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PdCO is a switchable optogenetic tool for inhibiting synaptic transmission in neuronal terminals in vivo, as demonstrated in a variety of contexts mainly in the mouse.

The basal ganglia direct and indirect pathways are classically described as anatomically segregated and functionally opposing. Here the authors describe a non-canonical direct pathway made of axon collaterals to the globus pallidus that promotes motor action.

Whether the posterior medial (POm) thalamic nucleus processes whisking kinematics was not clear from studies in head-fixed rodents. By studying freely moving mice, here authors demonstrate that the POm does encode whisker kinematics. Additionally, they show that both POm and the ventroposterior medial (VPM) thalamic nuclei process and can influence head kinematics.

Little is known about the synaptic organization of associative cortical structures such as the medial prefrontal cortex. Here, the authors use two-photon optogenetic stimulation to obtain a detailed cellular resolution map of functional synaptic connectivity of the mouse medial prefrontal cortex, finding unique spatial patterns of local-circuit connectivity in neurons that project to the basolateral amygdala.

The thalamus provides sensory input to the cortex, but many aspects of thalamocortical signaling remain unknown. Here, the authors reveal parallel non-overlapping thalamic pathways with distinct representations of tactile and decision-related information during a goal-directed sensorimotor task.

Georgakopoulos-Soares, Yizhar-Barnea, Mouratidis et al. identify neomers, short (16 base pair) DNA sequences that are absent in the genomes of healthy individuals but appear in tumors due to mutations. They show that neomers can accurately detect cancer from cell-free DNA and that neomers found in gene regulatory elements can alter regulatory activity.

This Perspective discusses the challenges involved in translating optogenetic research into clinical practice, including clinical and pragmatic choices, potential toxicity and immune responses, regulatory issues and ethical considerations.

Current optogenetic inhibition methods like light-controlled ion pumps require high-intensity light and disrupt physiological ion gradients. Here, the authors somatically target the anion-conducting opsin GtACR to eliminate spiking in distal axons and improve photocurrents, thus enhancing its utility.

Fear-related disorders are thought to reflect strong and persistent fear associations. The authors show that optogenetic high-frequency stimulation of direct amygdala inputs to the prefrontal cortex can destabilize fear memories and facilitate the extinction of previously acquired fear associations.

This study shows that mouse prefrontal neurons differentially categorize social and nonsocial olfactory cues. Social cue representations are refined with experience and are disrupted in a mouse model of autism with elevated cortical noise.

Interneurons defined by the fast-spiking phenotype and expression of the calcium-binding protein parvalbumin are thought to be involved in gamma oscillations. Here, optogenetic technology is used in mice to selectively modulate parvalbumin interneurons in vivo, revealing that inhibition of these interneurons suppresses gamma oscillations, whereas driving them is sufficient to generate emergent gamma-frequency rhythmicity.

Humans and animals can react to the affective state of others in distress. However, exposure to a stressed partner can trigger stress-related adaptations. Two studies shed light on the mechanisms underlying the behavioral responses toward stressed individuals and on the synaptic changes associated with social transmission of stress.

Optogenetic inhibition of specific axonal projections is a potentially powerful technique for assessing defined neural pathways’ contributions to behavior. The authors report that while optogenetic inhibition can efficiently attenuate presynaptic release, it can under some conditions lead to undesired effects such as depolarization and increased spontaneous release.

Sexual dimorphism in neuronal circuits is proposed to underlie sex differences in behaviour, such as virgin female mice acting maternally toward alien pups, while males ignore or attack them; here the authors show that specific tyrosine hydroxylase-expressing neurons in the hypothalamus are more numerous in mothers than in virgin females and males, and that they control parental behaviour in a sex-specific manner.

Channelrhodopsins such as ChR2 can drive spiking with millisecond precision. However, when ChR2 is highly expressed, a single light pulse can produce extra spikes, and ChR2 does not allow sustained spike trains above about 40 Hz. Rapid ChR2-driven spike trains can also cause plateau potentials. Here, the authors report an engineered opsin gene, ChETA, that overcomes these limitations and allows sustained spike trains up to 200 Hz.

Iron sulfide nanoclusters enable on-demand and local generation of nitric oxide, an important lipophilic messenger in the brain, allowing the modulation and investigation of nitric oxide-triggered neural signalling events.

Fasting-activated hypothalamic AgRP-expressing neurons trigger fasting-induced hypothalamic–pituitary–adrenal axis activation through projections to the paraventricular hypothalamus, where they activate CRH neurons by presynaptically inhibiting the terminals of tonically active GABAergic afferents from the bed nucleus of the stria terminalis.

Transgenic expression of microbial channelrhodopsins in neurons allows direct light activation of ionic currents. Here, the authors describe a modified channelrhodopsin that remains open for seconds once it is activated by light and can be 'switched off' by a second light flash, thereby obviating the need for constant illumination during an experiment.

Functional and structural characterization of rhodopsin-bestrophin fusion proteins from marine algae unveils the existence of giant light-sensitive anion channels with unusual biophysical properties.

The authors describe a thalamic population, innervated by multimodal brainstem inputs, that forms a CS–US association prior to the lateral amygdala. Its fast and plastic signal defines an amygdala activity pattern necessary for adaptive fear learning.

Scheggia et al. show that a specific subpopulation of cortical neurons expressing somatostatin in the prefrontal cortex has a primary role in orchestrating the ability of mice to discriminate positive and negative affective states in others.

Channelrhodopsins are light-gated cation channels used in optogenetics; here, the high-resolution crystal structure of a channelrhodopsin from Chlamydomonas reinhardtii is determined.

Social encounters are associated with varying degrees of stress. The authors show that modulation of stress system components in the medial amygdala alters preference for familiar vs. novel conspecifics. Inhibition of the relevant circuit in a group of familiar mice kept under semi-natural conditions increased pro-social behavior.

Using optogenetic tools, Carter et al. find a frequency-dependent causal relationship between locus coeruleus firing, sleep-to-wake transitions and locomotor arousal in mice.

The sensory thalamus gets cortical input that drives feed-forward inhibition of thalamocortical cells (TC) via reticular thalamic nucleus (nRT) neurons during oscillations. Using genetically modified mice, the authors find that oscillations can still be initiated by cortical inputs via a cortico-TC-nRT-TC pathway when there is a specific reduction in the strength of the cortico-nRT-TC pathway.

This Review provides a comprehensive overview of presynaptic applications of optogenetic tools, including the associated challenges, current limitations and future directions for this approach.

Here the authors describe a set of new optogenetic tools for use in primates that are meant to address the unique constraints of working with this species. They characterize opsin expression, the reliability of optogenetic stimulation and its effect on behavior, and methods for determining localization and expression levels prior to the completion of experiments.

In this Analysis, the authors directly experimentally compare microbial opsins used for the control of neural activity. They extract essential principles and key parameters that can help end users with the design and interpretation of optogenetic experiments and guide tool developers in the characterization of future tools.

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.

Optogenetic techniques involve the introduction of photoreceptors into selected cells to allow control over their activity using light. In this Primer, Emiliani et al. discuss the most commonly used optogenetic tools, illumination approaches and applications in medicine, cardiovascular science and plants, among many other uses.