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Optogenetics for light control of biological systems
Light arrays for primate optogenetics Behavioral studies in non-human primates may benefit greatly from manipulation of neural activity using optogenetics, but long-term optogenetic manipulation in large brains remains a challenge. Opto-Array is a new array of multiple LEDs that can be chronically implanted on the surface of the brain and used to illuminate the underlying tissue in non-human primates without a cranial window or fibre implant. The authors demonstrated the implant in macaques previously injected with an inhibitory opsin virus in primary visual cortex (V1), by using a two-choice visual discrimination task. Trials in which optogenetic silencing was applied over V1 reliably modified the monkey’s performance in a spatially constrained manner. The array works best for superficial tissue, but is a step towards achieving robust behavioural effects via a chronic implant in primates.
Forum: Optogenetics roundtable with Deisseroth and Gradinaru
Erratum: Optogenetics and the future of neuroscience
- Edward S Boyden
Abstract
Over the last 10 years, optogenetics has become widespread in neuroscience for the study of how specific cell types contribute to brain functions and brain disorder states. The full impact of optogenetics will emerge only when other toolsets mature, including neural connectivity and cell phenotyping tools and neural recording and imaging tools. The latter tools are rapidly improving, in part because optogenetics has helped galvanize broad interest in neurotechnology development.
Montgomery, K. et al. Nat. Methods 12, 969–974 (2015).
Optogenetic stimulation provides greater frequency resolution than the electrical stimulation that provides the basis for sound coding in current cochlear and auditory brainstem implants. In a new study, optogenetic stimulation of genetically engineered spiral ganglion neurons in mice activated the auditory pathway, and restored auditory activity in deaf mice. The findings might pave the way for better auditory prostheses.
Achieving non-invasive, temporally-precise control of the activity of specific neural populations could advance neuroscientific research and provide an opportunity for therapeutic neuromodulation. Chen et al. showed that expression of the channelrhodopsin ChRmine in ‘deep’ brain regions (including the VTA and hippocampus) allowed a transcranial light source to control the associated neural circuits and alter behaviour. The authors further demonstrated transcranial optogenetic control of neurons in the dorsal raphe after systemic viral delivery of ChRmine, revealing a surgery-free method to manipulate deep neural circuits.
Abstract
Optogenetics has emerged as a powerful tool for studying the neural basis of simple behaviors in rodents and small animals. In the primate model, however, optogenetics has had limited utility because optical methods have not been able to drive behavior. Here, we report that monkeys reliably shift their gaze toward the receptive field of optically driven channelrhodopsin-2-expressing V1 neurons. This result establishes optogenetics as a viable means for the causal analysis of behavior in the primate model.
Optogenetics is a technology that employs light to regulate genetically engineered cells, providing novel prospects for dental research. One of its most potential applications is for pain control. Optogenetics can precisely modify pain signals by targeting specific nociceptive neurons, eliminating the need for systemic drugs or invasive procedures.1 This could significantly improve the patient experience during dental procedures or chronic oral pain management.
Inglés-Prieto, Á. et al. Nat. Chem. Biol. doi:10.1038/nchembio.1933 (12 October 2015).
Optogenetic tools are being used increasingly for photocontrol of biological systems with high spatiotemporal precision. Inglés-Prieto et al. now expand the domain of optogenetics to high-throughput drug screening. Specifically, they study the mitogen-activated protein kinase/extracellular signal–regulated kinase (MAPK/ERK) pathway, which is stimulated by the activation of receptor tyrosine kinases (RTKs). In their screen, they use RTKs fused to light-oxygen-voltage–sensing domains ('opto-RTKs') that are activated by light-dependent dimerization; light thus stimulates the MAPK/ERK pathway activity and downstream reporter expression. Because activation and readout are both optical, fewer steps and no additional activation reagents are necessary, enabling screening with low variability. The authors demonstrate the power of their technique for several opto-RTKs, including 'orphan receptors' for which activating ligands are unknown.
The remarkable capacity of the heart to generate and propagate electrical signals with every heartbeat allows for the regular and synchronous cardiac contraction that keeps us alive. Our ability to modulate the intrinsic rhythm of the heart using external electrical signals has been a fundamental research tool and a life-saving development for many patients with a wide range of heart rhythm conditions. The development of defibrillation, cardioversion and pacemaking have been revolutionary in restoring normal heart rhythm. However, electrical stimulation using physical electrodes is non-specific and has poor spatial resolution. This lack of specificity can result in the painful stimulation of skeletal muscle and sensory neurons in patients with an implantable cardioverter–defibrillator.
Over 40 years ago, Francis Crick envisaged the potential one day to control neurons using light. This report was probably the first description of the field now referred to as optogenetics, a technique that combines genetic and optical approaches to modulate cell excitability with the use of light. The publication by Tobias Brügmann, Philipp Sasse and colleagues in 2010 was the first study to demonstrate optogenetic regulation of the heart, illustrating a powerful technique with potential clinical translation. The capacity of optogenetics to activate neurons had been demonstrated a few years before, and Brügmann and colleagues set out to investigate whether the same technique could offer a novel approach to regulate cardiac excitability. The study used cardiomyocytes that genetically express a light-sensitive ion channel (channelrhodopsin 2), which opens when illuminated with blue light and results in cell membrane depolarization. The investigators showed that short pulses of blue light could stimulate cardiomyocytes in vitro, and the pacemaker region of the cells could be controlled by altering the area of illumination.
Abstract
The synchronous activity of neuronal networks is considered crucial for brain function. However, the interaction between single-neuron activity and network-wide activity remains poorly understood. This study explored this interaction within cultured networks of rat cortical neurons. Employing a combination of high-density microelectrode array recording and optogenetic stimulation, we established an experimental setup enabling simultaneous recording and stimulation at a precise single-neuron level that can be scaled to the level of the whole network. Leveraging our system, we identified a network burst-dependent response change in single neurons, providing a possible mechanism for the network-burst-dependent loss of information within the network and consequent cognitive impairment during epileptic seizures. Additionally, we directly recorded a leader neuron initiating a spontaneous network burst and characterized its firing properties, indicating that the bursting activity of hub neurons in the brain can initiate network-wide activity. Our study offers valuable insights into brain networks characterized by a combination of bottom-up self-organization and top-down regulation.
Pisanello, F. et al. Neuron 82, 1245–1254 (2014).
To unravel the function of different brain subregions in a neural circuit, spatially selective and user-defined optogenetic control over these subregions is desirable. To achieve this goal, Pisanello et al. developed multipoint-emitting optical fibers. The tapered ends of these fibers are gold coated, with the exception of some small windows along the tip of the fiber. The researchers directed light emission to different windows by capitalizing on the behavior of light at reflective surfaces and by simply changing the input angle of a laser beam into the optical fiber. In the mouse striatum or cortex, the optogenetic activation of GABAergic neurons in different subregions led to the activation of different populations of neurons. This tool provides a versatile option for optically manipulating neural circuits.
Jeong, J.-W. et al. Cell 162, 662–674 (2015).
Pharmacological and optogenetic manipulations of neurons are two approaches for interrogating circuit function in the brain that are usually performed in separate experiments. Jeong et al. have now developed a device that can deliver both light and fluids in vivo. The device consists of an array of inorganic light-emitting diodes (μ-ILEDs) and four fluid-delivery channels connected to independent reservoirs. The device is wirelessly controlled by an infrared sensor that enables light delivery or a heating element that triggers fluid pumping via heat-sensitive expandable microspheres. The researchers used these devices to optogenetically activate and pharmacologically inhibit dopamine neurons in the ventral tegmental area of mice, causing a modulation of place preference behavior in freely moving animals.
Optogenetic manipulation of neurons at cellular resolution holds promise for the dissection of neural microcircuitry.
Abstract
Optogenetics is a powerful technique that allows target-specific spatiotemporal manipulation of neuronal activity for dissection of neural circuits and therapeutic interventions. Recent advances in wireless optogenetics technologies have enabled investigation of brain circuits in more natural conditions by releasing animals from tethered optical fibers. However, current wireless implants, which are largely based on battery-powered or battery-free designs, still limit the full potential of in vivo optogenetics in freely moving animals by requiring intermittent battery replacement or a special, bulky wireless power transfer system for continuous device operation, respectively. To address these limitations, here we present a wirelessly rechargeable, fully implantable, soft optoelectronic system that can be remotely and selectively controlled using a smartphone. Combining advantageous features of both battery-powered and battery-free designs, this device system enables seamless full implantation into animals, reliable ubiquitous operation, and intervention-free wireless charging, all of which are desired for chronic in vivo optogenetics. Successful demonstration of the unique capabilities of this device in freely behaving rats forecasts its broad and practical utilities in various neuroscience research and clinical applications.
Activation of microglia is sufficient to trigger chronic pain in mice, according to a new study published recently in PLoS Biology. Innovative use of optogenetics enabled selective manipulation of microglia, demonstrating a technique that could be used to study microglial involvement in other diseases.
The biological mechanisms that underlie chronic pain are poorly understood, but interaction between neurons and glia has recently emerged as an important aspect. Accumulating evidence demonstrates that microglia have an important role in this context, but their contribution to pain generation remains unclear.
Abstract
The practices of synthetic biology are being integrated into ‘multiscale’ designs enabling two-way communication across organic and inorganic information substrates in biological, digital and cyber-physical system integrations. Novel applications of ‘bio-informational’ engineering will arise in environmental monitoring, precision agriculture, precision medicine and next-generation biomanufacturing. Potential developments include sentinel plants for environmental monitoring and autonomous bioreactors that respond to biosensor signaling. As bio-informational understanding progresses, both natural and engineered biological systems will need to be reimagined as cyber-physical architectures. We propose that a multiple length scale taxonomy will assist in rationalizing and enabling this transformative development in engineering biology.
Abstract
Both in vivo neuropharmacology and optogenetic stimulation can be used to decode neural circuitry, and can provide therapeutic strategies for brain disorders. However, current neuronal interfaces hinder long-term studies in awake and freely behaving animals, as they are limited in their ability to provide simultaneous and prolonged delivery of multiple drugs, are often bulky and lack multifunctionality, and employ custom control systems with insufficiently versatile selectivity for output mode, animal selection and target brain circuits. Here, we describe smartphone-controlled, minimally invasive, soft optofluidic probes with replaceable plug-like drug cartridges for chronic in vivo pharmacology and optogenetics with selective manipulation of brain circuits. We demonstrate the use of the probes for the control of the locomotor activity of mice for over four weeks via programmable wireless drug delivery and photostimulation. Owing to their ability to deliver both drugs and photopharmacology into the brain repeatedly over long time periods, the probes may contribute to uncovering the basis of neuropsychiatric diseases.
Abstract
Flexible electronic/optoelectronic systems that can intimately integrate onto the surfaces of vital organ systems have the potential to offer revolutionary diagnostic and therapeutic capabilities relevant to a wide spectrum of diseases and disorders. The critical interfaces between such technologies and living tissues must provide soft mechanical coupling and efficient optical/electrical/chemical exchange. Here, we introduce a functional adhesive bioelectronic–tissue interface material, in the forms of mechanically compliant, electrically conductive, and optically transparent encapsulating coatings, interfacial layers or supporting matrices. These materials strongly bond both to the surfaces of the devices and to those of different internal organs, with stable adhesion for several days to months, in chemistries that can be tailored to bioresorb at controlled rates. Experimental demonstrations in live animal models include device applications that range from battery-free optoelectronic systems for deep-brain optogenetics and subdermal phototherapy to wireless millimetre-scale pacemakers and flexible multielectrode epicardial arrays. These advances have immediate applicability across nearly all types of bioelectronic/optoelectronic system currently used in animal model studies, and they also have the potential for future treatment of life-threatening diseases and disorders in humans.
Abstract
Natural scenes are highly dynamic, challenging the reliability of visual processing. Yet, humans and many animals perform accurate visual behaviors, whereas computer vision devices struggle with rapidly changing background luminance. How does animal vision achieve this? Here, we reveal the algorithms and mechanisms of rapid luminance gain control in Drosophila, resulting in stable visual processing. We identify specific transmedullary neurons as the site of luminance gain control, which pass this property to direction-selective cells. The circuitry further involves wide-field neurons, matching computational predictions that local spatial pooling drive optimal contrast processing in natural scenes when light conditions change rapidly. Experiments and theory argue that a spatially pooled luminance signal achieves luminance gain control via divisive normalization. This process relies on shunting inhibition using the glutamate-gated chloride channel GluClα. Our work describes how the fly robustly processes visual information in dynamically changing natural scenes, a common challenge of all visual systems.
Abstract
Orthopedic implants with high elastic modulus often suffer from poor osseointegration due to stress shielding, a phenomenon that suppresses the expression of intracellular mechanotransduction molecules (IMM) such as focal adhesion kinase (FAK). We find that reduced FAK expression under stress shielding is also mediated by decreased calcitonin gene-related peptide (CGRP) released from Piezo2+ mechanosensitive nerves surrounding the implant. To activate these nerves minimally invasively, we develop a fully implantable, wirelessly rechargeable optogenetic device. In mice engineered to express light-sensitive channels in Piezo2+ neurons, targeted stimulation of the L2-3 dorsal root ganglia (DRG) enhances localized CGRP release near the implant. This CGRP elevation activates the Protein Kinase A (PKA)/FAK signaling pathway in bone marrow mesenchymal stem cells (BMSCs), thereby enhancing osteogenesis and improving osseointegration. Here we show that bioelectronic modulation of mechanosensitive nerves offers a strategy to address implant failure, bridging neuroregulation and bone bioengineering.
Abstract
Neural micro-electrode arrays that are transparent over a broad wavelength spectrum from ultraviolet to infrared could allow for simultaneous electrophysiology and optical imaging, as well as optogenetic modulation of the underlying brain tissue. The long-term biocompatibility and reliability of neural micro-electrodes also require their mechanical flexibility and compliance with soft tissues. Here we present a graphene-based, carbon-layered electrode array (CLEAR) device, which can be implanted on the brain surface in rodents for high-resolution neurophysiological recording. We characterize optical transparency of the device at >90% transmission over the ultraviolet to infrared spectrum and demonstrate its utility through optical interface experiments that use this broad spectrum transparency. These include optogenetic activation of focal cortical areas directly beneath electrodes, in vivo imaging of the cortical vasculature via fluorescence microscopy and 3D optical coherence tomography. This study demonstrates an array of interfacing abilities of the CLEAR device and its utility for neural applications.
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