Impact of cortical network activity on short-term synaptic depression

Repetitive stimulation of synaptic connections in the cerebral cortex often induces short-term synaptic depression (STD), a property directly related to the probability of transmitter release and critical for the computational properties of the network. In order to explore how spontaneous activity in the network affects this property, we first studied STD in cortical slices that were either silent or that displayed spontaneous rhythmic slow oscillations resembling those recorded during slow wave sleep in vivo. STD was considerably reduced by the occurrence of spontaneous rhythmic activity in the cortical network. Once the rhythmic activity started, depression decreased over time in parallel with the duration and intensity of the ongoing activity until a plateau was reached. Thalamocortical and intracortical synaptic potentials studied in vivo also showed stronger depression in a silent than in an active cortical network, and the depression values in the active cortical network in vivo were indistinguishable from those found in active slices in vitro. We suggest that this phenomenon is due to the different steady states of the synapses in active and in silent networks.     

Cortical efferent control of subcortical sensory neurons by synaptic disinhibition

A long-standing hypothesis predicts that pyramidal neurons of the cerebral cortex control the influx of sensory information at the level of primary sensory representations areas. Yet little is known about the cellular mechanisms governing selective attention to behaviorally relevant objects in space. Neurons in the superficial layers of the superior colliculus are notably involved in this process, and they are directly targeted by retinal and cortical afferents. To study long-term and short-term effects of the visual cortex (VC) on subcortical visual neurons we established an in vitro model of the developing cortico-tectal projection. To this end, cortical explants expressing Green Fluorescent Protein were allowed to form connections with non-labeled dissociated tectal neurons. The presence of VC explants led to an enhancement of tectal activity by 2 mechanisms. First, glutamatergic input was increased. Second, intrinsic GABAergic inhibition was suppressed. The latter effect was shown to be acute and mediated through postsynaptic metabotropic glutamate receptor activation, G-protein acitivity, and endocannabinoid receptor activation. The VC-induced disinhibition was readily reversed by application of an mGluR antagonist. However, high-frequency activation of the glutamatergic cortico-tectal input turned the labile disinhibition into a persistent suppression of inhibition.     

Tuning curve shift by attention modulation in cortical neurons: a computational study of its mechanisms

Physiological studies of visual attention have demonstrated that focusing attention near a visual cortical neuron's receptive field (RF) results in enhanced evoked activity and RF shift. In this work, we explored the mechanisms of attention induced RF shifts in cortical network models that receive an attentional 'spotlight'. Our main results are threefold. First, whereas a 'spotlight' input always produces toward-attention shift of the population activity profile, we found that toward-attention shifts in RFs of single cells requires multiplicative gain modulation. Secondly, in a feedforward two-layer model, focal attentional gain modulation in first-layer neurons induces RF shift in second-layer neurons downstream. In contrast to experimental observations, the feedforward model typically fails to produce RF shifts in second-layer neurons when attention is directed beyond RF boundaries. We then show that an additive spotlight input combined with a recurrent network mechanism can produce the observed RF shift. Inhibitory effects in a surround of the attentional focus accentuate this RF shift and induce RF shrinking. Thirdly, we considered interrelationship between visual selective attention and adaptation. Our analysis predicts that the RF size is enlarged (respectively reduced) by attentional signal directed near a cell's RF center in a recurrent network (resp. in a feedforward network); the opposite is true for visual adaptation. Therefore, a refined estimation of the RF size during attention and after adaptation would provide a probe to differentiate recurrent versus feedforward mechanisms for RF shifts.     

Single neurons can induce phase transitions of cortical recurrent networks with multiple internal States

Fluctuations of membrane potential of cortical neurons, referred to here as internal states, are essential for brain function, but little is known about how these internal states emerge and are maintained, or what determines transitions between these states. We performed intracellular recordings from hippocampal CA3 pyramidal cells ex vivo and found that neurons display multiple and hierarchical internal states, which are linked to cholinergic activity and are characterized by several power law structures in membrane potential dynamics. Multiple recordings from adjacent neurons revealed that the internal states were coherent between neurons, indicating that the internal state of any given cell in a local network could represent the network activity state. Repeated stimulation of single neurons led over time to transitions to different internal states in both the stimulated neuron and neighboring neurons. Thus, single-cell activation is sufficient to shift the state of the entire local network. As the states shift to more active levels, theta- and gamma-frequency components developed in the form of subthreshold oscillations. State transitions were associated with changes in membrane conductance but were not accompanied by a change in reversal potential. These data suggest that the recurrent network organizes the internal states of individual neurons into synchronization through network activity with balanced excitation and inhibition, and that this organization is discrete, heterogeneous and dynamic in nature. Thus, neuronal states reflect the 'phase' of an active network, a novel demonstration of the dynamics and flexibility of cortical microcircuitry.     

Sparseness constrains the prolongation of memory lifetime via synaptic metaplasticity

Synaptic changes impair previously acquired memory traces. The smaller this impairment the larger is the longevity of memories. Two strategies have been suggested to keep memories from being overwritten too rapidly while preserving receptiveness to new contents: either introducing synaptic meta levels that store the history of synaptic state changes or reducing the number of synchronously active neurons, which decreases interference. We find that synaptic metaplasticity indeed can prolong memory lifetimes but only under the restriction that the neuronal population code is not too sparse. For sparse codes, metaplasticity may actually hinder memory longevity. This is important because in memory-related brain regions as the hippocampus population codes are sparse. Comparing 2 different synaptic cascade models with binary weights, we find that a serial topology of synaptic state transitions gives rise to larger memory capacities than a model with cross transitions. For the serial model, memory capacity is virtually independent of network size and connectivity.     

A dynamic shift of neural network activity before and after learning-set formation

Learning-set (LS) is a property of insight and hypothesis testing characterized by the ability to solve novel problems based on previous experiences with problem solving. However, the neural organization and mechanisms underlying LS remain unclear. To further characterize this process, positron emission tomography (PET) studies with [15O]H2O were performed to measure regional cerebral blood flow (rCBF) during the learning phase of the two-choice visual discrimination task under the LS paradigm in rhesus monkeys. When comparing studies before and after LS formation, the orbitofrontal and lateral prefrontal cortices were differentially activated, and functional connections between these structures and the striatum, which contributes to habit learning, were altered. We conclude that changes in the lateral prefrontal cortex during problem solving may contribute to the executive function of working memory and also inhibit control of a primitive learning system, thereby promoting LS formation.     

Duration-dependent FMRI adaptation and distributed viewer-centered face representation in human visual cortex

Two functional magnetic resonance imaging (fMRI) face viewpoint adaptation experiments were conducted to investigate whether fMRI adaptation in high-level visual cortex depends on the duration of adaptation and how different views of a face are represented in the human visual system. We found adaptation effects in multiple face-selective areas, which suggest a distributed, viewer-centered representation of faces in the human visual system. However, the nature of the adaptation effects was dependent on the length of adaptation. With long adaptation durations, face-selective areas along the hierarchy of the visual system gradually exhibited viewpoint-tuned adaptation. As the angular difference between the adapter and test stimulus increased, the blood oxygen level-dependent (BOLD) signal evoked by the test stimulus gradually increased as a function of the amount of 3-dimensional (3D) rotation. With short adaptation durations, however, face-selective areas in the ventral pathway, including the lateral occipital cortex and right fusiform area, exhibited viewpoint-sensitive adaptation. These areas showed an increase in the BOLD signal with a 3D rotation, but this signal increase was independent of the amount of rotation. Further, the right superior temporal sulcus showed little or very weak viewpoint adaptation with short adaptation durations. Our findings suggest that long- and short-term fMRI adaptations may reflect selective properties of different neuronal mechanisms.     

Degradation of signal timing in cortical areas V1 and V2 of senescent monkeys

Senescence in monkeys results in a degradation of the functional properties of cortical cells as well as prolonged hyperactivity. We have now compared the spontaneous and visually evoked activity levels, as well as the visual response latencies of cells in cortical areas V1 and V2 of young and very old monkeys. We found that V1 cells within layer 4 exhibit normal latencies. In contrast, in other parts of V1 and throughout V2 hyperactivity in old monkeys is accompanied by dramatic delays in both the intracortical and intercortical transfer of information. Extrastriate cortex (area V2) is affected more severely than striate cortex (V1). Delayed information processing in cerebral cortex should contribute to the declines in cortical function that accompany old age.     

Similar frontal and distinct posterior cortical regions mediate visual and auditory perceptual awareness

Activity in ventral visual cortex is a consistent neural correlate of visual consciousness. However, activity in this area seems insufficient to produce awareness without additional involvement of frontoparietal regions. To test the generality of the frontoparietal response, neural correlates of auditory awareness were investigated in a paradigm that previously has revealed frontoparietal activity during conscious visual perception. A within-experiment comparison showed that frontal regions were related to both visual and auditory awareness, whereas parietal activity was correlated with visual awareness and superior temporal activity with auditory awareness. These results indicate that frontal regions interact with specific posterior regions to produce awareness in different sensory modalities.     

Estrogen replacement increases spinophilin-immunoreactive spine number in the prefrontal cortex of female rhesus monkeys

While studies have shown that estrogen affects hippocampal spine density and function, behavioral studies in humans and nonhuman primates have also implicated the prefrontal cortex in the effects of estrogen on cognition. However, the potential for similar estrogen-induced increases in spines and synapses in the prefrontal cortex has not been investigated in primates. Moreover, it is not known if such an estrogen effect would be manifested throughout the neocortex or primarily in the regions involved in cognition. Therefore, we investigated the effects of estrogen on dendritic spines in the prefrontal and primary visual cortices of young rhesus monkeys. Young female monkeys were ovariectomized and administered either estradiol cypionate or vehicle by intramuscular injection. Using an antibody against the spine-associated protein, spinophilin, spine numbers were estimated in layer I of area 46 and in layer I of the opercular portion of area V1 (V1o). Spine numbers in layer I of area 46 were significantly increased (55%) in the ovariectomy + estrogen group compared to the ovariectomy + vehicle group, yet spine numbers in layer I of area V1o were equivalent across the two groups. The present results suggest that estrogen's effects on synaptic organization influence select neocortical layers and regions in a primate model, and provide a morphological basis for enhanced prefrontal cortical functions following estrogen replacement.     

Functional connectivity of cortical networks involved in bimanual motor sequence learning

Motor skill learning requires the involvement and integration of several cortical and subcortical regions. In this study, we focus on how the functional connectivity of cortical networks changes with the acquisition of a novel motor skill. Using functional magnetic resonance imaging, we measured the localized blood oxygenation level-dependent (BOLD) signal in cortical regions while subjects performed a bimanual serial reaction time task under 2 conditions: 1) explicitly learning a novel sequence (NOVEL) and 2) playing a previously learned sequence (LEARNED). To investigate stages of learning, each condition was further divided into nonoverlapping early and late conditions. Functional connectivity was measured using a task-specific low-frequency coherence analysis of the data. We show that within the cortical motor network, the sensorimotor cortex, premotor cortex, and supplementary motor area have significantly greater inter- and intrahemispheric coupling during the early NOVEL condition compared with the late NOVEL condition. Additionally, we observed greater connectivity between frontal regions and cortical motor regions in the early versus late NOVEL contrast. No changes in functional connectivity were observed in the LEARNED condition. These results demonstrate that the functional connectivity of the cortical motor network is modulated with practice and suggest that early skill learning is mediated by enhanced interregional coupling.     

Multiparametric changes in the receptive field of cortical auditory neurons induced by thalamic activation in the mouse

The functional organization of the sensory cortex is constructed to process sensory information based on experience and learning. Importantly, it is plastic so that it can quickly adapt to environmental changes. Because the thalamus gates all ascending information, it is critical to understand how the thalamocortical system contributes to the plasticity of the sensory cortex. We show here that the neuronal receptive field (RF) in the auditory cortex faithfully tends toward the RF of the electrically stimulated auditory thalamic neurons. We characterized the RF of auditory neurons by measuring the best frequency, minimum threshold, bandwidth, RF area, and averaged response magnitude. All these parameters of the cortical RF showed robust changes toward the values of the parameters of the stimulated thalamic neuron following focal thalamic stimulation. Our data suggest that the thalamocortical system possesses intrinsic mechanisms that underlie the input specificity of learning-induced or experience-dependent cortical plasticity.     

A computational model for the development of multiple maps in primary visual cortex

Primary visual cortex contains multiple maps of features of the visual scene, including visual field position, orientation, direction, ocular dominance and spatial frequency. The complex relationships between these maps provide clues to the strategies the cortex uses for representing and processing information. Here we simulate the combined development of all these map systems using a computational model, the elastic net. We show that this model robustly produces combined maps of these four variables that bear a close resemblance to experimental maps. In addition we show that the experimentally observed effects of monocular deprivation and single-orientation rearing can be reproduced in this model, and we make some testable predictions. These results provide strong support for the hypothesis that cortical representations attempt to optimize a trade-off between coverage and continuity.     

V1 activation in congenitally blind humans is associated with episodic retrieval

Recently we showed that the occipital cortex of congenitally blind humans is activated during verbal-memory tasks. Activation was found in regions corresponding to the retinotopic visual areas of sighted humans, including the calcarine sulcus (V1). No such occipital activation was found in sighted humans. One year later, the same blind subjects participated in a second fMRI scan, to study the contribution of semantic elements and episodic memory to the occipital activation. The subjects performed an episodic-memory task, requiring recognition of words that were originally presented in the first scan. We demonstrate here that the magnitude of V1 activation during the recognition task is correlated with memory performance, assessed during the scan. Across the blind, the better-remembered set of words elicited greater V1 activation than words from the poorly-remembered set, although the semantic components and the behavioral task were similar in the two sets. This indicates that on top of semantic processing (suggested previously), V1 activation in the blind is probably associated with long-term episodic memory. Indeed, within the blind, those who showed better recognition-memory performance had greater V1 activation compared with the poorer performers. We conclude that the posterior occipital cortex (including V1) of the congenitally blind is likely to be involved in episodic retrieval.     

Face recognition and cortical responses show similar sensitivity to noise spatial frequency

To find cortical correlates of face recognition, we manipulatedthe recognizability of face images in a parametric manner bymasking them with narrow-band spatial noise. Face recognitionperformance was best at the lowest and highest noise spatialfrequencies (NSFs, 2 and 45 c/image, respectively), and degradedgradually towards central NSFs (11–16 c/image). The strengthof the 130–180 ms neuromagnetic response (M170) in thetemporo-occipital cortex paralleled the recognition performance,whereas the mid-occipital response at 70–120 ms actedin the opposite manner, being strongest for the central NSFs.To noise stimuli without faces, M170 was small and rather insensitiveto NSF, whereas the mid-occipital responses resembled closelythe responses to the combined face and noise stimuli. Theseresults suggest that the 100 ms mid-occipital response is sensitiveto the central spatial frequencies that are critical for facerecognition, whereas the M170 response is sensitive to the visibilityof a face and closely related to face recognition.     

Three-dimensional structure-from-motion selectivity in the anterior superior temporal polysensory area, STPa, of the behaving monkey

Human and non-human primates are able to perceive three-dimensional structure from motion displays. Three-dimensional structure-from-motion (object-motion) displays were used to test the hypothesis that neurons in the anterior division of the superior temporal polysensory area (STPa) of monkeys can selectively respond to three-dimensional structure-from-motion. Monkeys performed a reaction time task that required the detection of a change in the fraction of structure in three-dimensional transparent sphere displays. Neurons were able to distinguish structured and unstructured three-dimensional optic flow. These cells could differentiate the change in structure-from-motion at stimulus presentation and when the animal was detecting the amount of structure in the display. Some of these neurons were also tuned for characteristics of the sphere stimuli. Cells were also tested with navigational motion and many were found to respond both to three-dimensional structure-from-motion and navigational motion. These results suggest that STPa neurons represent specific aspects of three-dimensional surface structure and that neurons within STPa contribute to the perception of three-dimensional structure-from-motion.     

Localization of the human cortical visual area MT based on computer aided histological analysis

We describe human area MT histologically based on the observer independent analysis of cortical myeloarchiteture, multiple complementary staining techniques and 3-D reconstruction. The topography of an architectonic field that presented constant structural characteristics across specimens was studied in relation to the sulcal geography of the occipito-temporal region. Objective and semi-automated analysis of local microstructure revealed a distinct cortical architecture and matched topographically the localization of MT derived from functional imaging. MT was localized by the histotopographic method in relation to definite macroscopic landmarks. This study demonstrates a new set of distinguishing architectonic features of human MT that permit localization on structural grounds and suggests that the characteristic laminar structure of this area may be related to its unique pattern of connections and to its role in visual perception.     

High response reliability of neurons in primary visual cortex (V1) of alert, trained monkeys

The reliability of neuronal responses determines the resources needed to represent the external world and constrains the nature of the neural code. Studies of anesthetized animals have indicated that neuronal responses become progressively more variable as information travels from the retina to the cortex. These results have been interpreted to indicate that perception must be based on pooling across relatively large numbers of cells. However, we find that in alert monkeys, responses in primary visual cortex (V1) are as reliable as the inputs from the retina and the thalamus. Moreover, when the effects of fixational eye movements were minimized, response variability (variance/mean - Fano factor, FF) in all V1 layers was low. When presenting optimal stimuli, the median FF was 0.3. High variability, FF approximately 1, was found only near threshold. Our results suggest that in natural vision, suprathreshold perception can be based on small numbers of optimally stimulated cells.     

Persistent responsiveness of long-latency auditory cortical activities in response to repeated stimuli of musical timbre and vowel sounds

Long-latency auditory-evoked magnetic field and potential show strong attenuation of N1m/N1 responses when an identical stimulus is presented repeatedly due to adaptation of auditory cortical neurons. This adaptation is weak in subsequently occurring P2m/P2 responses, being weaker for piano chords than single piano notes. The adaptation of P2m is more suppressed in musicians having long-term musical training than in nonmusicians, whereas the amplitude of P2 is enhanced preferentially in musicians as the spectral complexity of musical tones increases. To address the key issues of whether such high responsiveness of P2m/P2 responses to complex sounds is intrinsic and common to nonmusical sounds, we conducted a magnetoencephalographic study on participants who had no experience of musical training, using consecutive trains of piano and vowel sounds. The dipole moment of the P2m sources located in the auditory cortex indicated significantly suppressed adaptation in the right hemisphere both to piano and vowel sounds. Thus, the persistent responsiveness of the P2m activity may be inherent, not induced by intensive training, and common to spectrally complex sounds. The right hemisphere dominance of the responsiveness to musical and speech sounds suggests analysis of acoustic features of object sounds to be a significant function of P2m activity.     

Oligodendrocytes, their progenitors and other neuroglial cells in the aging primate cerebral cortex

In a previous study it was found that with age there is an increase in the frequency of paranodal profiles of myelinated nerve fibers in the cerebral cortex of monkeys. This indicates that there is an increase in the number of internodal myelin segments, and raises the question of whether additional oligodendrocytes are necessary to generate the increased numbers of internodal myelin segments. The present study shows that in layer 4C beta of monkey primary visual cortex there is an age-related increase in the number of oligodendrocytes. When young (4-10 years of age) and old (25-35 years of age) monkeys are compared, the increase is found to be approximately 50%, and it begins in middle age (12-19 years old). It is also shown that although there is no increase in the population of astrocytes in layer 4C beta with age, there appears to be a slight increase in the frequency of microglial cells. As their numbers increase, oligodendrocytes in pairs, rows and groups become more common, which suggests that additional oligodendrocytes are being generated by cell division. Since there is little evidence that mature oligodendrocytes can divide, it is probable that the new oligodendrocytes are generated from progenitor cells which, as many studies have shown, can be labeled by antibodies to NG2, a chondroitin sulfate proteoglycan. By comparing the appearance of these NG2-labeled cells with cells encountered in thin sections of normally prepared tissue, it is shown that the NG2-positive cells have the features of neuroglial cells that were previously described as beta astrocytes.