to modulating behavioural patterns that are relevant to a broad range of psychiatric diseases. Furthermore, these neurons could be activated by cocaine, and silencing this drug-induced activity during cocaine exposure (despite the fact that the manipulation of the cholinergic interneurons was not aversive by itself) blocked cocaine conditioning in freely moving mammals. View details for DOI 10.3389/fncir.2013.00160, View details for Web of Science ID 000328276300001, View details for PubMedCentralID PMC3840435. Local inputs are mainly from layer (L) IV and excitatory cells. Nuclear CaM was elevated within 15 s of stimulus onset, preceding the first signs of CREB phosphorylation in hippocampal pyramidal neurons. Saddoris, M. P., Sugam, J. These results reveal the presence of potent cellular-level subnetworks within the orbitofrontal cortex that can be precisely engaged to bidirectionally control feeding behaviours subject to, for example, social influences. Leuze, C., Aswendt, M., Ferenczi, E., Liu, C. W., Hsueh, B., Goubran, M., Tian, Q., Steinberg, G., Zeineh, M. M., Deisseroth, K., McNab, J. The spinal implant approach we describe here is likely to enable a wide range of studies to elucidate spinal circuits underlying pain, touch, itch, and movement. 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. Optogenetics has revolutionized the study of circuit function in the brain, by allowing activation of specific ensembles of neurons by light. rning. Optogenetics in Freely Moving Mammals: Dopamine and Reward. GBO abnormalities are a feature of several neuropsychiatric disorders associated with dysfunction of cortical fast-spiking interneurons containing the calcium-binding protein parvalbumin (PV). Karl Deisseroth. Experimentally, we introduced channelrhodopsin-2 into undifferentiated human embryonic stem cells via a lentiviral vector, and sorted and expanded the genetically engineered cells. View details for DOI 10.1523/JNEUROSCI.2137-12.2013, View details for PubMedCentralID PMC3686572. A precise and minimally invasive approach to optogenetics in the awake primate. Epilepsy is a devastating disease, currently treated with medications, surgery or electrical stimulation. It employs an array of microlenses to trade off spatial resolution against angular resolution, thereby allowing a 4-D light field to be captured using a single photographic exposure without the need for scanning. In males that exhibited rapid task learning, we found that the ventrolateral part of the ventromedial hypothalamus (VMHvl), an area with a known role in attack, was essential for aggression-seeking. In this issue of Neuron, Tozuka et al. This dual control over the induction of learning by climbing fibers and Purkinje cells can expand the learning capacity of motor circuits. Karl Deisseroth, Peter Hegemann and Gero Miesenbck Awarded Horwitz B., Deisseroth, K. A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge. Such intractable epilepsy cases are often associated with degeneration of inhibitory interneurons in the cortical areas resulting in impaired inhibitory drive onto the principal neurons. Phasic activation of dopaminergic neurons is associated with reward-predicting cues and supports learning during behavioral adaptation. In studying the signaling pathways by which synaptic inputs control the phosphorylation state of cyclic AMP-responsive element binding protein (CREB) and determine expression of CRE-regulated genes, we found two important Ca2+/calmodulin (CaM)-regulated mechanisms in hippocampal neurons: a CaM kinase cascade involving nuclear CaMKIV and a calcineurin-dependent regulation of nuclear protein phosphatase 1 activity. Zhang, M., Tortoriello, G., Hsueh, B., Tomer, R., Ye, L., Mitsios, N., Borgius, L., Grant, G., Kiehn, O., Watanabe, M., Uhlen, M., Mulder, J., Deisseroth, K., Harkany, T., Hokfelt, T. G. Virally mediated optogenetic excitation and inhibition of pain in freely moving nontransgenic mice. We further explore the mechanism of these stimulation-induced behavioral responses by identifying the most probable subset of axons activated using a patient-specific computational model. Here, we established knockin-mediated enhanced gene expression by improved tetracycline-controlled gene induction (KENGE-tet) and succeeded in generating transgenic mice expressing a highly light-sensitive channelrhodopsin-2 mutant at levels sufficient to drive the activities of multiple cell types. The BLA projection to the nucleus accumbens (NAc) is thought to modulate cue-triggered motivated behaviours, but our understanding of the interaction between these two brain regions has been limited by the inability to manipulate neural-circuit elements of this pathway selectively during behaviour. Action potential (AP) frequency was monitored during application of pilocarpine (200 m). In addition, amonafide can inhibit the cytotoxic actions of m-AMSA and etoposide. However, molecular insight into ACR1 is lacking owing to the absence of structural information underlying light-gated anion conductance. Together, these data elucidate the responses of D1- and D2-type MSNs in NAc to acute cocaine and during the formation of context-reward associations and define how prior cocaine exposure selectively dysregulates D1 signaling to drive relapse. These mice express optogenetic probes, such as enhanced halorhodopsin or several different versions of channelrhodopsins, behind various neuron-specific promoters. These data suggest that optogenetic tools can be readily applied in squirrel monkeys, an important first step in enabling precise, targeted manipulation of neural circuits in these highly trainable, cognitively sophisticated animals. These findings indicate that increased levels and release of NPY observed after seizures can modulate afferent inputs to CCK-basket cells, and therefore alter their impact on the oscillatory network activity and excitability in the hippocampus. View details for DOI 10.1038/s41598-019-54248-1. We show that optogenetic induction of phasic, but not tonic, firing in VTA dopamine neurons of mice undergoing a subthreshold social-defeat paradigm rapidly induced a susceptible phenotype as measured by social avoidance and decreased sucrose preference. View details for DOI 10.1016/j.neuron.2020.03.016. Taken together, our study reveals a crucial regulatory mechanism by PPTg excitatory inputs onto VTA non-DA neurons during appetitive Pavlovian conditioning. Recently emerging optogenetic technique has been proposed as an alternative approach to control such seizures but whether it may be effective in situations where inhibitory processes in the brain are compromised has not been addressed. First, millisecond-scale optical control will be best leveraged with simultaneous millisecond-scale optical imaging. Karl Deisseroth focuses on Neuroscience, Optogenetics, Dopamine, Premovement neuronal activity and Extramural. View details for Web of Science ID 000266608600043. Finally, we examine allele-specific structure of imprinted genes, revealing local and chromosome (chr)-wide differences. By probing the circuit implementation of these effects, we observed that optogenetic recruitment of these dopamine neurons potently alters the neural encoding of depression-related behaviours in the downstream nucleus accumbens of freely moving rodents, suggesting that processes affecting depression symptoms may involve alterations in the neural encoding of action in limbic circuitry. Using GAD65-GFP mice for CCK-basket cell identification, and whole-cell patch-clamp recordings, we explored whether the effect of NPY on afferent synapses to CCK-basket cells is modified in the hyper-excitable dentate gyrus. Progress in this regard has been hindered by the lack of genetic tools for studying DA neuron subtypes. Furman, M., Zhan, Q., McCafferty, C., Lerner, B. These findings describe a mechanism by which mPFC modulates expression of reward-seeking behavior, by regulating the dynamical interactions between specific distant subcortical regions. Channelrhodopsin-2 (ChR2), an algal light-activated ion channel we developed for use in mammals, can give rise to safe, light-driven stimulation of CNS neurons on a timescale of milliseconds. These findings reveal mechanisms underlying how and where drug memories are encoded and stored in the brain and may also inform the development of treatments for drug addiction. This method includes the design and utilization of both viruses and transgenic animals: these tools are inherently flexible and modular and may be used in different combinations to achieve the desired gene expression pattern. Iyer, S. M., Montgomery, K. L., Towne, C., Lee, S. Y., Ramakrishnan, C., Deisseroth, K., Delp, S. L. Medial prefrontal D1 dopamine neurons control food intake. Here we investigated brain region evolution at cell-type resolution in the cerebellar nuclei, the output structures of the cerebellum. View details for Web of Science ID 000294439100011. However, the circuit organization that integrates these internal and external stimuli is unclear. View details for DOI 10.1371/journal.pone.0072691. We use a range of culture, slice and mammalian in vivo preparations to demonstrate the versatility of this toolbox, and we quantitatively map parameter space for fast excitation, inhibition and bistable control. Learning valence-based responses to favorable and unfavorable options requires judgments of the relative value of the options, a process necessary for species survival. A., Liu, B., Zhang, S., Wang, H., Vautier, F., Ramakrishnan, C., Kim, Y. S., Fenno, L., Deisseroth, K., Morales, M. Optogenetic manipulation of an ascending arousal system tunes cortical broadband gamma power and reveals functional deficits relevant to schizophrenia. View details for DOI 10.1073/pnas.1017210108, View details for Web of Science ID 000290203100063. Yi, F. n., Garrett, T. n., Deisseroth, K. n., Haario, H. n., Stone, E. n., Lawrence, J. J. Using mouse brains, we show intact-tissue imaging of long-range projections, local circuit wiring, cellular relationships, subcellular structures, protein complexes, nucleic acids and neurotransmitters. View details for DOI 10.1016/j.cub.2011.08.028, View details for Web of Science ID 000295899600016. Here we report optical inhibition of motor neuron and muscle activity in vivo in the cooled sciatic nerves of Thy1-ChR2-EYFP mice. Finally, we visualize the passage of individual axon bundles through one NAc subregion in a post-mortem human sample using CLARITY 3D histology corroborated by 7T tractography. This approach is of therapeutic interest for intractable epilepsy, as it spares cortical function between seizures, in contrast with existing treatments, such as surgical lesioning or drugs. The brain, yet their general function remains unclear optical control will be best with. Dopamine and reward brief pulse of light into a stable step in membrane potential n., Gore, F.,. Small dendritic regions and individual spines methods have emerged as powerful tools for dissecting neural circuit dynamics, sorted..., posing fascinating scientific questions, and in pathological dynamics underlying neuropsychiatric symptomatology. 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