Sensory experience modifies the short-term dynamics of neocortical synapses.

Many representations of sensory stimuli in the neocortex are arranged as topographic maps. These cortical maps are not fixed, but show experience-dependent plasticity. For instance, sensory deprivation causes the cortical area representing the deprived sensory input to shrink, and neighbouring spared representations to enlarge, in somatosensory, auditory or visual cortex. In adolescent and adult animals, changes in cortical maps are most noticeable in the supragranular layers at the junction of deprived and spared cortex. However, the cellular mechanisms of this experience-dependent plasticity are unclear. Long-term potentiation and depression have been implicated, but have not been proven to be necessary or sufficient for cortical map reorganization. Short-term synaptic dynamics have not been considered. We developed a brain slice preparation involving rat whisker barrel cortex in vitro. Here we report that sensory deprivation alters short-term synaptic dynamics in both vertical and horizontal excitatory pathways within the supragranular cortex. Moreover, modifications of horizontal pathways amplify changes in the vertical inputs. Our findings help to explain the functional cortical reorganization that follows persistent changes of sensory experience.     

NMDA receptors in the visual cortex of young kittens are more effective than those of adult cats

Acidic amino acids, such as glutamate and aspartate, are thought to be excitatory transmitters in the cerebral neocortex and hippocampus. Receptors for these amino acids can be classified into at least three types on the basis of their agonists. Quisqualate-preferring receptors and kainate-preferring receptors are implicated in the mediation of synaptic transmission in many regions including the hippocampus and visual cortex, whereas N-methyl-D-aspartate (NMDA)-preferring receptors are thought to be involved in modulating synaptic efficacy, for example in longterm potentiation, a form of synaptic plasticity in the hippocampus. In the visual cortex of the cat and monkey, it is well established that synaptic plasticity, estimated by susceptibility of binocular responsiveness of cortical neurons to monocular visual deprivation, disappears after the 'critical' period of postnatal development. Here we report that during the critical period in young kittens, a selective NMDA-receptor antagonist blocks visual responses of cortical neurons much more effectively than it does in the adult cat. This suggests that NMDA receptors may be involved in establishing synaptic plasticity in the kitten visual cortex.     

A network of fast-spiking cells in the neocortex connected by electrical synapses

Encoding of information in the cortex is thought to depend on synchronous firing of cortical neurons. Inhibitory neurons are known to be critical in the coordination of cortical activity, but how interaction among inhibitory cells promotes synchrony is not well understood. To address this issue directly, we have recorded simultaneously from pairs of fast-spiking (FS) cells, a type of gamma-aminobutyric acid (GABA)-containing neocortical interneuron. Here we report a high occurrence of electrical coupling among FS cells. Electrical synapses were not found among pyramidal neurons or between FS cells and other cortical cells. Some FS cells were interconnected by both electrical and GABAergic synapses. We show that communication through electrical synapses allows excitatory signalling among inhibitory cells and promotes their synchronous spiking. These results indicate that electrical synapses establish a network of fast-spiking cells in the neocortex which may play a key role in coordinating cortical activity.     

Two networks of electrically coupled inhibitory neurons in neocortex

Inhibitory interneurons are critical to sensory transformations, plasticity and synchronous activity in the neocortex. There are many types of inhibitory neurons, but their synaptic organization is poorly understood. Here we describe two functionally distinct inhibitory networks comprising either fast-spiking (FS) or low-threshold spiking (LTS) neurons. Paired-cell recordings showed that inhibitory neurons of the same type were strongly interconnected by electrical synapses, but electrical synapses between different inhibitory cell types were rare. The electrical synapses were strong enough to synchronize spikes in coupled interneurons. Inhibitory chemical synapses were also common between FS cells, and between FS and LTS cells, but LTS cells rarely inhibited one another. Thalamocortical synapses, which convey sensory information to the cortex, specifically and strongly excited only the FS cell network. The electrical and chemical synaptic connections of different types of inhibitory neurons are specific, and may allow each inhibitory network to function independently.     

Two methods of catecholamine depletion in kitten visual cortex yield different effects on plasticity

As first clearly demonstrated by the experiments of Wiesel and Hubel, the developing visual cortex is exquisitely sensitive to sensory deprivation. Temporary closure of one eye of a kitten during a critical period that extends from 3 weeks to 3 months of age results in a dramatic cortical reorganization such that most neurones, originally binocularly driven, are dominated exclusively by the open eye. Recently, attention has been directed to chemical factors which may influence the degree of plasticity during the critical period. The work of Kasamatsu and pettigrew suggests that cortical catecholamines, especially noradrenaline (NA), are essential for the normal plastic response to visual deprivation. In an effort to clarify the role of NA in visual cortical plasticity, we have monocularly deprived kittens whose cortex had been depleted of catecholamines by the neurotoxin 6-hydroxydopamine (6-OHDA). We used two strategies to deplete cortical NA: the first, pioneered by Kasamatsu el al., utilized osmotic minipumps to deliver 6-OHDA to visual cortex; the second involved systemic neonatal injections of 6-OHDA, a technique which has proved effective in rodents. We found, using high-pressure liquid chromatography (HPLC), that both techniques produced a substantial reduction in the level of cortical NA. However, single unit recording in area 17 revealed that the plastic response to monocular deprivation (MD) was only diminished in the kittens depleted by minipump.     

Bilateral amblyopia after a short period of reverse occlusion in kittens

The majority of neurones in the visual cortex of both adult cats and kittens can be excited by visual stimulation of either eye. Nevertheless, if one eye is deprived of patterned vision early in life, most cortical cells can only be activated by visual stimuli presented to the nondeprived eye and behaviourally the deprived eye is apparently useless. Although the consequences of monocular deprivation can be severe, they can in many circumstances be rapidly reversed with the early implementation of reverse occlusion which forces the use of the initially deprived eye. However, by itself reverse occlusion does not restore a normal distribution of cortical ocular dominance and only promotes visual recovery in one eye. In an effort to find a procedure that might restore good binocular vision, we have examined the effects on acuity and cortical ocular dominance of a short, but physiologically optimal period of reverse occlusion, followed by a period of binocular vision beginning at 7.5 weeks of age. Surprisingly, despite the early introduction of binocular vision, both eyes attained acuities that were only approximately 1/3 of normal acuity levels. Despite the severe bilateral amblyopia, cortical ocular dominance appeared similar to that of normal cats. This is the first demonstration of severe bilateral amblyopia following consecutive periods of monocular occlusion.     

Inhibitory threshold for critical-period activation in primary visual cortex

Neuronal circuits across several systems display remarkable plasticity to sensory input during postnatal development. Experience-dependent refinements are often restricted to well-defined critical periods in early life, but how these are established remains mostly unknown. A representative example is the loss of responsiveness in neocortex to an eye deprived of vision. Here we show that the potential for plasticity is retained throughout life until an inhibitory threshold is attained. In mice of all ages lacking an isoform of GABA (gamma-aminobutyric acid) synthetic enzyme (GAD65), as well as in immature wild-type animals before the onset of their natural critical period, benzodiazepines selectively reduced a prolonged discharge phenotype to unmask plasticity. Enhancing GABA-mediated transmission early in life rendered mutant animals insensitive to monocular deprivation as adults, similar to normal wild-type mice. Short-term presynaptic dynamics reflected a synaptic reorganization in GAD65 knockout mice after chronic diazepam treatment. A threshold level of inhibition within the visual cortex may thus trigger, once in life, an experience-dependent critical period for circuit consolidation, which may otherwise lie dormant.     

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.     

Reduction in number of immunostained GABAergic neurones in deprived-eye dominance columns of monkey area 17

The primary visual cortex (area 17) of the Old World monkey is divided into alternating right- and left-eye dominance columns that are highly modifiable by visual experience during a critical period in development but display little morphological or physiological plasticity during adult life. However, changes in immunocytochemical staining for a calcium/calmodulin-dependent protein kinase occur in visual cortical neurones of adult monkeys after brief monocular deprivation and concentrations of putative neurotransmitters or their related enzymes can be altered with changes in neuronal activity in other systems. We therefore examined the effects of monocular deprivation on the immunocytochemical staining for gamma-aminobutyric acid (GABA) and its synthetic enzyme, glutamic acid decarboxylase (GAD), in adult monkey area 17. The staining for GABA and GAD in neuronal somata and terminals was markedly reduced within ocular dominance columns associated with a removed or a visually deprived eye, suggesting that the GABA concentration in cortical neurones may depend on their levels of activity. Thus area 17 of adult monkeys may retain a greater degree of plasticity than previously recognized and sensory experience can profoundly affect transmitter levels, in the cortex, apparently by regulating levels of a synthetic enzyme.     

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.     

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.     

Ocular dominance plasticity in adult cat visual cortex after transplantation of cultured astrocytes

During a critical restricted period of postnatal development, the visual cortical circuitry is susceptible to modifications that are dependent on experience. If vision is restricted to only one eye during this period, the territories innervated by the deprived eye shrink considerably, whereas those innervated by the non-deprived eye expand, and the deprived eye loses the ability to influence almost all of the cells in the cortex. Thus, changes in ocular dominance are paralleled and possibly mediated by synapse elimination and axonal sprouting. Hypotheses about the mechanisms underlying ocular-dominance plasticity assume the activation of NMDA (N-methyl-D-aspartate) receptors and subsequent calcium influx as a trigger of synaptic modifications. In addition, plasticity relies on functional neuromodulatory afferents. On the basis of immunocytochemical studies, it was recently proposed that the presence of immature astrocytes is a prerequisite for visual cortical plasticity, and that the end of the critical period is causally linked to the maturation of astrocytes. Here we report, in support of this hypothesis, that resupplementation of the visual cortex of adult cats with astrocytes cultured from the visual cortex of newborn kittens reinduces ocular-dominance plasticity in adult animals.     

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.     

Ocular dominance shift in kitten visual cortex caused by imbalance in retinal electrical activity

Monocular lid suture during the sensitive period early in the life of a kitten disrupts normal development of inputs from the two eyes to the visual cortex, causing a decrease in the fraction of cortical cells responding to the deprived eye. Such an ocular dominance shift has been assumed to depend on patterned visual experience, because no change in cortical physiology is produced by inequalities between the two eyes in retinal illumination or temporally modulated diffuse light stimulation. A higher-level process, involving gating signals from areas outside striate cortex, has been proposed to ensure that sustained changes in synaptic efficacy occur only in response to behaviourally significant visual inputs. To test whether such a process is necessary for ocular dominance plasticity, we treated 4-week-old kittens with visual deprivation and monocular tetrodotoxin (TTX) injections to create an imbalance in the electrical activities of the two retinas in the absence of patterned vision. After 1 week of treatment we determined the ocular dominance distribution of single units in primary visual cortex. In all kittens studied, a significant ocular dominance shift was found. In addition to this physiological change, there was an anatomical change in the lateral geniculate nucleus, where cells were larger in laminae receiving input from the more active eye. Our results indicate that patterned vision is not necessary for visual cortical plasticity, and that an imbalance in spontaneous retinal activity alone can produce a significant ocular dominance shift.     

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.     

Experience-dependent plasticity of dendritic spines in the developing rat barrel cortex in vivo

Do changes in neuronal structure underlie cortical plasticity? Here we used time-lapse two-photon microscopy of pyramidal neurons in layer 2/3 of developing rat barrel cortex to image the structural dynamics of dendritic spines and filopodia. We found that these protrusions were highly motile: spines and filopodia appeared, disappeared or changed shape over tens of minutes. To test whether sensory experience drives this motility we trimmed whiskers one to three days before imaging. Sensory deprivation markedly (approximately 40%) reduced protrusive motility in deprived regions of the barrel cortex during a critical period around postnatal days (P)11-13, but had no effect in younger (P8-10) or older (P14-16) animals. Unexpectedly, whisker trimming did not change the density, length or shape of spines and filopodia. However, sensory deprivation during the critical period degraded the tuning of layer 2/3 receptive fields. Thus sensory experience drives structural plasticity in dendrites, which may underlie the reorganization of neural circuits.     

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.     

Modulation of visual cortical plasticity by acetylcholine and noradrenaline

During a critical period of postnatal development, the temporary closure of one eye in kittens will permanently shift the ocular dominance (OD) of neurones in the striate cortex to the eye that remains open. The OD plasticity can be substantially reduced if the cortex is infused continuously with the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA) during the period of monocular deprivation, an effect that has been attributed to selective depletion of cortical noradrenaline. However, several other methods causing noradrenaline (NA) depletion leave the plasticity intact. Here we present a possible explanation for the conflicting results. Combined destruction of the cortical noradrenergic and cholinergic innervations reduces the physiological response to monocular deprivation although lesions of either system alone are ineffective. We also find that 6-OHDA can interfere directly with the action of acetylcholine (ACh) on cortical neurones. Taken together, our results suggest that intracortical 6-OHDA disrupts plasticity by interfering with both cholinergic and noradrenergic transmission and raise the possibility that ACh and NA facilitate synaptic modifications in the striate cortex by a common molecular mechanism.     

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.     

Behavioural report of single neuron stimulation in somatosensory cortex

Understanding how neural activity in sensory cortices relates to perception is a central theme of neuroscience. Action potentials of sensory cortical neurons can be strongly correlated to properties of sensory stimuli and reflect the subjective judgements of an individual about stimuli. Microstimulation experiments have established a direct link from sensory activity to behaviour, suggesting that small neuronal populations can influence sensory decisions. However, microstimulation does not allow identification and quantification of the stimulated cellular elements. The sensory impact of individual cortical neurons therefore remains unknown. Here we show that stimulation of single neurons in somatosensory cortex affects behavioural responses in a detection task. We trained rats to respond to microstimulation of barrel cortex at low current intensities. We then initiated short trains of action potentials in single neurons by juxtacellular stimulation. Animals responded significantly more often in single-cell stimulation trials than in catch trials without stimulation. Stimulation effects varied greatly between cells, and on average in 5% of trials a response was induced. Whereas stimulation of putative excitatory neurons led to weak biases towards responding, stimulation of putative inhibitory neurons led to more variable and stronger sensory effects. Reaction times for single-cell stimulation were long and variable. Our results demonstrate that single neuron activity can cause a change in the animal's detection behaviour, suggesting a much sparser cortical code for sensations than previously anticipated.