Selective gating of visual signals by microstimulation of frontal cortex

Several decades of psychophysical and neurophysiological studies have established that visual signals are enhanced at the locus of attention. What remains a mystery is the mechanism that initiates biases in the strength of visual representations. Recent evidence argues that, during spatial attention, these biases reflect nascent saccadic eye movement commands. We examined the functional interaction of saccade preparation and visual coding by electrically stimulating sites within the frontal eye fields (FEF) and measuring its effect on the activity of neurons in extrastriate visual cortex. Here we show that visual responses in area V4 could be enhanced after brief stimulation of retinotopically corresponding sites within the FEF using currents below that needed to evoke saccades. The magnitude of the enhancement depended on the effectiveness of receptive field stimuli as well as on the presence of competing stimuli outside the receptive field. Stimulation of non-corresponding FEF representations could suppress V4 responses. The results suggest that the gain of visual signals is modified according to the strength of spatially corresponding eye movement commands.     

Control of visual cortical signals by prefrontal dopamine

The prefrontal cortex is thought to modulate sensory signals in posterior cortices during top-down attention, but little is known about the underlying neural circuitry. Experimental and clinical evidence indicate that prefrontal dopamine has an important role in cognitive functions, acting predominantly through D1 receptors. Here we show that dopamine D1 receptors mediate prefrontal control of signals in the visual cortex of macaques (Macaca mulatta). We pharmacologically altered D1-receptor-mediated activity in the frontal eye field of the prefrontal cortex and measured the effect on the responses of neurons in area V4 of the visual cortex. This manipulation was sufficient to enhance the magnitude, the orientation selectivity and the reliability of V4 visual responses to an extent comparable with the known effects of top-down attention. The enhancement of V4 signals was restricted to neurons with response fields overlapping the part of visual space affected by the D1 receptor manipulation. Altering either D1- or D2-receptor-mediated frontal eye field activity increased saccadic target selection but the D2 receptor manipulation did not enhance V4 signals. Our results identify a role for D1 receptors in mediating the control of visual cortical signals by the prefrontal cortex and suggest how processing in sensory areas could be altered in mental disorders involving prefrontal dopamine.     

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.     

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.     

Dynamic coding of behaviourally relevant stimuli in parietal cortex.

A general function of cerebral cortex is to allow the flexible association of sensory stimuli with specific behaviours. Many neurons in parietal, prefrontal and motor cortical areas are activated both by particular movements and by sensory cues that trigger these movements, suggesting a role in linking sensation to action. For example, neurons in the lateral intraparietal area (LIP) encode both the location of visual stimuli and the direction of saccadic eye movements. LIP is not believed to encode non-spatial stimulus attributes such as colour. Here we investigated whether LIP would encode colour if colour was behaviourally linked to the eye movement. We trained monkeys to make an eye movement in one of two directions based alternately on the colour or location of a visual cue. When cue colour was relevant for directing eye movement, we found a substantial fraction of LIP neurons selective for cue colour. However, when cue location was relevant, colour selectivity was virtually absent in LIP. These results demonstrate that selectivity of cortical neurons can change as a function of the required behaviour.     

Visual behaviour mediated by retinal projections directed to the auditory pathway

An unresolved issue in cortical development concerns the relative contributions of intrinsic and extrinsic factors to the functional specification of different cortical areas. Ferrets in which retinal projections are redirected neonatally to the auditory thalamus have visually responsive cells in auditory thalamus and cortex, form a retinotopic map in auditory cortex and have visual receptive field properties in auditory cortex that are typical of cells in visual cortex. Here we report that this cross-modal projection and its representation in auditory cortex can mediate visual behaviour. When light stimuli are presented in the portion of the visual field that is 'seen' only by this projection, 'rewired' ferrets respond as though they perceive the stimuli to be visual rather than auditory. Thus the perceptual modality of a neocortical region is instructed to a significant extent by its extrinsic inputs. In addition, gratings of different spatial frequencies can be discriminated by the rewired pathway, although the grating acuity is lower than that of the normal visual pathway.     

Functional specificity of local synaptic connections in neocortical networks

Neuronal connectivity is fundamental to information processing in the brain. Therefore, understanding the mechanisms of sensory processing requires uncovering how connection patterns between neurons relate to their function. On a coarse scale, long-range projections can preferentially link cortical regions with similar responses to sensory stimuli. But on the local scale, where dendrites and axons overlap substantially, the functional specificity of connections remains unknown. Here we determine synaptic connectivity between nearby layer 2/3 pyramidal neurons in vitro, the response properties of which were first characterized in mouse visual cortex in vivo. We found that connection probability was related to the similarity of visually driven neuronal activity. Neurons with the same preference for oriented stimuli connected at twice the rate of neurons with orthogonal orientation preferences. Neurons responding similarly to naturalistic stimuli formed connections at much higher rates than those with uncorrelated responses. Bidirectional synaptic connections were found more frequently between neuronal pairs with strongly correlated visual responses. Our results reveal the degree of functional specificity of local synaptic connections in the visual cortex, and point to the existence of fine-scale subnetworks dedicated to processing related sensory information.     

Transformation from temporal to rate coding in a somatosensory thalamocortical pathway

The anatomical connections from the whiskers to the rodent somatosensory (barrel) cortex form two parallel (lemniscal and paralemniscal) pathways. It is unclear whether the paralemniscal pathway is directly involved in tactile processing, because paralemniscal neuronal responses show poor spatial resolution, labile latencies and strong dependence on cortical feedback. Here we show that the paralemniscal system can transform temporally encoded vibrissal information into a rate code. We recorded the representations of the frequency of whisker movement along the two pathways in anaesthetized rats. In response to varying stimulus frequencies, the lemniscal neurons exhibited amplitude modulations and constant latencies. In contrast, paralemniscal neurons in both thalamus and cortex coded the input frequency as changes in latency. Because the onset latencies increased and the offset latencies remained constant, the latency increments were translated into a rate code: increasing onset latencies led to lower spike counts. A thalamocortical loop that includes cortical oscillations and thalamic gating can account for these results. Thus, variable latencies and effective cortical feedback in the paralemniscal system can serve the processing of temporal sensory cues, such as those that encode object location during whisking. In contrast, fixed time locking in the lemniscal system is crucial for reliable spatial processing.     

Depth is encoded in the visual cortex by a specialized receptive field structure

Binocular neurons in the visual cortex are thought to perform the first stage of processing for the fine stereoscopic depth discrimination exhibited by animals with frontally located eyes. Because lateral separation of the eyes gives a slightly different view to each eye, there are small variations in position (disparities), mainly along the horizontal dimension, between corresponding features in the two retinal images. The visual system uses these disparities to gauge depth. We studied neurons in the cat's visual cortex to determine whether the visual system uses the anisotropy in the range of horizontal and vertical disparities. We report here that there is a corresponding anisotropy in the cortical representation of binocular information: receptive-field profiles for left and right eyes are matched for cells that are tuned to horizontal orientations of image contours. For neurons tuned to vertical orientations, left and right receptive fields are predominantly dissimilar. Therefore, a major modification is required of the conventional notion of disparity processing. The modified scheme allows a unified encoding of monocular form and binocular disparity information.     

The contribution of sensory experience to the maturation of orientation selectivity in ferret visual cortex.

Sensory experience begins when neural circuits in the cerebral cortex are still immature; however, the contribution of experience to cortical maturation remains unclear. In the visual cortex, the selectivity of neurons for oriented stimuli at the time of eye opening is poor and increases dramatically after the onset of visual experience. Here we investigate whether visual experience has a significant role in the maturation of orientation selectivity and underlying cortical circuits using two forms of deprivation: dark rearing, which completely eliminates experience, and binocular lid suture, which alters the pattern of sensory driven activity. Orientation maps were present in dark-reared ferrets, but fully mature levels of tuning were never attained. In contrast, only rudimentary levels of orientation selectivity were observed in lid-sutured ferrets. Despite these differences, horizontal connections in both groups were less extensive and less clustered than normal, suggesting that long-range cortical processing is not essential for the expression of orientation selectivity, but may be needed for the full maturation of tuning. Thus, experience is beneficial or highly detrimental to cortical maturation, depending on the pattern of sensory driven activity.     

Potentiation of cortical inhibition by visual deprivation

The fine-tuning of circuits in sensory cortex requires sensory experience during an early critical period. Visual deprivation during the critical period has catastrophic effects on visual function, including loss of visual responsiveness to the deprived eye, reduced visual acuity, and loss of tuning to many stimulus characteristics. These changes occur faster than the remodelling of thalamocortical axons, but the intracortical plasticity mechanisms that underlie them are incompletely understood. Long-term depression of excitatory intracortical synapses has been proposed as a general candidate mechanism for the loss of cortical responsiveness after visual deprivation. Alternatively (or in addition), the decreased ability of the deprived eye to activate cortical neurons could be due to enhanced intracortical inhibition. Here we show that visual deprivation leaves excitatory connections in layer 4 (the primary input layer to cortex) unaffected, but markedly potentiates inhibitory feedback between fast-spiking basket cells (FS cells) and star pyramidal neurons (star pyramids). Further, a previously undescribed form of long-term potentiation of inhibition (LTPi) could be induced at synapses from FS cells to star pyramids, and was occluded by previous visual deprivation. These data suggest that potentiation of inhibition is a major cellular mechanism underlying the deprivation-induced degradation of visual function, and that this form of LTPi is important in fine-tuning cortical circuitry in response to visual experience.     

Spontaneously emerging cortical representations of visual attributes

Spontaneous cortical activity--ongoing activity in the absence of intentional sensory input--has been studied extensively, using methods ranging from EEG (electroencephalography), through voltage sensitive dye imaging, down to recordings from single neurons. Ongoing cortical activity has been shown to play a critical role in development, and must also be essential for processing sensory perception, because it modulates stimulus-evoked activity, and is correlated with behaviour. Yet its role in the processing of external information and its relationship to internal representations of sensory attributes remains unknown. Using voltage sensitive dye imaging, we previously established a close link between ongoing activity in the visual cortex of anaesthetized cats and the spontaneous firing of a single neuron. Here we report that such activity encompasses a set of dynamically switching cortical states, many of which correspond closely to orientation maps. When such an orientation state emerged spontaneously, it spanned several hypercolumns and was often followed by a state corresponding to a proximal orientation. We suggest that dynamically switching cortical states could represent the brain's internal context, and therefore reflect or influence memory, perception and behaviour.     

Receptive field dynamics in adult primary visual cortex.

The adult brain has a remarkable ability to adjust to changes in sensory input. Removal of afferent input to the somatosensory, auditory, motor or visual cortex results in a marked change of cortical topography. Changes in sensory activity can, over a period of months, alter receptive field size and cortical topography. Here we remove visual input by focal binocular retinal lesions and record from the same cortical sites before and within minutes after making the lesion and find immediate striking increases in receptive field size for cortical cells with receptive fields near the edge of the retinal scotoma. After a few months even the cortical areas that were initially silenced by the lesion recover visual activity, representing retinotopic loci surrounding the lesion. At the level of the lateral geniculate nucleus, which provides the visual input to the striate cortex, a large silent region remains. Furthermore, anatomical studies show that the spread of geniculocortical afferents is insufficient to account for the cortical recovery. The results indicate that the topographic reorganization within the cortex was largely due to synaptic changes intrinsic to the cortex, perhaps through the plexus of long-range horizontal connections.     

A synaptic memory trace for cortical receptive field plasticity

Receptive fields of sensory cortical neurons are plastic, changing in response to alterations of neural activity or sensory experience. In this way, cortical representations of the sensory environment can incorporate new information about the world, depending on the relevance or value of particular stimuli. Neuromodulation is required for cortical plasticity, but it is uncertain how subcortical neuromodulatory systems, such as the cholinergic nucleus basalis, interact with and refine cortical circuits. Here we determine the dynamics of synaptic receptive field plasticity in the adult primary auditory cortex (also known as AI) using in vivo whole-cell recording. Pairing sensory stimulation with nucleus basalis activation shifted the preferred stimuli of cortical neurons by inducing a rapid reduction of synaptic inhibition within seconds, which was followed by a large increase in excitation, both specific to the paired stimulus. Although nucleus basalis was stimulated only for a few minutes, reorganization of synaptic tuning curves progressed for hours thereafter: inhibition slowly increased in an activity-dependent manner to rebalance the persistent enhancement of excitation, leading to a retuned receptive field with new preference for the paired stimulus. This restricted period of disinhibition may be a fundamental mechanism for receptive field plasticity, and could serve as a memory trace for stimuli or episodes that have acquired new behavioural significance.     

Requirement for subplate neurons in the formation of thalamocortical connections

The neurons of layer 4 in the adult cerebral cortex receive their major ascending inputs from the thalamus. In development, however, thalamic axons arrive at the appropriate cortical area long before their target layer 4 neurons have migrated into the cortical plate. The axons accumulate and wait in the zone below the cortical plate, the subplate, for several weeks before invading the cortical plate. The subplate is a transient zone that contains the first postmitotic neurons of the telencephalon. These neurons mature well before other cortical neurons, and disappear by cell death after the thalamic axons have grown into the overlying cortical plate. The close proximity of growing thalamocortical axons and subplate neurons suggests that they might be involved in interactions important for normal thalamocortical development. Here we show that early in development the deletion of subplate neurons located beneath visual cortex prevents axons from the lateral geniculate nucleus of the thalamus from recognizing and innervating visual cortex, their normal target. In the absence of subplate neurons, lateral geniculate nucleus axons continue to grow in the white matter past visual cortex despite the presence of their target layer 4 neurons. Thus the transient subplate neurons are necessary for appropriate cortical target selection by thalamocortical axons.     

Coding of smooth eye movements in three-dimensional space by frontal cortex

Through the development of a high-acuity fovea, primates with frontal eyes have acquired the ability to use binocular eye movements to track small objects moving in space. The smooth-pursuit system moves both eyes in the same direction to track movement in the frontal plane (frontal pursuit), whereas the vergence system moves left and right eyes in opposite directions to track targets moving towards or away from the observer (vergence tracking). In the cerebral cortex and brainstem, signals related to vergence eye movements--and the retinal disparity and blur signals that elicit them--are coded independently of signals related to frontal pursuit. Here we show that these types of signal are represented in a completely different way in the smooth-pursuit region of the frontal eye fields. Neurons of the frontal eye field modulate strongly during both frontal pursuit and vergence tracking, which results in three-dimensional cartesian representations of eye movements. We propose that the brain creates this distinctly different intermediate representation to allow these neurons to function as part of a system that enables primates to track and manipulate objects moving in three-dimensional space.     

Optimal transsaccadic integration explains distorted spatial perception

We scan our surroundings with quick eye movements called saccades, and from the resulting sequence of images we build a unified percept by a process known as transsaccadic integration. This integration is often said to be flawed, because around the time of saccades, our perception is distorted and we show saccadic suppression of displacement (SSD): we fail to notice if objects change location during the eye movement. Here we show that transsaccadic integration works by optimal inference. We simulated a visuomotor system with realistic saccades, retinal acuity, motion detectors and eye-position sense, and programmed it to make optimal use of these imperfect data when interpreting scenes. This optimized model showed human-like SSD and distortions of spatial perception. It made new predictions, including tight correlations between perception and motor action (for example, more SSD in people with less-precise eye control) and a graded contraction of perceived jumps; we verified these predictions experimentally. Our results suggest that the brain constructs its evolving picture of the world by optimally integrating each new piece of sensory or motor information.     

Small modulation of ongoing cortical dynamics by sensory input during natural vision

During vision, it is believed that neural activity in the primary visual cortex is predominantly driven by sensory input from the environment. However, visual cortical neurons respond to repeated presentations of the same stimulus with a high degree of variability. Although this variability has been considered to be noise owing to random spontaneous activity within the cortex, recent studies show that spontaneous activity has a highly coherent spatio-temporal structure. This raises the possibility that the pattern of this spontaneous activity may shape neural responses during natural viewing conditions to a larger extent than previously thought. Here, we examine the relationship between spontaneous activity and the response of primary visual cortical neurons to dynamic natural-scene and random-noise film images in awake, freely viewing ferrets from the time of eye opening to maturity. The correspondence between evoked neural activity and the structure of the input signal was weak in young animals, but systematically improved with age. This improvement was linked to a shift in the dynamics of spontaneous activity. At all ages including the mature animal, correlations in spontaneous neural firing were only slightly modified by visual stimulation, irrespective of the sensory input. These results suggest that in both the developing and mature visual cortex, sensory evoked neural activity represents the modulation and triggering of ongoing circuit dynamics by input signals, rather than directly reflecting the structure of the input signal itself.     

An evolutionary scaling law for the primate visual system and its basis in cortical function

A hallmark of mammalian brain evolution is the disproportionate increase in neocortical size as compared with subcortical structures. Because primary visual cortex (V1) is the most thoroughly understood cortical region, the visual system provides an excellent model in which to investigate the evolutionary expansion of neocortex. I have compared the numbers of neurons in the visual thalamus (lateral geniculate nucleus; LGN) and area V1 across primate species. Here I find that the number of V1 neurons increases as the 3/2 power of the number of LGN neurons. As a consequence of this scaling law, the human, for example, uses four times as many V1 neurons per LGN neuron (356) to process visual information as does a tarsier (87). I argue that the 3/2 power relationship is a natural consequence of the organization of V1, together with the requirement that spatial resolution in V1 should parallel the maximum resolution provided by the LGN. The additional observation that thalamus/neocortex follows the same evolutionary scaling law as LGN/V1 may suggest that neocortex generally conforms to the same organizational principle as V1.     

An area for vergence eye movement in primate frontal cortex

To view objects at different distances, humans rely on vergence eye movements to appropriately converge or diverge the eyes and on ocular accommodation to focus the object. Despite the importance of these coordinated eye movements (the 'near response') very little is known about the role of the cerebral cortex in their control. As near-response neurons exist within the nucleus reticularis tegmenti pontis, which receives input from the frontal eye field region of frontal cortex, and this cortical region is known to be involved in saccadic and smooth-pursuit eye movements, we propose that a nearby region might play a role in vergence and ocular accommodation. Here we provide evidence from rhesus monkeys that a region of frontal cortex located immediately anterior to the saccade-related frontal eye field region is involved in vergence and ocular accommodation, and in the sensorimotor transformations required for these eye movements. We conclude that the macaque frontal cortex is involved in the control of all voluntary eye movements, and suggest that the definition of the frontal eye fields should be expanded to include this region.