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After entering the cerebral cortex, sensory information spreads through six different horizontal neuronal layers that are interconnected by vertical axonal projections. It is believed that through these projections layers can influence each other's response to sensory stimuli, but the specific role that each layer has in cortical processing is still poorly understood. Here we show that layer six in the primary visual cortex of the mouse has a crucial role in controlling the gain of visually evoked activity in neurons of the upper layers without changing their tuning to orientation. This gain modulation results from the coordinated action of layer six intracortical projections to superficial layers and deep projections to the thalamus, with a substantial role of the intracortical circuit. This study establishes layer six as a major mediator of cortical gain modulation and suggests that it could be a node through which convergent inputs from several brain areas can regulate the earliest steps of cortical visual processing. Layer six in the mouse primary visual cortex is a major mediator of cortical gain modulation and may be a node through which convergent inputs from several brain areas can regulate the earliest steps of cortical visual processing. Visual processing stacks up The cerebral cortex, which is responsible for perception and other cognitive functions, is composed of multiple distinct layers of cells. Little is known about how individual layers function, but here, Massimo Scanziani and colleagues establish the role of a specific cortical layer in sensory processing. Using optogenetics to selectively drive or suppress layer-six neurons in the mouse visual cortex — a previously impossible manipulation — the authors show that the neurons modulate the size of the response of upper-layer neurons to visual stimuli without changing their selectivity. The authors conclude that layer six plays a part in controlling the gain of visual cortical processing by interacting with other neurons in both the cortex and the thalamus.

Animal behaviour arises from computations in neuronal circuits, but our understanding of these computations has been frustrated by the lack of detailed synaptic connection maps, or connectomes. For example, despite intensive investigations over half a century, the neuronal implementation of local motion detection in the insect visual system remains elusive. Here we develop a semi-automated pipeline using electron microscopy to reconstruct a connectome, containing 379 neurons and 8,637 chemical synaptic contacts, within the Drosophila optic medulla. By matching reconstructed neurons to examples from light microscopy, we assigned neurons to cell types and assembled a connectome of the repeating module of the medulla. Within this module, we identified cell types constituting a motion detection circuit, and showed that the connections onto individual motion-sensitive neurons in this circuit were consistent with their direction selectivity. Our results identify cellular targets for future functional investigations, and demonstrate that connectomes can provide key insights into neuronal computations. Reconstruction of a connectome within the fruitfly visual medulla, containing more than 300 neurons and over 8,000 chemical synapses, reveals a candidate motion detection circuit; such a circuit operates by combining displaced visual inputs, an operation consistent with correlation based motion detection. Visual system connectomics — from insects to mammals Three papers in this issue of Nature use the retina as a model for mapping neuronal circuits from the level of individual synaptic contacts to the long-range scale of dendritic interactions. Helmstaedter et al . used electron microscopy to map a mammalian retinal circuit of close to a thousand neurons. The work reveals a new type of retinal bipolar neuron and suggests functional mechanisms for known visual computations. The other two groups study the detection of visual motion in the Drosophila visual system — a classic neural computation model. Takemura et al . used semi-automated electron microscopy to reconstruct the basic connectome (8,637 chemical synapses among 379 neurons) of Drosophila 's optic medulla. Their results reveal a candidate motion detection circuit with a wiring plan consistent with direction selectivity. Maisak et al . used calcium imaging to show that T4 and T5 neurons are divided into specific subpopulations responding to motion in four cardinal directions, and are specific to 'ON' versus 'OFF' edges, respectively.

Fluorescent calcium sensors are widely used to image neural activity. Using structure-based mutagenesis and neuron-based screening, we developed a family of ultrasensitive protein calcium sensors (GCaMP6) that outperformed other sensors in cultured neurons and in zebrafish, flies and mice in vivo . In layer 2/3 pyramidal neurons of the mouse visual cortex, GCaMP6 reliably detected single action potentials in neuronal somata and orientation-tuned synaptic calcium transients in individual dendritic spines. The orientation tuning of structurally persistent spines was largely stable over timescales of weeks. Orientation tuning averaged across spine populations predicted the tuning of their parent cell. Although the somata of GABAergic neurons showed little orientation tuning, their dendrites included highly tuned dendritic segments (5–40-µm long). GCaMP6 sensors thus provide new windows into the organization and dynamics of neural circuits over multiple spatial and temporal scales. Sensitive protein sensors of calcium have been created; these new tools are shown to report neural activity in cultured neurons, flies and zebrafish and can detect single action potentials and synaptic activation in the mouse visual cortex in vivo . A new sensor for neural activity Genetically encoded calcium sensors have brought neuronal recording to the tiny brains of invertebrates, but the methodology has lagged behind classical electrophysiology in vertebrates. Now Douglas Kim and colleagues have used selective mutagenesis to engineer a new ultrasensitive probe, GCaMP6, demonstrating improved spatial and temporal resolution in vivo , from flies to zebrafish. In addition, in mouse visual cortex GCaMP6 can reliably detect single action potentials and single-spine orientation tuning. GCaMP6 sensors can be used to image large groups of neurons as well as tiny synaptic compartments over multiple imaging sessions separated by months, offering a flexible new tool for brain research and calcium signalling studies.

The response of cortical neurons to a sensory stimulus is modulated by the context. In the visual cortex, for example, stimulation of a pyramidal cell's receptive-field surround can attenuate the cell’s response to a stimulus in the centre of its receptive field, a phenomenon called surround suppression. Whether cortical circuits contribute to surround suppression or whether the phenomenon is entirely relayed from earlier stages of visual processing is debated. Here we show that, in contrast to pyramidal cells, the response of somatostatin-expressing inhibitory neurons (SOMs) in the superficial layers of the mouse visual cortex increases with stimulation of the receptive-field surround. This difference results from the preferential excitation of SOMs by horizontal cortical axons. By perturbing the activity of SOMs, we show that these neurons contribute to pyramidal cells' surround suppression. These results establish a cortical circuit for surround suppression and attribute a particular function to a genetically defined type of inhibitory neuron. The activity of somatostatin-expressing inhibitory neurons (SOMs) in the superficial layers of the mouse visual cortex increases with stimulation of the receptive-field surround, thereby contributing to the surround suppression of pyramidal cells. Role of specific inhibitory neurons in visual perception The neurons of the primary visual cortex respond preferentially to stimuli of particular spatial size and are suppressed when stimuli are larger than their receptive fields. This form of modulation of neural response by contextual information is thought to underlie many perceptual phenomena, but the source of the suppression is not well understood. These authors report the identification of a circuit in the mouse visual cortex that contributes to surround suppression through a mechanism involving somatostatin-expressing interneurons.

Optogenetic activation of parvalbumin-expressing versus other classes of interneurons is found to have distinct effects on the response properties of individual and populations of excitatory cells, as well as on visual behaviour in awake mice, providing evidence that this specific interneuron subtype has a unique role in visual coding and perception. Class distinction in cortical interneurons Cortical networks consist of a range of neuronal cells, including multiple classes of inhibitory interneurons. Intracortical inhibition is essential for normal brain function, but little is known about the specific roles of the neuronal subtypes. Two independent papers from the groups of Mriganka Sur and Yang Dan explore the functional consequences of activating different classes of interneurons in the mouse visual cortex. Using a variety of techniques, both papers demonstrate that activating parvalbumin-expressing versus other classes of interneurons has distinct effects on the response properties of individual excitatory cells, as well as on populations of these cells. The paper from Dan's group also finds effects on visual behaviour in awake mice. Inhibitory interneurons are essential components of the neural circuits underlying various brain functions. In the neocortex, a large diversity of GABA (γ-aminobutyric acid) interneurons has been identified on the basis of their morphology, molecular markers, biophysical properties and innervation pattern 1 , 2 , 3 . However, how the activity of each subtype of interneurons contributes to sensory processing remains unclear. Here we show that optogenetic activation of parvalbumin-positive (PV + ) interneurons in the mouse primary visual cortex (V1) sharpens neuronal feature selectivity and improves perceptual discrimination. Using multichannel recording with silicon probes 4 , 5 and channelrhodopsin-2 (ChR2)-mediated optical activation 6 , we found that increased spiking of PV + interneurons markedly sharpened orientation tuning and enhanced direction selectivity of nearby neurons. These effects were caused by the activation of inhibitory neurons rather than a decreased spiking of excitatory neurons, as archaerhodopsin-3 (Arch)-mediated optical silencing 7 of calcium/calmodulin-dependent protein kinase IIα (CAMKIIα)-positive excitatory neurons caused no significant change in V1 stimulus selectivity. Moreover, the improved selectivity specifically required PV + neuron activation, as activating somatostatin or vasointestinal peptide interneurons had no significant effect. Notably, PV + neuron activation in awake mice caused a significant improvement in their orientation discrimination, mirroring the sharpened V1 orientation tuning. Together, these results provide the first demonstration that visual coding and perception can be improved by increased spiking of a specific subtype of cortical inhibitory interneurons.

Selective attention mechanisms route behaviorally relevant information through large-scale cortical networks. Although evidence suggests that populations of cortical neurons synchronize their activity to preferentially transmit information about attentional priorities, it is unclear how cortical synchrony across a network is accomplished. Based on its anatomical connectivity with the cortex, we hypothesized that the pulvinar, a thalamic nucleus, regulates cortical synchrony. We mapped pulvino-cortical networks within the visual system, using diffusion tensor imaging, and simultaneously recorded spikes and field potentials from these interconnected network sites in monkeys performing a visuospatial attention task. The pulvinar synchronized activity between interconnected cortical areas according to attentional allocation, suggesting a critical role for the thalamus not only in attentional selection but more generally in regulating information transmission across the visual cortex.

It is controversial whether the adult primate early visual cortex is sufficiently plastic to cause visual perceptual learning (VPL). The controversy occurs partially because most VPL studies have examined correlations between behavioral and neural activity changes rather than cause-and-effect relationships. With an online-feedback method that uses decoded functional magnetic resonance imaging (fMRI) signals, we induced activity patterns only in early visual cortex corresponding to an orientation without stimulus presentation or participants' awareness of what was to be learned. The induced activation caused VPL specific to the orientation. These results suggest that early visual areas are so plastic that mere inductions of activity patterns are sufficient to cause VPL. This technique can induce plasticity in a highly selective manner, potentially leading to powerful training and rehabilitative protocols.

The blindsight pathway The primary visual cortex (V1) is crucial for vision, but nearly 40 years ago it was noted that, intriguingly, human patients with V1 injuries can still point to or avoid visual stimuli despite having no conscious perception of them. It has long been thought that this 'blindsight' relies on visual pathways that bypass the usual route from the lateral geniculate nucleus (LGN) to the V1. Using a combination of permanent and reversible lesions, along with behavioural testing and functional magnetic resonance imaging (fMRI) of multiple visual areas in macaques, Schmid et al . show that the LGN itself is a vital link in the 'alternate pathway'. In V1-lesioned animals, LGN inactivation abolishes both visual detection and fMRI activation in higher visual areas, implicating direct LGN projections not only in blindsight, but also as a viable secondary pathway for fast detection during normal vision. The primary visual cortex (V1) is crucial for vision, yet people with V1 injuries might still point to or avoid visual stimuli, despite having no conscious perception of them. It has been thought that this 'blindsight' relies on visual pathways that bypass the usual route from lateral geniculate nucleus (LGN) to V1. But it is shown here — using a combination of permanent and reversible lesions, behavioural testing and functional magnetic resonance imaging (fMRI) mapping — that a critical link in the alternative pathway is in fact the LGN. Injury to the primary visual cortex (V1) leads to the loss of visual experience. Nonetheless, careful testing shows that certain visually guided behaviours can persist even in the absence of visual awareness 1 , 2 , 3 , 4 . The neural circuits supporting this phenomenon, which is often termed blindsight, remain uncertain 4 . Here we demonstrate that the thalamic lateral geniculate nucleus (LGN) has a causal role in V1-independent processing of visual information. By comparing functional magnetic resonance imaging (fMRI) and behavioural measures with and without temporary LGN inactivation, we assessed the contribution of the LGN to visual functions of macaque monkeys ( Macaca mulatta ) with chronic V1 lesions. Before LGN inactivation, high-contrast stimuli presented to the lesion-affected visual field (scotoma) produced significant V1-independent fMRI activation in the extrastriate cortical areas V2, V3, V4, V5/middle temporal (MT), fundus of the superior temporal sulcus (FST) and lateral intraparietal area (LIP) and the animals correctly located the stimuli in a detection task. However, following reversible inactivation of the LGN in the V1-lesioned hemisphere, fMRI responses and behavioural detection were abolished. These results demonstrate that direct LGN projections to the extrastriate cortex have a critical functional contribution to blindsight. They suggest a viable pathway to mediate fast detection during normal vision.

The role of parvalbumin (PV)-positive interneurons in ocular dominance plasticity (ODP) has been a point of contention; here PV-positive cells are shown to initiate competitive periods of plasticity during the critical periods of eye development when ODP occurs, and transient reductions in inhibitory firing from PV-positive cells provides a return to normal firing rates in excitatory neurons, a key step in ODP progression. Influence of sensory experience on cortical microcircuitry It has long been known that early sensory experience can significantly affect the development and maturation of neural circuitry. One well-studied example of this is ocular dominance plasticity (ODP), in which loss of vision in one eye results in a reduction of cortical responsiveness to that eye. The mechanisms underlying the manifestation of ODP and the roles of inhibitory neurons in its expression have been a point of contention. Kuhlman et al . now show that parvalbumin-positive (PV + ) interneurons initiate competitive periods of plasticity during the critical periods of development when ODP occurs. Transient reductions in inhibitory firing from PV + cells provides for a return to normal firing rates in excitatory neurons, a key step in the progression of ODP in the adolescent cortex. Early sensory experience instructs the maturation of neural circuitry in the cortex 1 , 2 . This has been studied extensively in the primary visual cortex, in which loss of vision to one eye permanently degrades cortical responsiveness to that eye 3 , 4 , a phenomenon known as ocular dominance plasticity (ODP). Cortical inhibition mediates this process 4 , 5 , 6 , but the precise role of specific classes of inhibitory neurons in ODP is controversial. Here we report that evoked firing rates of binocular excitatory neurons in the primary visual cortex immediately drop by half when vision is restricted to one eye, but gradually return to normal over the following twenty-four hours, despite the fact that vision remains restricted to one eye. This restoration of binocular-like excitatory firing rates after monocular deprivation results from a rapid, although transient, reduction in the firing rates of fast-spiking, parvalbumin-positive (PV) interneurons, which in turn can be attributed to a decrease in local excitatory circuit input onto PV interneurons. This reduction in PV-cell-evoked responses after monocular lid suture is restricted to the critical period for ODP and appears to be necessary for subsequent shifts in excitatory ODP. Pharmacologically enhancing inhibition at the time of sight deprivation blocks ODP and, conversely, pharmacogenetic reduction of PV cell firing rates can extend the critical period for ODP. These findings define the microcircuit changes initiating competitive plasticity during critical periods of cortical development. Moreover, they show that the restoration of evoked firing rates of layer 2/3 pyramidal neurons by PV-specific disinhibition is a key step in the progression of ODP.

Key Points Normalization computes a ratio between the response of an individual neuron and the summed activity of a pool of neurons. The normalization model was developed to explain responses in the primary visual cortex (V1), and has been seen to operate in a variety of other regions of the visual system: light adaptation in the retina, contrast normalization in the retina and lateral geniculate nucleus, and visual processing in higher visual cortical areas beyond V1. Normalization has also been proposed to be at the root of the modulatory effects of visual attention on neural responses in the visual cortex. Normalization is seen in multiple species and brain regions. These include olfactory processing and representation in the fruitfly antennal lobe, the encoding of value in the posterior parietal cortex, multisensory integration of visual motion and vestibular signals, and auditory processing in the primary auditory cortex. Different (feedforward and feedback) neural circuits and mechanisms might perform normalization, including presynaptic inhibition, shunting inhibition, synaptic depression, changes in the amplitude of ongoing activity and balanced amplification. The effects of normalization can be measured behaviourally. The computational benefits of normalization include maximizing sensitivity, providing invariance with respect to some stimulus dimensions at the expense of others, facilitating the decoding of a distributed neural representation, facilitating the discrimination among representations of different stimuli, providing max-pooling (winner-take-all competition) and reducing redundancy. Understanding canonical neural computations such as normalization may shed light on psychiatric, neurological and developmental disorders. Normalization computes a ratio between the response of an individual neuron and the summed activity of a pool of neurons. Here, the authors review the evidence that it serves as a canonical computation — one that is applied to processing different types of information in multiple brain regions in multiple species. There is increasing evidence that the brain relies on a set of canonical neural computations, repeating them across brain regions and modalities to apply similar operations to different problems. A promising candidate for such a computation is normalization, in which the responses of neurons are divided by a common factor that typically includes the summed activity of a pool of neurons. Normalization was developed to explain responses in the primary visual cortex and is now thought to operate throughout the visual system, and in many other sensory modalities and brain regions. Normalization may underlie operations such as the representation of odours, the modulatory effects of visual attention, the encoding of value and the integration of multisensory information. Its presence in such a diversity of neural systems in multiple species, from invertebrates to mammals, suggests that it serves as a canonical neural computation.