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Newly emerging techniques will revolutionize our understanding of the mammalian brain. Deisseroth and colleagues detail the development and use of microbial opsins as optogenetic tools for the study of neural circuits and discuss the use of these tools as potential future therapies for neurological disorders.

High-resolution imaging has traditionally required thin sectioning, a process that disrupts long-range connectivity in the case of brains: here, intact mouse brains and human brain samples have been made fully transparent and macromolecule permeable using a new method termed CLARITY, which allows for intact-tissue imaging as well as repeated antibody labelling and in situ hybridization of non-sectioned tissue.

Different subregions of the bed nucleus of the stria terminalis are shown to increase and decrease anxiety in mice, and distinct neural projections arising from a single coordinating brain region modulate different anxiety features.

Ion channels driven by light have provided electrophysiologists with unprecedented control over the activity state of neurons; here Deisseroth and colleagues introduce new molecules that offer a similar level of control over signalling pathways to biochemists. Opsin/GPCR chimaeras were engineered, enabling the authors to modulate G-protein activity via light, which in turn could influence neuronal firing; activating these molecules expressed in vivo could drive conditioned place preference in behaving mice

Optogenetic induction of phasic, but not tonic, firing in VTA dopamine neurons induces susceptibility to stress in mice undergoing a subthreshold social-defeat paradigm and in previously resilient mice that have been subjected to repeated social-defeat stress, and this effect is projection-pathway specific.

Specific manipulation of midbrain dopamine neurons in freely moving rodents shows that their inhibition or excitation immediately modulates depression-like phenotypes that are induced by chronic mild stress, and that their activation alters the neural encoding of depression-related behaviours in the nucleus accumbens.

The neural mechanisms underlying ketamine-induced altered states of consciousness are not well understood. Here, the authors show that depersonalization and dissociative amnesia related to ketamine have opposing effects on the activity of the right anterior insula in response to social threat.

Increased activity of dopamine receptor type-2 (D2R)-expressing cells in the nucleus accumbens of rats during a ‘decision’ period reflects a ‘loss’ outcome of the previous decision and predicts a subsequent safe choice; by artificially increasing the activity of D2R neurons during the decision period, risk-seeking rats could be converted to risk-avoiding rats.

Conventional behavioural mouse models of depression are often used to study the disorder, but cannot capture the full picture of the human disease. Here, scientists present two views about the best research strategies to adopt if treatments are to be improved.

Here, a sparse neuronal projection from a part of the prefrontal cortex, the anterior cingulate, to the hippocampus is identified that, when activated, can elicit memory retrieval in mice.

Activation of the ventral medial prefrontal cortex–basomedial amygdala pathway is shown to suppress anxiety and fear-related freezing in mice, thus identifying the basomedial amygdala (and not intercalated cells, as posited by earlier models) as a novel target of top-down control.

How the numerous neuron subpopulations in the lateral (CeL) and medial (CeM) subdivisions of the central amygdala regulate appetitive behavior is poorly understood. Here, the authors report that appetitive neurons are confined to the CeM with separate subpopulations driving water only, versus water or food consumption.

Gao et al. provide evidence that two major classes of neurons exist in the paraventricular thalamus. One of these, termed type II PVT neurons, belongs to a previously ignored cell population that relays arousal information to the infralimbic cortex.

Huang and colleagues functionally map a brain circuit connecting the amygdala and the spinal cord that is altered after nerve injury and contributes to chronic pain.

The ACE pipeline utilized deep learning and advanced statistics for mapping neural activity at a granular level that is independent of atlas-defined regions.

Through the use of a combination of state-of-the-art techniques, different populations of ventral tegmental area dopamine neurons in the mouse are shown to form separate circuits with distinct connectivity: neurons receiving input from the laterodorsal tegmentum and lateral habenula are found to mediate reward and aversion, respectively.

Duncan and colleagues link specific human brain cell types to schizophrenia and other complex brain phenotypes, providing mechanistic insights and a cellular taxonomy for psychiatric disorders.

Natural or artificially induced electrical activity changes can alter ion balance so as to briefly influence firing. An optogenetics study delineates one mechanism: Cl⁻ shifts causing seconds-long excitability changes after silencing.

Coordinated gamma oscillations in the lateral hypothalamus, lateral septum and medial prefrontal cortex are shown to drive food-seeking behaviour in mice independently of nutritional need and to organize firing of feeding behaviour-related hypothalamic neurons.

The authors show that choice information is relayed from the ventrolateral orbitofrontal cortex to the dorsomedial striatum to lead accurate economic decision-making.

Optogenetics enables the precise and targeted manipulation of the activity of specific neurons and is a powerful tool for the dissection of neural circuits. Tye and Deisseroth describe the latest refinements in optogenetic technology and show how this approach is being used to investigate the circuits involved in psychiatric and neurological disorders.

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.

A clinical trial inspired and guided by optogenetics experiments in rodents reports the outcome of targeted transcranial magnetic stimulation in patients suffering from cocaine addiction.

Surface two-photon imaging of the brain cannot access somatic calcium signals of neurons from deep layers of the macaque cortex. Here, the authors present an implant and imaging system for chronic motion-stabilized two-photon imaging of dendritic calcium signals to drive an optical brain-computer interface in macaques.

A genetically encoded voltage indicator enables robust optical recording of membrane voltage changes in the fly brain.

In vertebrate vision, the two types of photoreceptors, rods and cones, operate under low and bright light intensities, respectively. Here the authors show that under bright light conditions, when rods are not sensing light, they act as relay cells for cone-driven surround inhibition.

Optogenetics is widely used to study the consequences of neuronal activity with high spatiotemporal precision. In this Review, Kimet al. discuss the integration of this approach with other technological and methodological advances to gain insights into neuronal function that were previously inaccessible.

Human stem cell-derived cortical organoids transplanted into rats mature and integrate into sensory and motivation circuits to influence behaviour.

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.

Studies in mice show that observational fear learning is encoded by neurons in the dorsomedial prefrontal cortex in a manner that is distinct from the encoding of fear learned by direct experience.

Lovett-Barron et al. register in situ gene expression to cellular-level neural dynamics in behaving zebrafish and find threat-selective populations spanning multiple hypothalamic peptidergic neuron classes, which converge on brainstem defensive action premotor neurons.

Frame-projected independent-fiber photometry (FIP) enables the concurrent monitoring and manipulation of neural activity at multiple sites in the brains of freely behaving mice.

Blood oxygenation level-dependent (BOLD) signals are the basis for much of the work on which regions of the human brain are active during particular tasks or behaviours, but there is controversy over their source and interpretation. Here a combination of optogenetics and BOLD signal monitoring shows that specific excitatory neurons within a mixed population are sufficient to produce positive BOLD signals, and could be used to map connections.

High-speed tracking of effortful responses and neuronal activity in rats during a forced swim test identifies medial prefrontal cortex (mPFC) neurons that respond during escape-related swimming but not normal locomotion, and optogenetics shows that mPFC neurons projecting to the brainstem dorsal raphe nucleus, which is implicated in depression, modulate this behavioural response to challenge

Using hemisphere-specific optogenetic activation of hippocampal fibers, this study finds that the magnitude of long-term potentiation in CA1 neurons depends on whether afferents originate in left or right CA3.

The amygdala, a brain region important for learning fearful memories, is thought to have a role in generalized anxiety, but the critical subregions and connections are unknown. This paper shows that optogenetic stimulation of basolateral amygdala (BLA) terminals in the central nucleus of the amygdala of rats with channelrhodopsin has an anxiolytic effect, whereas inhibition of the same projection with eNpHR3.0 increases anxiety related behaviours. These effects were not observed with direct optogenetic control of BLA somata themselves, indicating that selective activation of certain connections can have different effects.

From a therapeutic standpoint, one of the main drawbacks of artificial electrical stimulation of muscle is that large, fatigable motor units are recruited before smaller units, which is opposite to the normal physiological recruitment pattern. Researchers from Stanford University have circumvented this problem by stimulating muscle optically rather than electrically, providing enhanced functional performance and potential applications for the technique in neuromuscular physiology, neuroprosthetics and neurorehabilitation.