Explore the vast range of titles available.

Key Points Modern optogenetics enables temporally precise, acute or chronic, excitatory or inhibitory modulation of neuronal activity with cell type and anatomical specificity that can be tuned to timing and magnitude of naturally occurring patterns within the same experimental subject. Diverse opsin variants exhibit unique spectral and kinetic features that are specifically suited for distinct experimental requirements. Optogenetics can be used in combination with electrophysiological or optical recordings, providing powerful approaches to simultaneously monitor and perturb neural function. Activity-dependent labelling of opsins can be used to reactivate neural ensembles that encode particular behaviours or experiences. New anatomical techniques (such as viral-tracing methods and hydrogel-embedding methods for optical access) enable molecular and anatomical profiling of the same cells that were active in vivo , providing integrative understanding of neural circuitry. Optogenetics is widely used to study the consequences of neuronal activity with high spatiotemporal precision. In this Review, Kim et al . discuss the integration of this approach with other technological and methodological advances to gain insights into neuronal function that were previously inaccessible. Modern optogenetics can be tuned to evoke activity that corresponds to naturally occurring local or global activity in timing, magnitude or individual-cell patterning. This outcome has been facilitated not only by the development of core features of optogenetics over the past 10 years (microbial-opsin variants, opsin-targeting strategies and light-targeting devices) but also by the recent integration of optogenetics with complementary technologies, spanning electrophysiology, activity imaging and anatomical methods for structural and molecular analysis. This integrated approach now supports optogenetic identification of the native, necessary and sufficient causal underpinnings of physiology and behaviour on acute or chronic timescales and across cellular, circuit-level or brain-wide spatial scales.

Over the past decade, modern optogenetics has emerged from the convergence of developments in microbial opsin engineering, genetic methods for targeting, and optical strategies for light delivery. In this Historical Commentary, Karl Deisseroth reflects on the optogenetic landscape, from the important steps but slow progress in the beginning to the acceleration in discovery seen in recent years. Over the past 10 years, the development and convergence of microbial opsin engineering, modular genetic methods for cell-type targeting and optical strategies for guiding light through tissue have enabled versatile optical control of defined cells in living systems, defining modern optogenetics. Despite widespread recognition of the importance of spatiotemporally precise causal control over cellular signaling, for nearly the first half (2005–2009) of this 10-year period, as optogenetics was being created, there were difficulties in implementation, few publications and limited biological findings. In contrast, the ensuing years have witnessed a substantial acceleration in the application domain, with the publication of thousands of discoveries and insights into the function of nervous systems and beyond. This Historical Commentary reflects on the scientific landscape of this decade-long transition.

A central goal in neuroscience is to determine how the brain’s neuronal circuits generate perception, cognition and emotions and how these lead to appropriate behavioural actions. A methodological platform based on genetically encoded voltage indicators (GEVIs) that enables the monitoring of large-scale circuit dynamics has brought us closer to this ambitious goal. This Review provides an update on the current state of the art and the prospects of emerging optical GEVI imaging technologies.

The naturally occurring channelrhodopsin variant anion channelrhodopsin-1 (ACR1), discovered in the cryptophyte algae Guillardia theta , exhibits large light-gated anion conductance and high anion selectivity when expressed in heterologous settings, properties that support its use as an optogenetic tool to inhibit neuronal firing with light. However, molecular insight into ACR1 is lacking owing to the absence of structural information underlying light-gated anion conductance. Here we present the crystal structure of G. theta ACR1 at 2.9 Å resolution. The structure reveals unusual architectural features that span the extracellular domain, retinal-binding pocket, Schiff-base region, and anion-conduction pathway. Together with electrophysiological and spectroscopic analyses, these findings reveal the fundamental molecular basis of naturally occurring light-gated anion conductance, and provide a framework for designing the next generation of optogenetic tools. The crystal structure of anion channelrhodopsin-1 (ACR1) from the algae Guillardia theta provides insights into the basis of anion conductance.

Interest in deciphering the fundamental mechanisms and processes of the human mind represents a central driving force in modern neuroscience research. Activities in support of this goal rely on advanced methodologies and engineering systems that are capable of interrogating and stimulating neural pathways, from single cells in small networks to interconnections that span the entire brain. Recent research establishes the foundations for a broad range of creative neurotechnologies that enable unique modes of operation in this context. This review focuses on those systems with proven utility in animal model studies and with levels of technical maturity that suggest a potential for broad deployment to the neuroscience community in the relatively near future. We include a brief summary of existing and emerging neuroscience techniques, as background for a primary focus on device technologies that address associated opportunities in electrical, optical and microfluidic neural interfaces, some with multimodal capabilities. Examples of the use of these technologies in recent neuroscience studies illustrate their practical value. The vibrancy of the engineering science associated with these platforms, the interdisciplinary nature of this field of research and its relevance to grand challenges in the treatment of neurological disorders motivate continued growth of this area of study.This review summarizes advances in electrical, optical and microfluidic neural interfaces with characteristics that suggest near-term potential for broad deployment to the neuroscience community.

Light-controllable tools provide powerful means to manipulate and interrogate brain function with relatively low invasiveness and high spatiotemporal precision. Although optogenetic approaches permit neuronal excitation or inhibition at the network level, other technologies, such as optopharmacology (also known as photopharmacology) have emerged that provide molecular-level control by endowing light sensitivity to endogenous biomolecules. In this Review, we discuss the challenges and opportunities of photocontrolling native neuronal signalling pathways, focusing on ion channels and neurotransmitter receptors. We describe existing strategies for rendering receptors and channels light sensitive and provide an overview of the neuroscientific insights gained from such approaches. At the crossroads of chemistry, protein engineering and neuroscience, optopharmacology offers great potential for understanding the molecular basis of brain function and behaviour, with promises for future therapeutics.

The optogenetic revolution is transforming neuroscience. The dramatic recent progress in using light to both control and read out neural activity has highlighted the need for better probes, improved light delivery and more careful interpretation of results, which will all be required for optogenetics to fully realize its remarkable potential.

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.

Inherited retinal degenerations (IRDs) are a diverse group of conditions that are often characterized by the loss of photoreceptors and blindness. Recent innovations in molecular biology and genomics have allowed us to identify the causative defects behind these dystrophies and to design therapeutics that target specific mechanisms of retinal disease. Recently, the FDA approved the first in vivo gene therapy for one of these hereditary blinding conditions. Current clinical trials are exploring new therapies that could provide treatment for a growing number of retinal dystrophies. While the field has had early success with gene augmentation strategies for treating retinal disease based on loss-of-function mutations, many novel approaches hold the promise of offering therapies that span the full spectrum of causative mutations and mechanisms. Here, we provide a comprehensive review of the approaches currently in development including a discussion of retinal neuroprotection, gene therapies (gene augmentation, gene editing, RNA modification, optogenetics), and regenerative stem or precursor cell-based therapies. Our review focuses on technologies that are being developed for clinical translation or are in active clinical trials and discusses the advantages and limitations for each approach.

Key Points Optogenetics uses light and genetics to manipulate and monitor the activities of defined cell populations, and this technique has transformed basic neuroscience research. Optogenetic tools are genetically encoded proteins designed to manipulate and monitor neuronal circuits, and there are two types of proteins used: actuators (proteins that transduce light into neuronal signals for manipulation) and indicators (proteins that transduce neuronal signals into optical signals for monitoring). An optogenetic approach involves light-based (optical) interventions and/or recordings of natural neural activity to elucidate the role of specified neuronal circuit elements in mammalian behaviour. Numerous cognitive and emotional functions have already been studied using optogenetic approaches, including sensory perception, pain, decision-making, preference and avoidance, social interactions, and feeding behaviour; optogenetics has also been used in animal models of neuropsychiatric conditions. Animal models for optogenetically induced disease states may facilitate the evaluation of drug candidates. Optogenetics paves the way to novel therapeutic approaches in which chemistry is replaced by micro-optoelectronics and genetic modification of specific cells and in which modulation of specific neuronal circuits is the central mechanism of action. Optogenetics has already had a major impact on neuroscience research, particularly in the study of cognitive and emotional processes. Here, Song and Knöpfel discuss emerging applications of optogenetic technologies, focusing on their potential to transform neuroscience drug discovery programmes and to provide novel therapeutic approaches for conditions such as Parkinson disease, mood disorders and epilepsy. Optogenetics — the use of light and genetics to manipulate and monitor the activities of defined cell populations — has already had a transformative impact on basic neuroscience research. Now, the conceptual and methodological advances associated with optogenetic approaches are providing fresh momentum to neuroscience drug discovery, particularly in areas that are stalled on the concept of 'fixing the brain chemistry'. Optogenetics is beginning to translate and transit into drug discovery in several key domains, including target discovery, high-throughput screening and novel therapeutic approaches to disease states. Here, we discuss the exciting potential of optogenetic technologies to transform neuroscience drug discovery.