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.     

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.     

Influence of the thalamus on spatial visual processing in frontal cortex

Each of our movements activates our own sensory receptors, and therefore keeping track of self-movement is a necessary part of analysing sensory input. One way in which the brain keeps track of self-movement is by monitoring an internal copy, or corollary discharge, of motor commands. This concept could explain why we perceive a stable visual world despite our frequent quick, or saccadic, eye movements: corollary discharge about each saccade would permit the visual system to ignore saccade-induced visual changes. The critical missing link has been the connection between corollary discharge and visual processing. Here we show that such a link is formed by a corollary discharge from the thalamus that targets the frontal cortex. In the thalamus, neurons in the mediodorsal nucleus relay a corollary discharge of saccades from the midbrain superior colliculus to the cortical frontal eye field. In the frontal eye field, neurons use corollary discharge to shift their visual receptive fields spatially before saccades. We tested the hypothesis that these two components-a pathway for corollary discharge and neurons with shifting receptive fields-form a circuit in which the corollary discharge drives the shift. First we showed that the known spatial and temporal properties of the corollary discharge predict the dynamic changes in spatial visual processing of cortical neurons when saccades are made. Then we moved from this correlation to causation by isolating single cortical neurons and showing that their spatial visual processing is impaired when corollary discharge from the thalamus is interrupted. Thus the visual processing of frontal neurons is spatiotemporally matched with, and functionally dependent on, corollary discharge input from the thalamus. These experiments establish the first link between corollary discharge and visual processing, delineate a brain circuit that is well suited for mediating visual stability, and provide a framework for studying corollary discharge in other sensory systems.     

Top-down signal from prefrontal cortex in executive control of memory retrieval.

Knowledge or experience is voluntarily recalled from memory by reactivation of the neural representations in the cerebral association cortex. In inferior temporal cortex, which serves as the storehouse of visual long-term memory, activation of mnemonic engrams through electric stimulation results in imagery recall in humans, and neurons can be dynamically activated by the necessity for memory recall in monkeys. Neuropsychological studies and previous split-brain experiments predicted that prefrontal cortex exerts executive control upon inferior temporal cortex in memory retrieval; however, no neuronal correlate of this process has ever been detected. Here we show evidence of the top-down signal from prefrontal cortex. In the absence of bottom-up visual inputs, single inferior temporal neurons were activated by the top-down signal, which conveyed information on semantic categorization imposed by visual stimulus-stimulus association. Behavioural performance was severely impaired with loss of the top-down signal. Control experiments confirmed that the signal was transmitted not through a subcortical but through a fronto-temporal cortical pathway. Thus, feedback projections from prefrontal cortex to the posterior association cortex appear to serve the executive control of voluntary recall.     

视觉神经表征中底-顶和顶-底的双向激活——来自人与猴的实验证据

长期以来,建立在坚实生理学证据之上的底-顶加工说和特征检测理论在视觉研究中占主导地位。对于顶-底加工人们只能靠一般常识,即知识或经验通过激活记忆中的神经表征影响视觉过程。但是近年来,来自人和猴的研究为顶-底的加工提供了实验证据。 首先位于猴腹侧加工系统内的物体和面孔视觉记忆表征,提供了神经编码是怎样创立、组织和再激活的最佳实验证据。联想性编码是通过学习由一些具有特殊功能的神经元建立的,这些神经元具有将时间性关联刺激的表征联系起来的能力。其次,不仅来自视网膜的底-顶信号,而且来自前额叶的顶-底信号都能触发联想性编码的提取,既可以作为有意识回忆的神经基础,又是顶-底加工影响视觉过程的基础。脑损伤病人研究、具有高时间分辨率的人类功能性核磁共振成像(functional magnetic resonance imaging, fMRI)和猴fMRI研究以及猴细胞电生理分析相结合,将进一步加强人们对视觉脑机制的全面理解。     

Relative reward preference in primate orbitofrontal cortex

The orbital part of prefrontal cortex appears to be crucially involved in the motivational control of goal-directed behaviour. Patients with lesions of orbitofrontal cortex show impairments in making decisions about the expected outcome of actions. Monkeys with orbitofrontal lesions respond abnormally to changes in reward expectations and show altered reward preferences. As rewards constitute basic goals of behaviour, we investigated here how neurons in the orbitofrontal cortex of monkeys process information about liquid and food rewards in a typical frontal task, spatial delayed responding. The activity of orbitofrontal neurons increases in response to reward-predicting signals, during the expectation of rewards, and after the receipt of rewards. Neurons discriminate between different rewards, mainly irrespective of the spatial and visual features of reward-predicting stimuli and behavioural reactions. Most reward discriminations reflect the animals' relative preference among the available rewards, as expressed by their choice behaviour, rather than physical reward properties. Thus, neurons in the orbitofrontal cortex appear to process the motivational value of rewarding outcomes of voluntary action.     

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.     

Top-down gain control of the auditory space map by gaze control circuitry in the barn owl

High-level circuits in the brain that control the direction of gaze are intimately linked with the control of visual spatial attention. Immediately before an animal directs its gaze towards a stimulus, both psychophysical sensitivity to that visual stimulus and the responsiveness of high-order neurons in the cerebral cortex that represent the stimulus increase dramatically. Equivalent effects on behavioural sensitivity and neuronal responsiveness to visual stimuli result from focal electrical microstimulation of gaze control centres in monkeys. Whether the gaze control system modulates neuronal responsiveness in sensory modalities other than vision is unknown. Here we show that electrical microstimulation applied to gaze control circuitry in the forebrain of barn owls regulates the gain of midbrain auditory responses in an attention-like manner. When the forebrain circuit was activated, midbrain responses to auditory stimuli at the location encoded by the forebrain site were enhanced and spatial selectivity was sharpened. The same stimulation suppressed responses to auditory stimuli represented at other locations in the midbrain map. Such space-specific, top-down regulation of auditory responses by gaze control circuitry in the barn owl suggests that the central nervous system uses a common strategy for dynamically regulating sensory gain that applies across modalities, brain areas and classes of vertebrate species. This approach provides a path for discovering mechanisms that underlie top-down gain control in the central nervous system.     

Deficient pheromone responses in mice lacking a cluster of vomeronasal receptor genes

The mammalian vomeronasal organ (VNO), a part of the olfactory system, detects pheromones--chemical signals that modulate social and reproductive behaviours. But the molecular receptors in the VNO that detect these chemosensory stimuli remain undefined. Candidate pheromone receptors are encoded by two distinct and complex superfamilies of genes, V1r and V2r (refs 3 and 4), which code for receptors with seven transmembrane domains. These genes are selectively expressed in sensory neurons of the VNO. However, there is at present no functional evidence for a role of these genes in pheromone responses. Here, using chromosome engineering technology, we delete in the germ line of mice an approximately 600-kilobase genomic region that contains a cluster of 16 intact V1r genes. These genes comprise two of the 12 described V1r gene families, and represent approximately 12% of the V1r repertoire. The mutant mice display deficits in a subset of VNO-dependent behaviours: the expression of male sexual behaviour and maternal aggression is substantially altered. Electrophysiologically, the epithelium of the VNO of such mice does not respond detectably to specific pheromonal ligands. The behavioural impairment and chemosensory deficit support a role of V1r receptors as pheromone receptors.     

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.     

Motion streaks provide a spatial code for motion direction.

Although many neurons in the primary visual cortex (V1) of primates are direction selective, they provide ambiguous information about the direction of motion of a stimulus. There is evidence that one of the ways in which the visual system resolves this ambiguity is by computing, from the responses of V1 neurons, velocity components in two or more spatial orientations and then combining these velocity components. Here I consider another potential neural mechanism for determining motion direction. When a localized image feature moves fast enough, it should become smeared in space owing to temporal integration in the visual system, creating a spatial signal-a 'motion streak'-oriented in the direction of the motion. The orientation masking and adaptation experiments reported here show that these spatial signals for motion direction exist in the human visual system for feature speeds above about 1 feature width per 100 ms. Computer simulations show that this psychophysical finding is consistent with the known response properties of V1 neurons, and that these spatial signals, when appropriately processed, are sufficient to determine motion direction in natural images.     

Cross-modal and cross-temporal association in neurons of frontal cortex

The prefrontal cortex is essential for the temporal integration of sensory information in behavioural and linguistic sequences. Such information is commonly encoded in more than one sense modality, notably sight and sound. Connections from sensory cortices to the prefrontal cortex support its integrative function. Here we present the first evidence that prefrontal cortex cells associate visual and auditory stimuli across time. We gave monkeys the task of remembering a tone of a certain pitch for 10 s and then choosing the colour associated with it. In this task, prefrontal cortex cells responded selectively to tones, and most of them also responded to colours according to the task rule. Thus, their reaction to a tone was correlated with their subsequent reaction to the associated colour. This correlation faltered in trials ending in behavioural error. We conclude that prefrontal cortex neurons are part of integrative networks that represent behaviourally meaningful cross-modal associations. The orderly and timely activation of neurons in such networks is crucial for the temporal transfer of information in the structuring of behaviour, reasoning and language.     

Attentional modulation in visual cortex depends on task timing

Paying attention to a stimulus selectively increases the ability to process it. For example, when subjects attend to a specific region of a visual scene, their sensitivity to changes at that location increases. A large number of studies describe the behavioural consequences and neurophysiological correlates of attending to spatial locations. There has, in contrast, been little study of the allocation of attention over time. Because subjects can anticipate predictable events with great temporal precision, it seems probable that they might dynamically shift their attention when performing a familiar perceptual task whose constraints changed over time. We trained monkeys to respond to a stimulus change where the probability of occurrence changed over time. Recording from area V4 of the visual cortex in these animals, we found that the modulation of neuronal responses changed according to the probability of the change occurring at that instant. Thus, we show that the attentional modulation of sensory neurons reflects a subject's anticipation of the timing of behaviourally relevant events.     

Gaze direction controls response gain in primary visual-cortex neurons

To localize objects in space, the brain needs to combine information about the position of the stimulus on the retinae with information about the location of the eyes in their orbits. Interaction between these two types of information occurs in several cortical areas, but the role of the primary visual cortex (area V1) in this process has remained unclear. Here we show that, for half the cells recorded in area V1 of behaving monkeys, the classically described visual responses are strongly modulated by gaze direction. Specifically, we find that selectivity for horizontal retinal disparity-the difference in the position of a stimulus on each retina which relates to relative object distance-and for stimulus orientation may be present at a given gaze direction, but be absent or poorly expressed at another direction. Shifts in preferred disparity also occurred in several neurons. These neural changes were most often present at the beginning of the visual response, suggesting a feedforward gain control by eye position signals. Cortical neural processes for encoding information about the three-dimensional position of a stimulus in space therefore start as early as area V1.     

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.     

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.     

Direct visuomotor transformations for reaching

The posterior parietal cortex (PPC) is thought to have a function in the sensorimotor transformations that underlie visually guided reaching, as damage to the PPC can result in difficulty reaching to visual targets in the absence of specific visual or motor deficits. This function is supported by findings that PPC neurons in monkeys are modulated by the direction of hand movement, as well as by visual, eye position and limb position signals. The PPC could transform visual target locations from retinal coordinates to hand-centred coordinates by combining sensory signals in a serial manner to yield a body-centred representation of target location, and then subtracting the body-centred location of the hand. We report here that in dorsal area 5 of the PPC, remembered target locations are coded with respect to both the eye and hand. This suggests that the PPC transforms target locations directly between these two reference frames. Data obtained in the adjacent parietal reach region (PRR) indicate that this transformation may be achieved by vectorially subtracting hand location from target location, with both locations represented in eye-centred coordinates.     

Induction of visual orientation modules in auditory cortex

Modules of neurons sharing a common property are a basic organizational feature of mammalian sensory cortex. Primary visual cortex (V1) is characterized by orientation modules--groups of cells that share a preferred stimulus orientation--which are organized into a highly ordered orientation map. Here we show that in ferrets in which retinal projections are routed into the auditory pathway, visually responsive neurons in 'rewired' primary auditory cortex are also organized into orientation modules. The orientation tuning of neurons within these modules is comparable to the tuning of cells in V1 but the orientation map is less orderly. Horizontal connections in rewired cortex are more patchy and periodic than connections in normal auditory cortex, but less so than connections in V1. These data show that afferent activity has a profound influence on diverse components of cortical circuitry, including thalamocortical and local intracortical connections, which are involved in the generation of orientation tuning, and long-range horizontal connections, which are important in creating an orientation map.     

Correlated binocular activity guides recovery from monocular deprivation

Monocular deprivation (MD) has much more rapid and severe effects on the ocular dominance of neurons in the primary visual cortex (V1) than does binocular deprivation. This finding underlies the widely held hypothesis that the developmental plasticity of ocular dominance reflects competitive interactions for synaptic space between inputs from the two eyes. According to this view, the relative levels of evoked activity in afferents representing the two eyes determine functional changes in response to altered visual experience. However, if the deprived eye of a monocularly deprived kitten is simply reopened, there is substantial physiological and behavioural recovery, leading to the suggestion that absolute activity levels, or some other non-competitive mechanisms, determine the degree of recovery from MD. Here we provide evidence that correlated binocular input is essential for such recovery. Recovery is far less complete if the two eyes are misaligned after a period of MD. This is a powerful demonstration of the importance of cooperative, associative mechanisms in the developing visual cortex.     

Lateral habenula as a source of negative reward signals in dopamine neurons

Midbrain dopamine neurons are key components of the brain's reward system, which is thought to guide reward-seeking behaviours. Although recent studies have shown how dopamine neurons respond to rewards and sensory stimuli predicting reward, it is unclear which parts of the brain provide dopamine neurons with signals necessary for these actions. Here we show that the primate lateral habenula, part of the structure called the epithalamus, is a major candidate for a source of negative reward-related signals in dopamine neurons. We recorded the activity of habenula neurons and dopamine neurons while rhesus monkeys were performing a visually guided saccade task with positionally biased reward outcomes. Many habenula neurons were excited by a no-reward-predicting target and inhibited by a reward-predicting target. In contrast, dopamine neurons were excited and inhibited by reward-predicting and no-reward-predicting targets, respectively. Each time the rewarded and unrewarded positions were reversed, both habenula and dopamine neurons reversed their responses as the bias in saccade latency reversed. In unrewarded trials, the excitation of habenula neurons started earlier than the inhibition of dopamine neurons. Furthermore, weak electrical stimulation of the lateral habenula elicited strong inhibitions in dopamine neurons. These results suggest that the inhibitory input from the lateral habenula plays an important role in determining the reward-related activity of dopamine neurons.