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On the anniversary of the Boyden et al. (2005) paper that introduced the use of channelrhodopsin in neurons, Nature Neuroscience asks selected members of the community to comment on the utility, impact and future of this important technique.

In the brain of fruit flies, the mushroom body achieves flexible learning by using interconnected short- and long-term memory units for dopamine-mediated integration of innate valences with learnt valences obtained through experience.

Use of a head-mounted miniature microscope in awake, behaving mice reveals that neural ensembles in the basal and lateral amygdala encode associations between conditioned and unconditioned stimuli in a way that matches models of supervised learning.

Learning new associations that reappraise the behavioral significance of previously irrelevant cues requires gamma-frequency synchronization between parvalbumin interneurons in the left and right prefrontal cortex.

A new microendoscopic method reveals that hippocampal dendritic spines in the CA1 region undergo a complete turnover in less than six weeks in adult mice; this contrasts with the much greater stability of synapses in the neocortex and provides a physical basis for the fact that episodic memories are only retained by the mouse hippocampus for a few weeks.

VARNAM is a red-shifted genetically encoded voltage sensor based on the Ace opsin. It is applied in Drosophila, mouse brain slices and behaving mice. It can be readily combined with blue-light-sensitive tools for dual-color applications.

The mouse neocortex supports sensory performance through transient increases in sensory coding redundancy, neural codes that are robust to cellular variability, and inter-area fluctuation modes that transmit sensory data and task responses in non-interfering channels.

Analgesia from the expectation of pain relief is mediated by rostral anterior cingulate cortex neurons that project to the pontine nucleus.

An integrated, miniature (1.9 g) fluorescence microscope containing light source, optics and sensor allows high-speed, wide field of view imaging of calcium spiking in hundreds of neurons in freely moving mice. The mass-producible portable microscope is also useful for a variety of fluorescence assays for which size, cost and portability can be concerns.

Neumüller and colleagues identify and characterize potent HER2 exon 20 insertion-selective inhibitors with efficacy, which preserve wild-type epidermal growth factor receptor signaling in preclinical models of non-small cell lung cancer in vivo.

A miniature epifluorescence microscope that can be carried by a freely-moving adult mouse allows cellular-level imaging of neuronal spiking or measurement of microcirculation during normal behavioral activities.

The authors use Ca²⁺ imaging in freely behaving mice to look at the long-term dynamics of CA1 hippocampal place codes. They find that, in a familiar environment, there is substantial change in the population of place-coding cells over time, but the ensembles of these cells are sufficiently stable to preserve an accurate spatial representation across weeks.

A microscopy system that enables simultaneous recording from hundreds of neurons in the mouse visual cortex reveals that the brain enhances its coding capacity by representing visual inputs in dimensions perpendicular to correlated noise.

Time-lapse imaging studies of more than a day in the fly brain have been infeasible until now. Here the authors present a laser microsurgery approach to create a permanent window in the fly cuticle to enable time-lapse imaging of neural architecture and dynamics for up to 10–50 days.

In mouse models of Parkinson’s disease and dyskinesia, striatal spiny projection neurons of the direct and indirect pathways have abnormal, imbalanced levels of spontaneous and locomotor-related activity, with the two different disease states characterized by opposite abnormalities.

A multi-beam two-photon microscope enables imaging of calcium activity or neurovascular dynamics in the brain with millisecond-scale temporal resolution.

A structure-based design allows the development of a potent PROTAC to degrade BAF ATPase subunits SMARCA2 and SMARCA4 via recruitment of E3 ubiquitin ligase VHL and induce cancer cell death.

Genetically encoded indicators of neuronal activity have diversified and improved in performance in recent years, becoming essential tools for neuroscientists. Lin and Schnitzer review indicators for pH, neurotransmitter, voltage and calcium, with an emphasis on quantifying key indicator attributes and relating them to their applications in neuroscience.

Development of the bright green and red fluorescent proteins, Clover and mRuby2, creates a fluorescence resonance energy transfer (FRET) pair with the highest Förster radius among existing ratiometric FRET pairs. Substitution of this pair for current FRET pairs in several existing sensors reliably and substantially improves sensor performance.

Using two-photon microendoscopy and genetically encoded calcium indicators the tuning properties of the first neural station of the gustatory system are explored; results reveal that ganglion neurons are matched to specific taste receptor cells, supporting a labelled line model of information transfer in the taste system.

Genetically encoded optical voltage sensors measure the electrical activity of various tissues with limited effectiveness, due to the sensors’ suboptimal performance metrics. Gong et al.create a sensor with increased brightness, fast kinetics and improved dynamic ranges when compared with previous sensors.

This paper describes the use of optical microendoscopy to visualize sarcomeres and their micron-scale motions in live mice and humans, revealing unanticipated local variations in sarcomere lengths. Imaging of human sarcomeres is expected to enable advances in biomechanical modelling, orthopedic therapeutics, and the understanding and treatment of neuromuscular disorders

A newly engineered infrared fluorescent protein will allow microscopists to peer more deeply into living animals.

A combination of gradient refractive index lenses with plano-convex lenses produces high-resolution microlenses with image quality similar to a conventional high quality microscope objective. The microlenses are capable of imaging dendritic spines on hippocampal neurons in live mice.

CA1 neurons encode an animal's position within the environment. Here the authors identified in hippocampal neuronal activity a detrimental type of noise that limits accuracy of spatial position, relative to body size.

Wang et al. demonstrate that the effects of aberrations and scattering caused by the mouse skull can be reduced with three-photon microscopy. Their approach allows structural and functional imaging of the brain through an intact skull.

By spinning around, the ATP synthase converts energy from electrochemical to chemical form for storage. A cunning assay reveals intricate details of the rotation.

The enzymes and pathway involved in the biosynthesis of coenzyme F₄₃₀ are identified, completing our understanding of how members of the cyclic modified tetrapyrrole family are constructed.

Natural selection has created many species in which individual survival rests on computations performed by the organism's own physiology.

Interactions with male and female intruders activated overlapping neuronal populations in the ventromedial hypothalamus of inexperienced adult male mice, and these ensembles gradually separated as the mice acquired social and sexual experience with conspecifics.

A sizable fraction of granule cells convey information about the expectation of reward, with different populations responding to reward delivery, anticipation and omission, with some responses evolving over time with learning.

Lecoq and colleagues introduce a two-photon microscope with two articulated arms that can image nearly any two brain regions, nearby or distant, simultaneously. They validate this new system by imaging calcium signals in two visual cortical areas in behaving mice, and find evidence suggesting activity fluctuations can propagate between cortical areas

Mice are trained to use a custom-made robotic manipulandum to enable study of motor learning. The device can be used in conjunction with neurophysiological and microscopy techniques that require head fixation.

Tony Ko and his colleagues introduce a fluorescence microendoscopy imaging approach for time-lapse studies of deep brain tissue previously inaccessible to conventional optical imaging techniques. It can be used to study the cellular effects of brain disease over weeks to months with comparable resolution to light microscopy. They use the approach to monitor individual hippocampal neurons, neuronal dendrites and blood vessels and to follow the process of glioma angiogenesis.

A collection of opsins for two-photon modulation of neuronal activity in vitro and in vivo is presented in this resource. The opsins have kinetic, expression and spectral properties ideally suited to typical raster-scanning two-photon microscopy. Also online, Packer et al. use the red-shifted opsin C1V1_T and simple raster-scanning illumination to stimulate individual spines and dendrites and map synaptic circuits.

In this technical report, St-Pierre and colleagues introduce a new genetically encoded voltage sensor called Accelerated Sensor of Action Potentials 1 (ASAP1), which consists of a circularly permuted GFP inserted in the extracellular voltage-sensing domain of a phosphatase. ASAP1 surpasses existing sensors in reliably detecting single action potentials and tracking subthreshold potentials and high-frequency spike trains.

A robotic system is described that uses machine vision guidance to pick, manipulate, inspect and dissect individual flies, enabling large-scale and automated approaches to the analysis of morphology, behavior and neural dynamics.

Memories are thought to be represented in the brain by the 'memory trace' — altered levels of activity in specific neurons and synapses in a neural network. In this Review, Silva and colleagues discuss emerging evidence that the neurons and synapses involved in encoding a particular memory are not random but are specifically 'allocated' based on complex molecular signatures that are determined by the recent activity history of the neuron.