Light-sensitive Channels Research Articles

Postnatal Loss of P/Q-Type Channels Confined to Rhombic-Lip-Derived Neurons Alters Synaptic Transmission at the Parallel Fiber to Purkinje Cell Synapse and Replicates GenomicCacna1aMutation Phenotype of Ataxia and Seizures in Mice

Ataxia, episodic dyskinesia, and thalamocortical seizures are associated with an inherited loss of P/Q-type voltage-gated Ca(2+) channel function. P/Q-type channels are widely expressed throughout the neuraxis, obscuring identification of the critical networks underlying these complex neurological disorders. We showed recently that the conditional postnatal loss of P/Q-type channels in cerebellar Purkinje cells (PCs) in mice (purky) leads to these aberrant phenotypes, suggesting that intrinsic alteration in PC output is a sufficient pathogenic factor for disease initiation. The question arises whether P/Q-type channel deletion confined to a single upstream cerebellar synapse might induce the pathophysiological abnormality of genomically inherited P/Q-type channel disorders. PCs integrate two excitatory inputs, climbing fibers from inferior olive and parallel fibers (PFs) from granule cells (GCs) that receive mossy fiber (MF) input derived from precerebellar nuclei. In this study, we introduce a new mouse model with a selective knock-out of P/Q-type channels in rhombic-lip-derived neurons including the PF and MF pathways (quirky). We found that in quirky mice, PF-PC synaptic transmission is reduced during low-frequency stimulation. Using focal light stimulation of GCs that express optogenetic light-sensitive channels, channelrhodopsin-2, we found that modulation of PC firing via GC input is reduced in quirky mice. Phenotypic analysis revealed that quirky mice display ataxia, dyskinesia, and absence epilepsy. These results suggest that developmental alteration of patterned input confined to only one of the main afferent cerebellar excitatory synaptic pathways has a significant role in generating the neurological phenotype associated with the global genomic loss of P/Q-type channel function.

Infrared neural stimulation in the cochlea.

The application of photonics to manipulate and stimulate neurons and to study neural networks has gained momentum over the last decade. Two general methods have been used: the genetic expression of light or temperature sensitive ion channels in the plasma membrane of neurons (Optogenetics and Thermogenetics) and the direct stimulation of neurons using infrared radiation (Infrared Neural Stimulation, INS). Both approaches have their strengths and challenges, which are well understood with a profound understanding of the light tissue interaction(s). This paper compares the opportunities of the methods for the use in cochlear prostheses. Ample data are already available on the stimulation of the cochlea with INS. The data show that the stimulation is selective, feasible at rates that would be sufficient to encode acoustic information and may be beneficial over conventional pulsed electrical stimulation. A third approach, using lasers in stress confinement to generate pressure waves and to stimulate the functional cochlea mechanically will also be discussed.

Common mechanisms regulating dark noise and quantum bump amplification inDrosophilaphotoreceptors

Absolute visual thresholds are limited by "dark noise," which in Drosophila photoreceptors is dominated by brief (∼10 ms), small (∼2 pA) inward current events, occurring at ∼2/s, believed to reflect spontaneous G protein activations. These dark events were increased in rate and amplitude by a point mutation in myosin III (NINAC), which disrupts its interaction with the scaffolding protein, INAD. This phenotype mimics that previously described in null mutants of ninaC (no inactivation no afterpotential; encoding myosin III) and an associated protein, retinophilin (rtp). Dark noise was similarly increased in heterozygote mutants of diacylglycerol kinase (rdgA/+). Dark noise in ninaC, rtp, and rdgA/+ mutants was greatly suppressed by mutations of the Gq α-subunit (Gαq) and the major light-sensitive channel (trp) but not rhodopsin. ninaC, rtp, and rdgA/+ mutations also all facilitated residual light responses in Gαq and PLC hypomorphs. Raising cytosolic Ca(2+) in the submicromolar range increased dark noise, facilitated activation of transient receptor potential (TRP) channels by exogenous agonist, and again facilitated light responses in Gαq hypomorphs. Our results indicate that RTP, NINAC, INAD, and diacylglycerol kinase, together with a Ca(2+)-dependent threshold, share common roles in suppressing dark noise and regulating quantum bump generation; consequently, most spontaneous G protein activations fail to generate dark events under normal conditions. By contrast, quantum bump generation is reliable but delayed until sufficient G proteins and PLC are activated to overcome threshold, thereby ensuring generation of full-size bumps with high quantum efficiency.

In vivo optogenetic control of striatal and thalamic neurons in non-human primates.

Electrical and pharmacological stimulation methods are commonly used to study neuronal brain circuits in vivo, but are problematic, because electrical stimulation has limited specificity, while pharmacological activation has low temporal resolution. A recently developed alternative to these methods is the use of optogenetic techniques, based on the expression of light sensitive channel proteins in neurons. While optogenetics have been applied in in vitro preparations and in in vivo studies in rodents, their use to study brain function in nonhuman primates has been limited to the cerebral cortex. Here, we characterize the effects of channelrhodopsin-2 (ChR2) transfection in subcortical areas, i.e., the putamen, the external globus pallidus (GPe) and the ventrolateral thalamus (VL) of rhesus monkeys. Lentiviral vectors containing the ChR2 sequence under control of the elongation factor 1α promoter (pLenti-EF1α -hChR2(H134R)-eYFP-WPRE, titer 109 particles/ml) were deposited in GPe, putamen and VL. Four weeks later, a probe combining a conventional electrode and an optic fiber was introduced in the previously injected brain areas. We found light-evoked responses in 31.5% and 32.7% of all recorded neurons in the striatum and thalamus, respectively, but only in 2.5% of recorded GPe neurons. As expected, most responses were time-locked increases in firing, but decreases or mixed responses were also seen, presumably via ChR2-mediated activation of local inhibitory connections. Light and electron microscopic analyses revealed robust expression of ChR2 on the plasma membrane of cell somas, dendrites, spines and terminals in the striatum and VL. This study demonstrates that optogenetic experiments targeting the striatum and basal ganglia-related thalamic nuclei can be successfully achieved in monkeys. Our results indicate important differences of the type and magnitude of responses in each structure. Experimental conditions such as the vector used, the number and rate of injections, or the light stimulation conditions have to be optimized for each structure studied.

Feeling the Light

Light sensing involves contraction of the photoreceptor cell membrane physically gating the light-sensitive channels.

Cortical Neurovascular Coupling Driven by Stimulation of Channelrhodopsin-2

While functional imaging is widely used in studies of the brain, how well the hemodynamic signal represents the underlying neural activity is still unclear. And there is a debate on whether hemodynamic signal is more tightly related to synaptic activity or action potentials. This study intends to address these questions by examining neurovascular coupling driven by pyramidal cells in the motor cortex of rats. Pyramidal cells in the motor cortex of rats were selectively transduced with the light sensitive cation channel channelrhodopsin-2 (ChR2). Electrophysiological recordings and optical intrinsic signal imaging were performed simultaneously and synchronously to capture the neural activity and hemodynamics induced by optical stimulation of ChR2-expressing pyramidal cells. Our results indicate that both synaptic activity (local field potential, LFP) and action potentials (multi-unit activity, MUA) are tightly related to hemodynamic signals. While LFPs in γ band are better in predicting hemodynamic signals elicited by short stimuli, MUA has better predictions to hemodynamic signals elicited by long stimuli. Our results also indicate that strong nonlinearity exists in neurovascular coupling.

Computational modeling of light activated ion channels

Channelrhodpsin-2 (ChR2) is a light sensitive ion channel protein currently investigated for millisecond time scale optogenetic control of neural activity [1]. Two competing mathematical models, a 3-state and a 4-state rate transition model are currently available to mimic the ChR2 photocurrent kinetics [2]. While both models are able to capture the key temporal features of ChR2 photocurrent in response to light stimulation pulses of different intensities and durations, little is known about their efficacy to model the neural response to light stimulation protocols of various frequencies and pulse width characteristics. Moreover, it is unclear to what degree the two models can capture the photocurrent kinetics of the recently engineered ChR2 mutants, designed to allow for more precise optical control of neural activity [3]. To address these issues, we investigate a 3-state and a 4-state transition rate model to mimic the photocurrent kinetic of wild type ChR2 (ChR2wt) and a newly validated ChR2 mutant with fast photocurrent kinetics (ChRETA) consistent with the experimental measurements in Gunaydin et al. [3]. We incorporate these models into a fast spiking hippocampal interneuron model [4] in order to examine to what degree the neural response to different experimental stimulation protocols can be successfully simulated. We find that the 3-state model can qualitatively reproduce the neural activity induced by periodic short time interval (2 ms) light pulse stimulation only for low frequencies (<20Hz). The model however fails to capture the experimentally observed features of neural response to higher frequencies (80 and 200 Hz) for both variants of ChR2 investigated. The 4-state model is able to reliably mimic the neural response to light pulse stimulation of all frequencies in both ChR2 variants. Furthermore, for ChR2wt, the 4-state model but not the 3-state model is able to reproduce both the burst-like neural firing activity induced by single, brief (2ms width) light pulses and the plateau potentials observed in neurons for high frequency (200 Hz) light stimulation. Both models were able to mimic the occurrence of missed spikes in ChR2wt when prolonged (60 light pulses) light stimulation is delivered, with better fidelity provided by the 4-state model. Finally, the 4-state model better captures the neural response to Poisson and Gaussian distributed light stimulation pulses. Motivated by the overall better performance of the 4-state model, we investigate the conditions under which a characteristic specific to the 3-state model, namely the mono-exponential decay of the ChR2 photocurrent kinetics (often reported in experimental literature) can occur in the 4-state model. Using analytical methods, we show that for each variant, the photocurrent component associated with the unreported decay constant is vanishingly small, which may explain the experimental difficulty in its empirical evaluation. In summary, we have systematically analyzed the 3-state and 4-state transition rate models for ChR2 photocurrent kinetics and demonstrated that independent of the variant, the 4-state model is able to better capture both qualitative and quantitative features of photocurrent kinetics and the neural response to several different light stimulation protocols. The results suggest that the 4-state transition rate model is a suitable candidate for a universal mathematical framework to model the photocurrent kinetic of ChR2 proteins.

Protein Gq Modulates Termination of Phototransduction and Prevents Retinal Degeneration

Appropriate termination of the phototransduction cascade is critical for photoreceptors to achieve high temporal resolution and to prevent excessive Ca(2+)-induced cell toxicity. Using a genetic screen to identify defective photoresponse mutants in Drosophila, we isolated and identified a novel Gα(q) mutant allele, which has defects in both activation and deactivation. We revealed that G(q) modulates the termination of the light response and that metarhodopsin/G(q) interaction affects subsequent arrestin-rhodopsin (Arr2-Rh1) binding, which mediates the deactivation of metarhodopsin. We further showed that the Gα(q) mutant undergoes light-dependent retinal degeneration, which is due to the slow accumulation of stable Arr2-Rh1 complexes. Our study revealed the roles of G(q) in mediating photoresponse termination and in preventing retinal degeneration. This pathway may represent a general rapid feedback regulation of G protein-coupled receptor signaling.

The light-sensitive conductance of melanopsin-expressing Joseph and Hesse cells in amphioxus

Two types of microvillar photoreceptors in the neural tube of amphioxus, an early chordate, sense light via melanopsin, the same photopigment as in “circadian” light detectors of higher vertebrates. Because in amphioxus melanopsin activates a Gq/phospholipase C cascade, like phototransduction in arthropods and mollusks, possible commonalities in the photoconductance were investigated. Unlike other microvillar photoreceptors, reversal of the photocurrent can only be attained upon replacement of extracellular Na+. In addition to Na+, Ca2+ is also permeant, as indicated by the fact that (a) in normal ionic conditions the photocurrent remains inward at Vm > ENa; (b) in Na-free solution a small residual inward photocurrent persists at Vm near resting level, provided that Ca is present; and (c) Vrev exhibits a modest shift with [Ca]o manipulations. The unusual reversal is accounted for by an uncommonly low permeability of the light-dependent channels to K+, as [K]o only marginally affects the photocurrent amplitude and its reversal. Lanthanum and ruthenium red (RuR), two TRP channel antagonists, reversibly suppress the response to photostimulation of moderate intensity; therefore, the melanopsin-initiated cascade may recruit ion channels of the same family as those of rhabdomeric photoreceptors. With brighter lights, blockage declines, so that both La3+ and RuR induce a right shift in the sensitivity curve without a reduction of its asymptote. Nonetheless, an effect on the transduction cascade, rather than the channels, was ruled out on the basis of the voltage dependency of the blockade and the lack of effects of intracellular application of the same substances. The mechanisms of action of these antagonists thus entail a state-dependent blockade, with a higher affinity for the channel in the closed conformation. Collectively, the results indicate a kinship of the light-sensitive channels of amphioxus with those of invertebrate rhabdomeric visual cells and support the representation of this lineage of photoreceptors among chordates.

Integrated device for combined optical neuromodulation and electrical recording for chronic in vivo applications

Studying brain function and its local circuit dynamics requires neural interfaces that can record and stimulate the brain with high spatiotemporal resolution. Optogenetics, a technique that genetically targets specific neurons to express light-sensitive channel proteins, provides the capability to control central nervous system neuronal activity in mammals with millisecond time precision. This technique enables precise optical stimulation of neurons and simultaneous monitoring of neural response by electrophysiological means, both in the vicinity of and distant to the stimulation site. 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). Here we report a fully chronic implant of a new version of this device in ChR2-expressing rats, and demonstrate its use in freely moving animals over periods up to 8 months. In its present configuration, we show the device delivering optical excitation to a single cortical site while mapping the neural response from the surrounding 30 channels of the 6 × 6 element MEA, thereby enabling recording of optically modulated single-unit and local field potential activity across several millimeters of the neocortical landscape.

The Lego-logic of optogenetics

Daisy-chaining light-sensitive ion channels, pumps and fluorescent proteins extends the possibilities for control of neuronal activity.

LiGluR Restores Visual Responses in Rodent Models of Inherited Blindness

Inherited retinal degeneration results from many different mutations in either photoreceptor-specific or nonphotoreceptor-specific genes. However, nearly all mutations lead to a common blinding phenotype that initiates with rod cell death, followed by loss of cones. In most retinal degenerations, other retinal neuron cell types survive for long periods after blindness from photoreceptor loss. One strategy to restore light responsiveness to a retina rendered blind by photoreceptor degeneration is to express light-regulated ion channels or transporters in surviving retinal neurons. Recent experiments in rodents have restored light-sensitivity by expressing melanopsin or microbial opsins either broadly throughout the retina or selectively in the inner segments of surviving cones or in bipolar cells. Here, we present an approach whereby a genetically and chemically engineered light-gated ionotropic glutamate receptor (LiGluR) is expressed selectively in retinal ganglion cells (RGCs), the longest-surviving cells in retinal blinding diseases. When expressed in the RGCs of a well-established model of retinal degeneration, the rd1 mouse, LiGluR restores light sensitivity to the RGCs, reinstates light responsiveness to the primary visual cortex, and restores both the pupillary reflex and a natural light-avoidance behavior.

Nucleus Accumbens Medium Spiny Neurons Target Non-Dopaminergic Neurons in the Ventral Tegmental Area

The midbrain ventral tegmental area (VTA) projection to the nucleus accumbens (NAc) is implicated in motivation and reinforcement. A significant number of NAc medium spiny neurons (MSNs) project back to the VTA, although the nature of this projection is essentially unknown. For example, do NAc MSNs directly target accumbens-projecting dopamine neurons and do they act via the GABA(A) or GABA(B) receptor? To address these issues, we expressed the light-sensitive channel rhodopsin-2 in the rat NAc and made electrophysiological recordings from VTA neurons ex vivo. We found that the NAc directly targets non-dopaminergic VTA neurons, including some that project back to the NAc. These MSN GABAergic terminals are opioid sensitive and act via GABA(A) receptors.

Getting heart cells on the same wavelength: infrared triggering of Ca2+transients in cardiac myocytes

Getting heart cells on the same wavelength: infrared triggering of Ca²⁺transients in cardiac myocytes

A brief history of trp: commentary and personal perspective

The history of the discovery of the transient receptor potential (TRP) cation channel superfamily began in 1969 with Cosens and Manning's isolation of the Drosophila transient receptor potential mutant, in which the photoreceptor response decays during continuous illumination. Early studies from Minke found that the elementary light response was unaffected in trp mutants, and he attributed the defect to an intermediate stage of phototransduction. Montell and Rubin cloned the trp gene in 1989: they recognised it as a transmembrane protein, but also concluded that it did not encode the light-sensitive channels. In 1991, Minke and Selinger proposed that TRP represented a Ca2+ transporter required for refilling intracellular InsP3-sensitive Ca2+ stores, in turn required for activation of the light-sensitive channels. Also in 1991, after developing a photoreceptor patch clamp preparation, I showed that the light-sensitive channels themselves were highly permeable to Ca2+, questioning the need for such a dedicated Ca2+ transporter. In 1992, in collaboration with Minke, I resolved this paradox by showing there were two classes of light-sensitive channels, one highly Ca2+ permeable and eliminated in trp mutants. This represented the first and compelling evidence that TRP represented a light-sensitive channel and was supported by the cloning of the second light-sensitive channel, TRPL, by Kelly's lab. Three years later, in 1995, the labs of Montell and Birnbaumer independently cloned TRPC1, the first of 29 vertebrate TRP isoforms distributed amongst seven subfamilies.

Activation of TRP Channels by Phosphoinositide Depletion and Protons in Drosophila Photoreceptors

Phototransduction in Drosophila microvillar photoreceptors is mediated via a G-protein coupled phospholipase C (PLCβ4 encoded by the norpA gene), resulting in the activation of two classes of Ca2+ and cation permeable channels, TRP and TRPL. Representative of the TRPC subfamily, these are the founding members of the TRP ion channel superfamily, but exactly how the channels are activated is unresolved. PLC's obvious action is to hydrolyze PIP2 generating DAG and InsP3 whilst simultaneously reducing PIP2, the concentration of which can be accurately controlled using genetically encoded PIP2 biosensors to monitor levels. The fact that hydrolysis of PIP2 by PLC also releases a proton is seldom recognized and has neither been measured in vivo, nor implicated previously in a signaling context. We have now shown that light induces a rapid (< 10 ms) acidification originating in the microvilli which is eliminated in norpA mutants lacking PLC. Furthermore, following depletion of PIP2 and other phosphoinositides by a variety of experimental manipulations, both TRP and TRPL channels become remarkably sensitive to rapid and reversible activation by lipophilic protonophores such as 2-4 dinitrophenol, whilst heterologously expressed TRPL channels can be directly activated by acidification of the cytosolic surface of inside-out patches. These results indicate that a combination of phosphoinositide depletion and cytosolic acidification is sufficient to activate the light-sensitive channels. Together with the demonstration of light-induced, PLC dependent acidification, this suggests that TRPC channels in Drosophila photoreceptors may be activated in a combinatorial fashion by PLC's dual action of phosphoinositide depletion and proton release.

Multicompartmental Model of Neurons Expressing Channelrhodopsin

Event Abstract Back to Event Multicompartmental Model of Neurons Expressing Channelrhodopsin Konstantin Nikolic1* and Nir Grossman1 1 Imperial College London, United Kingdom Optogenetic technology combines genetics and optics to create tools for controlling and interfering with cell functions. In the case of neuroscience it is a very important tool for interfacing with neurons and neural circuits. Light-sensitive proteins such as channelrhodopsin-2 (ChR2) or halorhodopsin (NpHR) are also ion channels or pumps and can be genetically expressed in the host cells. The specific parts of cells where expression occurs become light sensitive and external light sources can be used, in very precise spatio-temporal fashion if needed, to remotely generate ionic flux which causes membrane depolarisation or hyperpolarisation, depending on the type of ion channels. Design of various mutants of ChR2 and other light sensitive ion channels and pumps is now well within the reach of modern molecular biology. In contrary to conventional electrical stimulations, the ChR2 evoked currents are sensitive to the state of neurons they drive. ChR2 behaves as a complex light-controlled, voltage-dependent current driver (1-3), coupled to a dynamic-threshold voltage-oscillator (neuron). We developed a model of neurons expressing ChR2 which includes: (1) a photocycle model of ChR2 which gives the time evolution of functional states of ChR2 complex as a function of time and light intensity [1,2], (2) the current-voltage characteristic of ChR2 ion channels [3] (zero reverse potential was assumed, as suggested by experiments), (3) full mutlicompartmental Hodgkin-Huxley type model of the neuron [3]. The simulation code was developed on two platforms: Matlab and Simulink and it is available upon request. The model and the conclusions presented in this study can help to interpret experimental results, design illumination protocols and seek improvement strategies in the nascent optogenetics technology. The software is a very useful tool for computational modelling of networks of neurons which incorporate photosensitized neurons, as well as for simulations of neural computations within individual neurons. Acknowledgment: European Commission, FP7-ICT-2009, Proj. No. 270324 [1] K. Nikolic et al. (2009). Photocycles of channelrhodopsin-2. Photochemistry & Photobiology 85, 400-411 [2] K. Nikolic et al. (2006). Modeling and engineering aspects of ChannelRhodopsin2 system for neural photostimulation, Proc 28th Conf IEEE Eng Med Biol Soc, 1626-1629 [3] N. Grossman et al. (2011). Modeling Study of the Light Stimulation of a Neuron Cell with Channelrhodopsin-2 Mutants. IEEE Trans Biomed Eng, in-press ISSN:1558-2531 Figure 1 Keywords: computational neuroscience Conference: 4th INCF Congress of Neuroinformatics, Boston, United States, 4 Sep - 6 Sep, 2011. Presentation Type: Poster Presentation Topic: Computational neuroscience Citation: Nikolic K and Grossman N (2011). Multicompartmental Model of Neurons Expressing Channelrhodopsin. Front. Neuroinform. Conference Abstract: 4th INCF Congress of Neuroinformatics. doi: 10.3389/conf.fninf.2011.08.00004 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 17 Oct 2011; Published Online: 19 Oct 2011. * Correspondence: Dr. Konstantin Nikolic, Imperial College London, London, United Kingdom, konstantin.nikolic@uwl.ac.uk Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Konstantin Nikolic Nir Grossman Google Konstantin Nikolic Nir Grossman Google Scholar Konstantin Nikolic Nir Grossman PubMed Konstantin Nikolic Nir Grossman Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Dissecting the Immune Component of Neurologic Disorders: A Grand Challenge for the 21st Century

Dissecting the Immune Component of Neurologic Disorders: A Grand Challenge for the 21st Century

Optogenetic Approaches in Neuroscience

The recently introduced term 'optogenetics' describes a variety of techniques for expressing genes in nerve cells that render them responsive to light. This approach makes use of light-sensitive channel proteins that can be used to manipulate neuronal function. Using genetic strategies, these channel proteins can be expressed in neurons defined by a common genetic identity, which can then be selectively activated or silenced through illumination. Inthis minireview, we shall describe the basic principles of such manipulative optogenetic approaches in neuroscience and summarize how these tools are being exploited to investigate neuronal circuits and behavior.

Multi-array silicon probes with integrated optical fibers: light-assisted perturbation and recording of local neural circuits in the behaving animal.

Recordings of large neuronal ensembles and neural stimulation of high spatial and temporal precision are important requisites for studying the real-time dynamics of neural networks. Multiple-shank silicon probes enable large-scale monitoring of individual neurons. Optical stimulation of genetically targeted neurons expressing light-sensitive channels or other fast (milliseconds) actuators offers the means for controlled perturbation of local circuits. Here we describe a method to equip the shanks of silicon probes with micron-scale light guides for allowing the simultaneous use of the two approaches. We then show illustrative examples of how these compact hybrid electrodes can be used in probing local circuits in behaving rats and mice. A key advantage of these devices is the enhanced spatial precision of stimulation that is achieved by delivering light close to the recording sites of the probe. When paired with the expression of light-sensitive actuators within genetically specified neuronal populations, these devices allow the relatively straightforward and interpretable manipulation of network activity.