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The repulsive guidance molecule RGMa is involved in the formation of afferent connections in the dentate gyrus.

In the developing dentate gyrus, afferent fiber projections terminate in distinct laminas. This relies on an accurately regulated spatiotemporal network of guidance molecules. Here, we have analyzed the functional role of the glycosylphosphatidylinositol (GPI)-anchored repulsive guidance molecule RGMa. In situ hybridization in embryonic and postnatal brain showed expression of RGMa in the cornu ammonis and hilus of the hippocampus. In the dentate gyrus, RGM immunostaining was confined to the inner molecular layer, whereas the outer molecular layers targeted by entorhinal fibers remained free. To test the repulsive capacity of RGMa, different setups were used: the stripe and explant outgrowth assays with recombinant RGMa, and entorhino-hippocampal cocultures incubated either with a neutralizing RGMa antibody (Ab) or with the GPI anchor-digesting drug phosphatidylinositol-specific phospholipase C. Entorhinal axons were clearly repelled by RGMa in the stripe and outgrowth assays. After disrupting the RGMa function, the specific laminar termination pattern in entorhino-hippocampal cocultures was lost, and entorhinal axons entered inappropriate hippocampal areas. Our data indicate an important role of RGMa for the layer-specific termination of the perforant pathway as a repulsive signal that compels entorhinal fibers to stay in their correct target zone.

Afferent Pathways↗

Functional roles of the cingulo-frontal network in performance on working memory.

We examined the relationship between brain activities and task performance on working memory. A large-scale study was initially administered to identify good and poor performers using the operation span and reading span tasks. On the basis of those span scores, we divided 20 consenting participants into high- and low-span groups. In an fMRI study, the participants performed verification of arithmetic problems and retention of target words either concurrently or separately. The behavioral results showed that performance was better in the high-span group than in the low-span group under a dual-task condition, but not under two single-task conditions. The anterior cingulate cortex (ACC), left prefrontal cortex (PFC), left inferior frontal cortex, and bilateral parietal cortex were primarily activated for both span groups. We found that signal changes in the ACC were greater in the high-span group than in the low-span group under the dual-task condition, but not under the single-task conditions. Structural equation modeling indicated that an estimate of effective connectivity from the ACC to the left PFC was positive for the high-span group and negative for the-low span group, suggesting that closer cooperation between the two brain regions was strongly related to working memory performance. We conclude that central executive functioning for attention shifting is modulated by the cingulo-frontal network.

Adult↗

Cortical activation in patients with functional hemispherectomy.

Functional hemispherectomy, a safe and effective therapeutical procedure in medically intractable epilepsy, offers the chance to investigate a strictly unilateral cortical activation in ipsilateral limb movement. We assessed the pattern of cortical activation in a group of patients following functional hemispherectomy. We measured regional cerebral blood flow (rCBF) in 6 patients postoperatively and 6 normal subjects with positron emission tomography using 15[O]H2O as a tracer. Brain activation was achieved by passive elbow movements of the affected arm. Analysis of group results and between-group comparisons were performed with statistical parametric mapping, (SPM96). In normal subjects brain activation was found contralaterally in the cranial sensorimotor cortex and the supplementary motor area and ipsilaterally in the inferior parietal cortex. In patients significant rCBF increases were found in the inferior parietal cortex, caudal sensorimotor cortex and the supplementary motor area ipsilaterally. The activation was weaker than in normal subjects. Compared with normal subjects patients showed additional activation in the premotor cortex, caudal sensorimotor cortex and the inferior parietal cortex of the remaining hemisphere. Less activation compared with normal subjects was found in the cranial sensorimotor cortex and the supplementary motor area. A functional network connecting the inferior parietal cortex, premotor cortex and the supplementary motor area as well as the existence of ipsilateral projections originating from these regions may explain why these areas are predominantly involved in reorganization confined to a single hemisphere.

Adult↗

A neural network model of memory and higher cognitive functions.

I first describe a neural network model of associative memory in a small region of the brain. The model depends, unconventionally, on disinhibition of inhibitory links between excitatory neurons rather than long-term potentiation (LTP) of excitatory projections. The model may be shown to have advantages over traditional neural network models both in terms of information storage capacity and biological plausibility. The learning and recall algorithms are independent of network architecture, and require no thresholds or finely graded synaptic strengths. Several copies of this local network are then connected by means of many, weak, reciprocal, excitatory projections that allow one region to control the recall of information in another to produce behaviors analogous to serial memory, classical and operant conditioning, secondary reinforcement, refabrication of memory, and fabrication of possible future events. The network distinguishes between perceived and recalled events, and can predicate its response on the absence as well as the presence of particular stimuli. Some of these behaviors are achieved in ways that seem to provide instances of self-awareness and imagination, suggesting that consciousness may emerge as an epiphenomenon in simple brains.

Algorithms↗

Social cognition, brain networks and schizophrenia.

BACKGROUND: A better understanding of the neural basis of social cognition including mindreading (or theory of mind) and empathy might help to explain some deficits in social functioning in people with schizophrenia. Our aim was to review neuroimaging and neuropsychological studies on social cognition, as they may shed light on the neural mechanisms of social cognition and its dysfunction in patients with schizophrenia. METHOD: A selective literature review was undertaken. RESULTS: Neuroimaging and neuropsychological studies suggest convergence upon specific networks for mindreading and empathy (the temporal cortex, amygdala and the prefrontal cortex). The frontal lobe is likely to play a central role in enabling social cognition, but mindreading and empathic abilities may require relatively different weighting of subcomponents within the same frontal-temporal social cognition network. CONCLUSIONS: Disturbances in social cognition may represent an abnormal interaction between frontal lobe and its functionally connected cortical and subcortical areas. Future studies should seek to explore the heterogeneity of social dysfunction within schizophrenia.

Brain Mapping↗

Effect of focal and nonfocal cerebral lesions on functional connectivity studied with MR imaging.

BACKGROUND AND PURPOSE: Functional connectivity MR (fcMR) imaging is used to map regions of brain with synchronous, regional, slow fluctuations in cerebral blood flow. We tested the hypothesis that focal cerebral lesions do not eradicate expected functional connectivity. METHODS: Functional MR (fMR) and fcMR maps were acquired for 12 patients with focal cerebral tumors, cysts, arteriovenous malformations, or in one case, agenesis of the corpus callosum. Task activation secondary to text listening, finger tapping, and word generation was mapped by use of fMR imaging. Functional connectivity was measured by selecting "seed" voxels in brain regions showing activation (based on the fMR data) and cross correlating with every other voxel (based on data acquired while the subject performed no task). Concurrence of the fMR and fcMR maps was measured by comparing the location and number of voxels selected by both methods. RESULTS: Technically adequate fMR and fcMR maps were obtained for all patients. In patients with focal lesions, the fMR and fcMR maps correlated closely. The fcMR map generated for the patient with agenesis of the corpus callosum failed to reveal functional connectivity between blood flow in the left and right sensorimotor cortices and in the frontal lobe language regions. Nonetheless, synchrony between blood flow in the auditory cortices was preserved. On average, there was 40% concurrence between all fMR and fcMR maps. CONCLUSION: Patterns of functional connectivity remain intact in patients with focal cerebral lesions. Disruption of major neuronal networks, such as agenesis of the corpus callosum, may diminish the normal functional connectivity patterns. Therefore, functional connectivity in such patients cannot be fully demonstrated with fcMR imaging.

Agenesis of Corpus Callosum↗

Visually evoked gamma responses in the human brain are enhanced during voluntary hyperventilation.

Hypocapnia induced by hyperventilation (HV) has powerful effects on neuronal excitability and synaptic transmission. We have studied the effect of hyperventilation on the phase-locked oscillatory components of the evoked responses in the human brain. We recorded visually evoked magnetoencephalographic responses before, during, and after voluntary hyperventilation to pattern-reversal checkerboard stimuli. Gamma-band (30-45 Hz) responses phase-locked to the stimuli were generated in the occipital visual cortex. A wavelet-based time-frequency analysis revealed that the gamma responses increased during HV whereas their frequency did not change significantly. A recent in vitro study in the rat hippocampus demonstrated that the stability of spontaneous gamma activity increases during hypocapnia as a result of enhanced GABAergic transmission. To test if a similar mechanism could account for our findings, we performed simulations on a network of 100 Hodgkin-Huxley neurons connected by inhibitory synapses. We found that enhanced GABA(A) transmission, paired with enhanced excitability, can explain the increase in evoked gamma activity without changing the frequency.

Adult↗

Forming sparse representations by local anti-Hebbian learning.

How does the brain form a useful representation of its environment? It is shown here that a layer of simple Hebbian units connected by modifiable anti-Hebbian feed-back connections can learn to code a set of patterns in such a way that statistical dependency between the elements of the representation is reduced, while information is preserved. The resulting code is sparse, which is favourable if it is to be used as input to a subsequent supervised associative layer. The operation of the network is demonstrated on two simple problems.

Brain↗

Synaptic mechanisms for auditory-vocal integration and the correction of vocal errors.

A central goal of neuroscience is to understand the cellular mechanisms enabling the cultural transmission of behaviors, such as speech and music. Birdsong is a rare non-human instance of a culturally transmitted vocal behavior. The songbird's brain provides a powerful system in which to study the cellular mechanisms underlying auditory-guided vocal learning. Identifying those mechanisms requires an analysis of synaptic function, because the synapse is the fundamental organizational unit of the neuronal networks that mediate behavior. Intracellular recordings provide a powerful method for simultaneously probing the activities of a single neuron and the synaptic networks in which that cell is embedded. This chapter details initial steps in the in vivo intracellular analysis of the synaptic connectivity of neurons important to singing and song learning. Our analysis is focused upon HVC and involves studies of interneurons as well as projection neurons of the two major output pathways of HVC. We test predictions derived from several models of how such learning may take place, including contributions from "comparator" and "corollary discharge" auditory feedback cancellation mechanisms. Our studies in anesthetized animals and brain slices provide insight into the synaptic properties of HVC that might be well suited for these mechanisms, although extrapolation to synaptic behavior in the awake, singing bird must be made with caution. We suggest that future work must extend the analysis of synaptic properties into the intact brain of the songbird, preferably as the bird learns to sing.

Animals↗

Multiple neural systems controlling food intake and body weight.

Discovery of the leptin receptor and its downstream peptidergic pathways has reconfirmed the crucial role of the hypothalamus in the regulation of food intake and energy balance. Strategically located in the midst of the mammalian neuraxis, the hypothalamus receives at least three distinct types of relevant information via direct or indirect neural connections as well as hormone receptors and substrate sensors bestowed on hypothalamic neurons. First, the medial and to a lesser extent the lateral hypothalamus receive a rich mix of information pertaining to the internal state of relative energy repletion/depletion. Second, specific hypothalamic nuclei receive information about the behavioral state, such as diurnal clock, physical activity-level, reproductive cycle, developmental stage, as well as imminent (e.g. fight and flight) and chronic (e.g. infection) stressors, that can potentially impact on short-term availability of fuels and long-term energy balance. Third, the hypothalamus, particularly its lateral aspects, receives information from areas in the forebrain involved in the acquisition, storage, and retrieval of sensory representations of the external food space and internal food experience, as well as from the executive forebrain involved in behavior selection and initiation. In addition, rich intrahypothalamic connections facilitate further distribution of incoming information to various hypothalamic nuclei. On the other hand, the hypothalamus has widespread neural projections to the same cortical areas it receives inputs, and many hypothalamic neurons are one synapse away from most endocrine systems and from both sympathetic and parasympathetic effector organs involved in the flux, storage, mobilization, and utilization of fuels. It is argued that processing within cortico-limbic areas and communication with hypothalamic areas are particularly important in human food intake control that is more and more guided by cognitive rather than metabolic aspects in the obesigenic environment of affluent societies. A distributed neural network for the control of food intake and energy balance consisting of a central processor and several parallel processing loops is hypothesized. Detailed neurochemical, anatomical, and functional analysis of reciprocal connections of the numerous peptidergic neuron populations in the hypothalamus with extrahypothalamic brain areas will be necessary to better understand what hypothalamus, forebrain, and brainstem tell each other and who is in charge under specific conditions of internal and external nutrient availability.

Animals↗

Planarian Gtsix3, a member of the Six/so gene family, is expressed in brain branches but not in eye cells.

Six/sine oculis (Six/so) class genes, with representatives in vertebrates and invertebrates, include members with key developmental roles in the anterior part of the central nervous system (CNS) and eye. Having characterized the role of the first planarian gene of the Six/so family in eye development, we attempted to identify novel genes of this family related to the platyhelminth eye genetic network. We isolated a new Six/so gene in the planarian Girardia tigrina, Gtsix-3, which belongs to the Six3/6 class. Whole mount in situ hybridization revealed Gtsix3 expression in a stripe surrounding the cephalic ganglia in adults. This spatial pattern corresponds to the cephalic branches, the nerve cells that connect the CNS with the marginal sensory organs located continuously at the edge of the head. During head regeneration, Gtsix-3 shows delayed activation compared to other head genes, with an initial two spot pattern that later evolves to a continuous lateral expression in the new regenerated cephalic ganglia with a final reduction to the adult pattern. However, Gtsix-3 is not activated in tail regeneration and no eye expression is observed at any regenerative stage. These findings provide a new marker for the developing anterior nervous system and evidence the complexity of planarian brain.

Amino Acid Sequence↗

Structure of a tonically transmitting synapse between identified interneurone in the locust brain.

The ultrastructure and distribution of synapses between large second-order and third-order neurones of a locust ocellus are described. Pairs of neurones, shown by physiological tests to be connected by a tonically transmitting, excitatory connection, have been injected with hexamminecobaltic ions, which allows their profiles to be recognised with electron microscopy. The synapses are made in the lateral ocellar tract, between the axons of some of the second-order neurones and a network of fine processes from the third-order neurone. A physiological connection is composed of several thousand discrete anatomical synapses. Each anatomical synapse is composed of a presynaptic density associated with a cloud of round, electron-lucent vesicles overlying an intercellular cleft. Parallel with the presynaptic density is a row of omega-shaped invaginations of the presynaptic plasmalemma. The synapses are diadic and are close to synapses from small, unidentified neuronal profiles onto the third-order neurone.

Animals↗

Emergence of neural integration in the head-direction system by visual supervision.

Head-direction (HD) cells in subcortical areas of the mammalian brain are tuned to a particular head direction in space; a population of such neurons forms a neural compass that may be relevant for spatial navigation. The development of neural circuits constituting the head-direction system is poorly understood. Inspired by electrophysiological experiments about the role of recurrent synaptic connections, we investigate a learning rule that teaches neurons to amplify feed-forward inputs. We simulate random head movements of a rat, during which neurons receive both visual and vestibular (head-velocity) inputs. Remarkably, as recurrent connections learn to amplify exclusively the visual inputs, a neural network emerges that performs spatio-temporal integration. That is, during head movements in darkness, neurons resemble HD cells by maintaining a fixed tuning to head direction. The proposed learning rule exhibits similarities with known forms of anti-Hebbian synaptic plasticity. We conclude that selective amplification could serve as a general principle for the synaptic development of multimodal feedback circuits in the brain.

Algorithms↗

The DFNB31 gene product whirlin connects to the Usher protein network in the cochlea and retina by direct association with USH2A and VLGR1.

Mutations in the DFNB31 gene encoding the PDZ scaffold protein whirlin are causative for hearing loss in man and mouse. Whirlin is known to be essential for the elongation process of the stereocilia of sensory hair cells in the inner ear, though its complete spatial and temporal expression patterns remained elusive. Here, we demonstrate that, in embryonic development, the gene is not only expressed in the inner ear, but also in the developing brain and the retina. Various isoforms of whirlin are widely and differentially expressed, and we provide evidence that whirlin directly associates with USH2A isoform b and VLGR1b, two proteins that we previously reported to be part of the Usher protein interactome. These proteins co-localize with whirlin at the synaptic regions of both photoreceptor cells and outer hair cells in the cochlea. These findings indicate that whirlin is part of a macromolecular PDZ protein scaffold that functions in the organization of the pre- and/or postsynaptic side of photoreceptor and hair cell synapses. Whirlin might be involved in synaptic adhesion through interaction with USH2A and VLGR1b as well as in synaptic development as suggested by its spatial and temporal expression patterns. In addition, we demonstrate that whirlin, USH2A and Vlgr1b co-localize at the connecting cilium and the outer limiting membrane of photoreceptor cells and in spiral ganglion neurons of the inner ear. Our data show that whirlin is connected to the dynamic Usher protein interactome and indicate that whirlin has a pleiotropic function in both the retina and the inner ear.

Animals↗

Atlas of serotonin-containing neurons in the optic lobes and brain of the crayfish, Cherax destructor.

An atlas of neurons in the brain of the crayfish Cherax destructor that are immunoreactive to antibodies raised against serotonin has been compiled from whole mount preparations. Neuronal networks of serotonin-containing cells are identified in the optic lobes and protocerebrum, in the deutocerebrum, and in the tritocerebrum. The consistency of the whole-mount technique allows 50 out of a total of about 100 immunoreactive cells to be individually identified according to their neuronal architecture or the location of their cell somata or axons. Apart from six neurons with axons in the oesophageal connectives, all the immunoreactive cells are intrinsic to the optic lobes and brain.

Animals↗

Neural processes underlying conscious perception: experimental findings and a global neuronal workspace framework.

One striking property of perception is that it can be achieved in two seemingly different ways: either consciously or non-consciously. What distinguishes these two types of processing at the neural level? So far, empirical findings suggest that conscious perception is associated with an increase in activity at the sensory level, the specific involvement of a fronto-parietal network and an increase in long-distance functional connectivity and synchrony within a broad network of areas. We interpret these data in the framework of the global neuronal workspace model which proposes that the neural basis of conscious access is a sudden self-amplifying process leading to a global brain-scale pattern of activity. In contradiction with several theories which assume that there is a continuum of perception, associated with a gradual change in the intensity of brain activation, the model predicts a sharp non-linear transition between non-conscious and conscious processing.

Animals↗

Eye movement patterns in hemianopic dyslexia.

Homonymous parafoveal field loss impairs reading at the visual-sensory level. To elucidate the role of parafoveal visual field in reading, reading eye movements were recorded, by means of an infra-red registration technique, in 50 patients with homonymous hemianopia and visual field sparing ranging from 1 degree to 5 degrees; for comparison, a group of 25 normal subjects was studied. The degree of reading impairment in patients was found to depend on the extent of visual field sparing. Patients with right-sided loss of parafoveal visual field were more impaired than patients with left-sided loss. Eye movement reading patterns paralleled this observation. Left-sided field loss mainly impairs return eye movements to the beginning of a line, while right-sided field loss is characteristically associated with prolonged fixations times, reduced amplitudes of saccades to the right, and many regressive saccades. The analysis of the durations of fixations, and the amplitudes of saccadic eye shifts to the right, and their mutual dependencies, suggests that the perceptual window ('reading span') is altered: its spatial size is reduced, while its temporal extent is increased. The analysis of reading eye movements in 20 patients, who were treated for their hemianopic reading disorder, revealed, in part, a normalization of the eye movement pattern after treatment, indicating that the lost parafoveal field region can be successfully substituted by oculomotor adaptation. Our observations underline the importance of the parafoveal visual field for reading and support the hypothesis of a serial interplay between sensory-perceptual and cognitive factors in reading. Furthermore, reading eye movements appear to be guided primarily by parafoveal information processing; however, eye movement patterns show relative plasticity with respect to 'local' adaptation when the parafoveal field region is lost. The adaptation can best be explained by a change of the perceptual window which appears to be guided mainly by top-down influences. As to the brain lesion which may be responsible for the lack of effective oculomotor compensation, damage to the occipital white matter appears the most crucial condition because it may disconnect visual cortical areas, and interrupt subcortical-cortical connections which are part of a neural network subserving directed visual attention and associated saccadic eye shifts.

Adolescent↗

Recruitment of periventricular parietal regions in processing cluttered point-light biological motion.

Recent findings point to the existence of a cortical-subcortical parietal network that drives attention-related integration of features and elements. Here we ask whether the functioning of this network might be modulated by early periventricular lesions. To this end, a cohort of adolescents who were born premature with different severity of bilateral periventricular leukomalacia (PVL) and two groups of matched peers (term-born adolescents and former preterms with normal MRI scan) were shown a set of impoverished point-light stimuli. Observers had to detect a point-light walker embedded in an array of distracters mimicking the motion of the target's dots. Patients exhibited higher susceptibility to distortions caused by distracters. In patients only, sensitivity to the point-light figure highly correlates not just with performance on additionally administered feature integration tasks but also on visual attention-demanding IQ tasks. Moreover, the sensitivity index, as well as the values of both IQ factors, decreases with an increase in the volumetric PVL extent in the parieto-occipital region. No relationship was found between these variables and the lesion extent in the frontal or temporal periventricular regions. The data suggest that visual integration and attention in processing cluttered point-light displays are intimately connected. Most importantly, periventricular parieto-occipital regions might be part of a distributed network recruited in deployment of the posterior attentional system. The functioning of this system seems to be vulnerable to bilateral periventricular damage even if it occurs very early in brain development.

Adolescent↗