Topography of contextual modulations mediated by short-range interactions in primary visual cortex.

Neurons in primary visual cortex (V1) respond differently to a simple visual element presented in isolation from when it is embedded within a complex image. This difference, a specific modulation by surrounding elements in the image, is mediated by short- and long-range connections within V1 and by feedback from other areas. Here we study the role of short-range connections in this process, and relate it to the layout of local inhomogeneities in the cortical maps of orientation and space. By measuring correlation between neuron pairs located in optically imaged maps of V1 orientation columns we show that the strength of local connections between cells is a graded function of lateral separation across cortex, largely radially symmetrical and relatively independent of orientation preferences. We then show the contextual influence of flanking visual elements on neuronal responses varies systematically with a neuron's position within the cortical orientation map. The strength of this contextual influence on a neuron can be predicted from a model of local connections based on simple overlap with particular features of the orientation map. This indicates that local intracortical circuitry could endow neurons with a graded specialization for processing angular visual features such as corners and T junctions, and this specialization could have its own functional cortical map, linked with the orientation map.     

Functional imaging with cellular resolution reveals precise micro-architecture in visual cortex

Neurons in the cerebral cortex are organized into anatomical columns, with ensembles of cells arranged from the surface to the white matter. Within a column, neurons often share functional properties, such as selectivity for stimulus orientation; columns with distinct properties, such as different preferred orientations, tile the cortical surface in orderly patterns. This functional architecture was discovered with the relatively sparse sampling of microelectrode recordings. Optical imaging of membrane voltage or metabolic activity elucidated the overall geometry of functional maps, but is averaged over many cells (resolution >100 microm). Consequently, the purity of functional domains and the precision of the borders between them could not be resolved. Here, we labelled thousands of neurons of the visual cortex with a calcium-sensitive indicator in vivo. We then imaged the activity of neuronal populations at single-cell resolution with two-photon microscopy up to a depth of 400 microm. In rat primary visual cortex, neurons had robust orientation selectivity but there was no discernible local structure; neighbouring neurons often responded to different orientations. In area 18 of cat visual cortex, functional maps were organized at a fine scale. Neurons with opposite preferences for stimulus direction were segregated with extraordinary spatial precision in three dimensions, with columnar borders one to two cells wide. These results indicate that cortical maps can be built with single-cell precision.     

Dynamic properties of neurons in cortical area MT in alert and anaesthetized macaque monkeys.

In order to see the world with high spatial acuity, an animal must sample the visual image with many detectors that restrict their analyses to extremely small regions of space. The visual cortex must then integrate the information from these localized receptive fields to obtain a more global picture of the surrounding environment. We studied this process in single neurons within the middle temporal visual area (MT) of macaques using stimuli that produced conflicting local and global information about stimulus motion. Neuronal responses in alert animals initially reflected predominantly the ambiguous local motion features, but gradually converged to an unambiguous global representation. When the same animals were anaesthetized, the integration of local motion signals was markedly impaired even though neuronal responses remained vigorous and directional tuning characteristics were intact. Our results suggest that anaesthesia preferentially affects the visual processing responsible for integrating local signals into a global visual representation.     

Entrained rhythmic activities of neuronal ensembles as perceptual memory of time interval

The ability to process temporal information is fundamental to sensory perception, cognitive processing and motor behaviour of all living organisms, from amoebae to humans. Neural circuit mechanisms based on neuronal and synaptic properties have been shown to process temporal information over the range of tens of microseconds to hundreds of milliseconds. How neural circuits process temporal information in the range of seconds to minutes is much less understood. Studies of working memory in monkeys and rats have shown that neurons in the prefrontal cortex, the parietal cortex and the thalamus exhibit ramping activities that linearly correlate with the lapse of time until the end of a specific time interval of several seconds that the animal is trained to memorize. Many organisms can also memorize the time interval of rhythmic sensory stimuli in the timescale of seconds and can coordinate motor behaviour accordingly, for example, by keeping the rhythm after exposure to the beat of music. Here we report a form of rhythmic activity among specific neuronal ensembles in the zebrafish optic tectum, which retains the memory of the time interval (in the order of seconds) of repetitive sensory stimuli for a duration of up to approximately 20 s. After repetitive visual conditioning stimulation (CS) of zebrafish larvae, we observed rhythmic post-CS activities among specific tectal neuronal ensembles, with a regular interval that closely matched the CS. Visuomotor behaviour of the zebrafish larvae also showed regular post-CS repetitions at the entrained time interval that correlated with rhythmic neuronal ensemble activities in the tectum. Thus, rhythmic activities among specific neuronal ensembles may act as an adjustable 'metronome' for time intervals in the order of seconds, and serve as a mechanism for the short-term perceptual memory of rhythmic sensory experience.     

Global and fine information coded by single neurons in the temporal visual cortex.

When we see a person's face, we can easily recognize their species, individual identity and emotional state. How does the brain represent such complex information? A substantial number of neurons in the macaque temporal cortex respond to faces. However, the neuronal mechanisms underlying the processing of complex information are not yet clear. Here we recorded the activity of single neurons in the temporal cortex of macaque monkeys while presenting visual stimuli consisting of geometric shapes, and monkey and human faces with various expressions. Information theory was used to investigate how well the neuronal responses could categorize the stimuli. We found that single neurons conveyed two different scales of facial information in their firing patterns, starting at different latencies. Global information, categorizing stimuli as monkey faces, human faces or shapes, was conveyed in the earliest part of the responses. Fine information about identity or expression was conveyed later, beginning on average 51 ms after global information. We speculate that global information could be used as a 'header' to prepare destination areas for receiving more detailed information.     

Long-term motor cortex plasticity induced by an electronic neural implant

It has been proposed that the efficacy of neuronal connections is strengthened when there is a persistent causal relationship between presynaptic and postsynaptic activity. Such activity-dependent plasticity may underlie the reorganization of cortical representations during learning, although direct in vivo evidence is lacking. Here we show that stable reorganization of motor output can be induced by an artificial connection between two sites in the motor cortex of freely behaving primates. An autonomously operating electronic implant used action potentials recorded on one electrode to trigger electrical stimuli delivered at another location. Over one or more days of continuous operation, the output evoked from the recording site shifted to resemble the output from the corresponding stimulation site, in a manner consistent with the potentiation of synaptic connections between the artificially synchronized populations of neurons. Changes persisted in some cases for more than one week, whereas the output from sites not incorporated in the connection was unaffected. This method for inducing functional reorganization in vivo by using physiologically derived stimulus trains may have practical application in neurorehabilitation after injury.     

Gain control by layer six in cortical circuits of vision

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.     

Network anatomy and in vivo physiology of visual cortical neurons

In the cerebral cortex, local circuits consist of tens of thousands of neurons, each of which makes thousands of synaptic connections. Perhaps the biggest impediment to understanding these networks is that we have no wiring diagrams of their interconnections. Even if we had a partial or complete wiring diagram, however, understanding the network would also require information about each neuron's function. Here we show that the relationship between structure and function can be studied in the cortex with a combination of in vivo physiology and network anatomy. We used two-photon calcium imaging to characterize a functional property--the preferred stimulus orientation--of a group of neurons in the mouse primary visual cortex. Large-scale electron microscopy of serial thin sections was then used to trace a portion of these neurons' local network. Consistent with a prediction from recent physiological experiments, inhibitory interneurons received convergent anatomical input from nearby excitatory neurons with a broad range of preferred orientations, although weak biases could not be rejected.     

Experience with moving visual stimuli drives the early development of cortical direction selectivity

The onset of vision occurs when neural circuits in the visual cortex are immature, lacking both the full complement of connections and the response selectivity that defines functional maturity. Direction-selective responses are particularly vulnerable to the effects of early visual deprivation, but it remains unclear how stimulus-driven neural activity guides the emergence of cortical direction selectivity. Here we report observations from a motion training protocol that allowed us to monitor the impact of experience on the development of direction-selective responses in visually naive ferrets. Using intrinsic signal imaging techniques, we found that training with a single axis of motion induced the rapid emergence of direction columns that were confined to cortical regions preferentially activated by the training stimulus. Using two-photon calcium imaging techniques, we found that single neurons in visually naive animals exhibited weak directional biases and lacked the strong local coherence in the spatial organization of direction preference that was evident in mature animals. Training with a moving stimulus, but not with a flashed stimulus, strengthened the direction-selective responses of individual neurons and preferentially reversed the direction biases of neurons that deviated from their neighbours. Both effects contributed to an increase in local coherence. We conclude that early experience with moving visual stimuli drives the rapid emergence of direction-selective responses in the visual cortex.     

Adaptive coding of visual information in neural populations

Our perception of the environment relies on the capacity of neural networks to adapt rapidly to changes in incoming stimuli. It is increasingly being realized that the neural code is adaptive, that is, sensory neurons change their responses and selectivity in a dynamic manner to match the changes in input stimuli. Understanding how rapid exposure, or adaptation, to a stimulus of fixed structure changes information processing by cortical networks is essential for understanding the relationship between sensory coding and behaviour. Physiological investigations of adaptation have contributed greatly to our understanding of how individual sensory neurons change their responses to influence stimulus coding, yet whether and how adaptation affects information coding in neural populations is unknown. Here we examine how brief adaptation (on the timescale of visual fixation) influences the structure of interneuronal correlations and the accuracy of population coding in the macaque (Macaca mulatta) primary visual cortex (V1). We find that brief adaptation to a stimulus of fixed structure reorganizes the distribution of correlations across the entire network by selectively reducing their mean and variability. The post-adaptation changes in neuronal correlations are associated with specific, stimulus-dependent changes in the efficiency of the population code, and are consistent with changes in perceptual performance after adaptation. Our results have implications beyond the predictions of current theories of sensory coding, suggesting that brief adaptation improves the accuracy of population coding to optimize neuronal performance during natural viewing.     

Cortical microstimulation influences perceptual judgements of motion direction

Neurons in the visual cortex respond selectively to perceptually salient features of the visual scene, such as the direction and speed of moving objects, the orientation of local contours, or the colour or relative depth of a visual pattern. It is commonly assumed that the brain constructs its percept of the visual scene from information encoded in the selective responses of such neurons. We have now tested this hypothesis directly by measuring the effect on psychophysical performance of modifying the firing rates of physiologically characterized neurons. We required rhesus monkeys to report the direction of motion in a visual display while we electrically stimulated clusters of directionally selective neurons in the middle temporal visual area (MT, or V5), an extrastriate area that plays a prominent role in the analysis of visual motion information. Microstimulation biased the animals' judgements towards the direction of motion encoded by the stimulated neurons. This result indicates that physiological properties measured at the neuronal level can be causally related to a specific aspect of perceptual performance.     

Guarding the gateway to cortex with attention in visual thalamus

The massive visual input from the eye to the brain requires selective processing of some visual information at the expense of other information, a process referred to as visual attention. Increases in the responses of visual neurons with attention have been extensively studied along the visual processing streams in monkey cerebral cortex, from primary visual areas to parietal and frontal cortex. Here we show, by recording neurons in attending macaque monkeys (Macaca mulatta), that attention modulates visual signals before they even reach cortex by increasing responses of both magnocellular and parvocellular neurons in the first relay between retina and cortex, the lateral geniculate nucleus (LGN). At the same time, attention decreases neuronal responses in the adjacent thalamic reticular nucleus (TRN). Crick argued for such modulation of the LGN by observing that it is inhibited by the TRN, and suggested that "if the thalamus is the gateway to the cortex, the reticular complex might be described as the guardian of the gateway", a reciprocal relationship we now show to be more than just hypothesis. The reciprocal modulation in LGN and TRN appears only during the initial visual response, but the modulation of LGN reappears later in the response, suggesting separate early and late sources of attentional modulation in LGN.     

Inhibitory feedback required for network oscillatory responses to communication but not prey stimuli

Stimulus-induced oscillations occur in visual, olfactory and somatosensory systems. Several experimental and theoretical studies have shown how such oscillations can be generated by inhibitory connections between neurons. But the effects of realistic spatiotemporal sensory input on oscillatory network dynamics and the overall functional roles of such oscillations in sensory processing are poorly understood. Weakly electric fish must detect electric field modulations produced by both prey (spatially localized) and communication (spatially diffuse) signals. Here we show, through in vivo recordings, that sensory pyramidal neurons in these animals produce an oscillatory response to communication-like stimuli, but not to prey-like stimuli. On the basis of well-characterized circuitry, we construct a network model of pyramidal neurons that predicts that diffuse delayed inhibitory feedback is required to achieve oscillatory behaviour only in response to communication-like stimuli. This prediction is experimentally verified by reversible blockade of feedback inhibition that removes oscillatory behaviour in the presence of communication-like stimuli. Our results show that a sensory system can use inhibitory feedback as a mechanism to 'toggle' between oscillatory and non-oscillatory firing states, each associated with a naturalistic stimulus.     

Functional mapping of single spines in cortical neurons in vivo

The individual functional properties and spatial arrangement of afferent synaptic inputs on dendrites have a critical role in the processing of information by neurons in the mammalian brain. Although recent work has identified visually-evoked local dendritic calcium signals in the rodent visual cortex, sensory-evoked signalling on the level of dendritic spines, corresponding to individual afferent excitatory synapses, remains unexplored. Here we used a new variant of high-resolution two-photon imaging to detect sensory-evoked calcium transients in single dendritic spines of mouse cortical neurons in vivo. Calcium signals evoked by sound stimulation required the activation of NMDA (N-methyl-D-aspartate) receptors. Active spines are widely distributed on basal and apical dendrites and pure-tone stimulation at different frequencies revealed both narrowly and widely tuned spines. Notably, spines tuned for different frequencies were highly interspersed on the same dendrites: even neighbouring spines were mostly tuned to different frequencies. Thus, our results demonstrate that NMDA-receptor-dependent single-spine synaptic inputs to the same dendrite are highly heterogeneous. Furthermore, our study opens the way for in vivo mapping of functionally defined afferent sensory inputs with single-synapse resolution.     

Retrospective and prospective coding for predicted reward in the sensory thalamus

Reward is important for shaping goal-directed behaviour. After stimulus-reward associative learning, an organism can assess the motivational value of the incoming stimuli on the basis of past experience (retrospective processing), and predict forthcoming rewarding events (prospective processing). The traditional role of the sensory thalamus is to relay current sensory information to cortex. Here we find that non-primary thalamic neurons respond to reward-related events in two ways. The early, phasic responses occurred shortly after the onset of the stimuli and depended on the sensory modality. Their magnitudes resisted extinction and correlated with the learning experience. The late responses gradually increased during the cue and delay periods, and peaked just before delivery of the reward. These responses were independent of sensory modality and were modulated by the value and timing of the reward. These observations provide new evidence that single thalamic neurons can code for the acquired significance of sensory stimuli in the early responses (retrospective coding) and predict upcoming reward value in the late responses (prospective coding).     

Teneurins instruct synaptic partner matching in an olfactory map

Neurons are interconnected with extraordinary precision to assemble a functional nervous system. Compared to axon guidance, far less is understood about how individual pre- and postsynaptic partners are matched. To ensure the proper relay of olfactory information in the fruitfly Drosophila, axons of ～50 classes of olfactory receptor neurons (ORNs) form one-to-one connections with dendrites of ～50 classes of projection neurons (PNs). Here, using genetic screens, we identified two evolutionarily conserved, epidermal growth factor (EGF)-repeat containing transmembrane Teneurin proteins, Ten-m and Ten-a, as synaptic-partner-matching molecules between PN dendrites and ORN axons. Ten-m and Ten-a are highly expressed in select PN-ORN matching pairs. Teneurin loss- and gain-of-function cause specific mismatching of select ORNs and PNs. Finally, Teneurins promote homophilic interactions in vitro, and Ten-m co-expression in non-partner PNs and ORNs promotes their ectopic connections in vivo. We propose that Teneurins instruct matching specificity between synaptic partners through homophilic attraction.     

Modulation of human global／local perception by low spatial frequency filtering

We investigated the effect of low spatial frequency (SF) filtering on neural substrates underlying global and local processing in the peripheral vision by measuring hemodynamic responses with functional magnetic resonance imaging (fMRI). Subjects identified global or local shapes of compound letters that were either broadband in spatialfrequency spectrum or contrast balanced (CB) to removed low SFs and displayed randomly in the left or right visual fields. Attention to both broadband and CB global shapes generated stronger activation over the medial occipital cortex relative to local attention. Lateralized activations in association with global processing were observed over the right temporal-parietal junction for broadband stimuli whereas over the right fusiform gyrns for CB stimuli. Attention to CB local shapes resulted in activations in the medial frontal cortex, bilateral inferior frontal and superior temporal cortices.The results were discussed in terms of the competition between global and local information in determining brain activations in association with global/local processing of compound stimuli.     

Division and subtraction by distinct cortical inhibitory networks in vivo

Brain circuits process information through specialized neuronal subclasses interacting within a network. Revealing their interplay requires activating specific cells while monitoring others in a functioning circuit. Here we use a new platform for two-way light-based circuit interrogation in visual cortex in vivo to show the computational implications of modulating different subclasses of inhibitory neurons during sensory processing. We find that soma-targeting, parvalbumin-expressing (PV) neurons principally divide responses but preserve stimulus selectivity, whereas dendrite-targeting, somatostatin-expressing (SOM) neurons principally subtract from excitatory responses and sharpen selectivity. Visualized in vivo cell-attached recordings show that division by PV neurons alters response gain, whereas subtraction by SOM neurons shifts response levels. Finally, stimulating identified neurons while scanning many target cells reveals that single PV and SOM neurons functionally impact only specific subsets of neurons in their projection fields. These findings provide direct evidence that inhibitory neuronal subclasses have distinct and complementary roles in cortical computations.     

Turning on and off recurrent balanced cortical activity

The vast majority of synaptic connections onto neurons in the cerebral cortex arise from other cortical neurons, both excitatory and inhibitory, forming local and distant 'recurrent' networks. Although this is a basic theme of cortical organization, its study has been limited largely to theoretical investigations, which predict that local recurrent networks show a proportionality or balance between recurrent excitation and inhibition, allowing the generation of stable periods of activity. This recurrent activity might underlie such diverse operations as short-term memory, the modulation of neuronal excitability with attention, and the generation of spontaneous activity during sleep. Here we show that local cortical circuits do indeed operate through a proportional balance of excitation and inhibition generated through local recurrent connections, and that the operation of such circuits can generate self-sustaining activity that can be turned on and off by synaptic inputs. These results confirm the long-hypothesized role of recurrent activity as a basic operation of the cerebral cortex.