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A striking organization of a large family of human neural cadherin-like cell adhesion genes.

We have identified 52 novel human cadherin-like genes organized into three closely linked clusters. Comparison of the genomic DNA sequences with those of representative cDNAs reveals a striking genomic organization similar to that of immunoglobulin and T cell receptor gene clusters. The N-terminal extracellular and transmembrane domains of each cadherin protein are encoded by a distinct and unusually large exon. These exons are organized in a tandem array. By contrast, the C-terminal cytoplasmic domain of each protein is identical and is encoded by three small exons located downstream from the cluster of N-terminal exons. This unusual organization has interesting implications regarding the molecular code required to establish complex networks of neuronal connections in the brain and the mechanisms of cell-specific cadherin-like gene expression.

Amino Acid Sequence↗

Dopamine D1 and D4 receptor subtypes differentially modulate recurrent excitatory synapses in prefrontal cortical pyramidal neurons.

Although dopamine (DA) effects in the prefrontal cortex (PFC) have been studied extensively, the function of steady-state ambient levels of DA in the regulation of afferent excitatory transmission in PFC pyramidal neurons remains relatively unexplored. Using intracellular sharp-electrode and whole-cell recordings combined with intracellular labeling in brain slices, we found that D1/D5 receptor blockade did not alter synaptic responses in the PFC, but D1/D5 receptor activation consistently enhanced recurrent synaptic excitation in the majority of pyramidal neurons tested. In contrast, D4 receptor blockade resulted in an evoked complex multiple spike discharge pattern that contained both early and late (presumably multisynaptic) components of the evoked response that is contingent upon the preservation of axon collaterals of the neuron under study. Moreover, GABAergic interneurons were found to play a role in both responses; blockade of GABA(a)-mediated inhibition caused bath application of DA to convert monosynaptic excitatory postsynaptic potentials (EPSPs) to complex spike bursts riding on the late component of the EPSP. On the other hand, during the blockade of GABA(a)-mediated conductances, administration of a D4 receptor antagonist failed to facilitate evoked multiple spike discharge. Morphological analysis of axon collaterals of labeled neurons revealed that neurons in which the D4 receptor blockade induced the putative polysynaptic response had axon collaterals that were largely preserved. These data suggest that DA exerts a bidirectional modulation of PFC pyramidal neurons in brain slices provided that local network connections with interneurons are preserved, with D4 receptors under tonic stimulation by ambient low levels of DA, whereas D1/D5 receptors activated upon phasic DA input.

Animals↗

Dynamic imaging of coherent sources: Studying neural interactions in the human brain.

Functional connectivity between cortical areas may appear as correlated time behavior of neural activity. It has been suggested that merging of separate features into a single percept ("binding") is associated with coherent gamma band activity across the cortical areas involved. Therefore, it would be of utmost interest to image cortico-cortical coherence in the working human brain. The frequency specificity and transient nature of these interactions requires time-sensitive tools such as magneto- or electroencephalography (MEG/EEG). Coherence between signals of sensors covering different scalp areas is commonly taken as a measure of functional coupling. However, this approach provides vague information on the actual cortical areas involved, owing to the complex relation between the active brain areas and the sensor recordings. We propose a solution to the crucial issue of proceeding beyond the MEG sensor level to estimate coherences between cortical areas. Dynamic imaging of coherent sources (DICS) uses a spatial filter to localize coherent brain regions and provides the time courses of their activity. Reference points for the computation of neural coupling may be based on brain areas of maximum power or other physiologically meaningful information, or they may be estimated starting from sensor coherences. The performance of DICS is evaluated with simulated data and illustrated with recordings of spontaneous activity in a healthy subject and a parkinsonian patient. Methods for estimating functional connectivities between brain areas will facilitate characterization of cortical networks involved in sensory, motor, or cognitive tasks and will allow investigation of pathological connectivities in neurological disorders.

Algorithms↗

Dynamic encoding of natural luminance sequences by LGN bursts.

In the lateral geniculate nucleus (LGN) of the thalamus, visual stimulation produces two distinct types of responses known as tonic and burst. Due to the dynamics of the T-type Ca(2+) channels involved in burst generation, the type of response evoked by a particular stimulus depends on the resting membrane potential, which is controlled by a network of modulatory connections from other brain areas. In this study, we use simulated responses to natural scene movies to describe how modulatory and stimulus-driven changes in LGN membrane potential interact to determine the luminance sequences that trigger burst responses. We find that at low resting potentials, when the T channels are de-inactivated and bursts are relatively frequent, an excitatory stimulus transient alone is sufficient to evoke a burst. However, to evoke a burst at high resting potentials, when the T channels are inactivated and bursts are relatively rare, prolonged inhibitory stimulation followed by an excitatory transient is required. We also observe evidence of these effects in vivo, where analysis of experimental recordings demonstrates that the luminance sequences that trigger bursts can vary dramatically with the overall burst percentage of the response. To characterize the functional consequences of the effects of resting potential on burst generation, we simulate LGN responses to different luminance sequences at a range of resting potentials with and without a mechanism for generating bursts. Using analysis based on signal detection theory, we show that bursts enhance detection of specific luminance sequences, ranging from the onset of excitatory sequences at low resting potentials to the offset of inhibitory sequences at high resting potentials. These results suggest a dynamic role for burst responses during visual processing that may change according to behavioral state.

Animals↗

Disturbed fluctuations of resting state EEG synchronization in Alzheimer's disease.

OBJECTIVE: We examined the hypothesis that cognitive dysfunction in Alzheimer's disease is associated with abnormal spontaneous fluctuations of EEG synchronization levels during an eyes-closed resting state. METHODS: EEGs were recorded during an eyes-closed resting state in Alzheimer patients (N=24; 9 males; mean age 76.3 years; SD 7.8; range 59-86) and non-demented subjects with subjective memory complaints (N=19; 9 males; mean age 76.1 years; SD 6.7; range: 67-89). The mean level of synchronization was determined in different frequency bands with the synchronization likelihood and fluctuations of the synchronization level were analysed with detrended fluctuation analysis (DFA). RESULTS: The mean level of EEG synchronization was lower in Alzheimer patients in the upper alpha (10-13Hz) and beta (13-30Hz) band. Spontaneous fluctuations of synchronization were diminished in Alzheimer patients in the lower alpha (8-10Hz) and beta bands. In patients as well as controls the synchronization fluctuations showed a scale-free pattern. CONCLUSIONS: Alzheimer's disease is characterized both by a lower mean level of functional connectivity as well as by diminished fluctuations in the level of synchronization. The dynamics of these fluctuations in patients and controls was scale-free which might point to self-organized criticality of neural networks in the brain. SIGNIFICANCE: Impaired functional connectivity can manifest itself not only in decreased levels of synchronization but also in disturbed fluctuations of synchronization levels.

Aged↗

Functional connectivity during real vs imagined visuomotor tasks: an EEG study.

It is proposed that real and imagined movements activate identical neural networks. Cortical oscillatory activity is proposed as a mechanism through which distributed neuronal networks may bind into coherent ensembles and coupling of oscillators is used as a tool to investigate modulations of cortical connectivity. The aim of the present study was to test the hypothesis that, although the same brain network is involved in both real and imagined movements, the functional connectivity within the network differs. To do so, we measured interregional coupling, quantified using coherence between scalp EEG electrodes, during different periods of a prehension task during real and imagined movements. The results demonstrated a different pattern of coupling in the beta frequency range between electrodes overlying occipital and motor cortices during executed and imagined movements. These findings are consistent with the hypothesis that the neural networks during real and imagined movements are not identical.

Adult↗

Modulation of functional connectivity during the resting state and the motor task.

Quite a few studies in functional magnetic resonance imaging (fMRI) have tested that, even in a resting state, motor cortices constitute a network. It has never been investigated how the network modulates from the resting state to the motor task state. In this report, by a newly developed approach taking into account n-to-1 connectivity using 1-to-1 connectivity measures instead of conventional pairwise connectivity, we show the existence of a large organized functional connectivity network related to motor function in the resting brain with fMRI. More importantly, we found that such a network can be modulated from a conscious resting state to planning, initiation, coordination, guidance, and termination of voluntary movement state, exhibited by significant changes of functional connectivity of some brain regions in different brain activity. Moreover, a quantitative description of such a functional modulation has also been presented.

Adult↗

Changes in effective connectivity during incidental and intentional perception of fearful faces.

The present fMRI study examined effective connectivity within an emotional network composed of three brain areas: Amygdala (AMY), Anterior Cingulate Cortex (AAC) and Orbito-Frontal (OFC) in processing fearful faces. Two tasks: an incidental perception (gender identification) and an intentional detection (effortful discrimination) task were performed by 14 and 10 young healthy volunteers, respectively. Participants were scanned while viewing fearful, neutral and ambiguous facial expressions. Effective connectivity was assessed using Structural Equation Modeling (SEM). Results show that the hypothetical network fits the experimental data for both tasks and in both hemispheres. The comparison between Tasks 1 and 2 reveals significant differences in strength and direction of the connectivity patterns for the left and to a less stringent threshold for the right hemisphere. The path coefficients analysis suggests that the fearful information generated in AMY, reaches the OFC through the ACC in incidental perception, while in intentional perception, the route followed is in a reverse direction from OFC to ACC. Our findings confirm a differential brain connectivity between incidental and intentional processing of fearful faces.

Adult↗

Sparsification from dilute connectivity in a neural network model of memory.

Several hypotheses concerning implementations of associative memory in the brain rely on analyses of the capabilities of simple network models. However, the low connectivity of cerebral networks imposes constraints which sometimes do not arise clearly from such analyses. We investigate an aspect of a simple, dilute network's operation that is sometimes overlooked, namely the setting of activation thresholds. An examination of several criteria for optimal threshold assignment affords several new insights. It becomes apparent that the network's capacity (which is simply derived) is insufficient to characterize the quality of its performance. We derive the degree of 'sparsification' or decrease in firing probability that arises from dilution, and also the consequent losses in representational ability, and propose that they should also be taken into account. To evaluate the model's performance and suitability, we argue that one should explicitly consider the trade-off that exists between storage of patterns and preservation of information, and its consequent constraints.

Association Learning↗

[Selective brain cooling].

The brain is especially sensitive to heat stress. To limit the increase of intracranial heat in case of hyperthermia or fever, a system of selective cooling is put on. It includes two heat-exchangers. The first one, in the face and scalp skin, disperses calories through sweat evaporation. The second one is intracranial, close to the arteries which irrigate the brain. They are connected by a vascular network. In these conditions, the arterial blood temperature, of which cerebral temperature depends upon, is reduced by the cooled venous blood which comes from subcutaneous tissues through the skull wall. On feverish children, increasing such a selective cooling by face fanning can limit cerebral thermal stress.

Adult↗

Incorporating anatomically realistic cellular-level connectivity in neural network models of the rat hippocampus.

The specific connectivity patterns among neuronal classes can play an important role in the regulation of firing dynamics in many brain regions. Yet most neural network models are built based on vastly simplified connectivity schemes that do not accurately reflect the biological complexity. Taking the rat hippocampus as an example, we show here that enough quantitative information is available in the neuroanatomical literature to construct neural networks derived from accurate models of cellular connectivity. Computational simulations based on this approach lend themselves to a direct investigation of the potential relationship between cellular connectivity and network activity. We define a set of fundamental parameters to characterize cellular connectivity, and are collecting the related values for the rat hippocampus from published reports. Preliminary simulations based on these data uncovered a novel putative role for feedforward inhibitory neurons. In particular, "mopp" cells in the dentate gyrus are suitable to help maintain the firing rate of granule cells within physiological levels in response to a plausibly noisy input from the entorhinal cortex. The stabilizing effect of feedforward inhibition is further shown to depend on the particular ratio between the relative threshold values of the principal cells and the interneurons. We are freely distributing the connectivity data on which this study is based through a publicly accessible web archive (http://www.krasnow.gmu.edu/L-Neuron).

Animals↗

Nervous system dynamics during fragmentation and regeneration in Enchytraeus japonensis (Oligochaeta, Annelida).

Enchytraeus japonensis is a small terrestrial oligochaete which primarily reproduces asexually by fragmentation and regeneration. In order to introduce a molecular approach to the study of regeneration we developed a whole-mount immunostaining procedure for the worm. Using an antibody directed against acetylated tubulin in conjunction with confocal laser-scanning microscopy, we succeeded in clarifying the three- dimensional structure of the entire nervous system in the full-grown worm and its dynamics during the fragmentation and regeneration process. In addition, we examined the expression of neurotransmitters and neuropeptides in the worm using a fluorescently-labeled antagonist and various antibodies. In particular, we found two circumferential structures in the body wall muscle of each segment that react strongly with alpha-bungarotoxin, an antagonist of nicotinic acetylcholine receptors, and detected nerve fibers just underneath these structures. During the fragmentation process, the circular body wall muscles contract near one of these circumferential structures in the middle of the segment, which causes constriction and results in fission of the body. This alpha-bungarotoxin-positive structure was designated the neuromuscular junction of the circular muscle. During the regeneration process nerve fibers grow from the remaining ventral nerve cord and gradually form networks in both the anterior and posterior regeneration buds. The growing fibers extend to the prostomium (a sensory organ) at the anterior end prior to connecting to the presumptive brain rudiment. A neural network appears around the pygidium, and this is followed by growth of the body at the posterior end. The nervous system appears to play an important role in both anterior and posterior regeneration.

Animals↗

Development and characterization of pathways descending to the spinal cord in the embryonic chick.

1. We used an isolated preparation of the embryonic chick brain stem and spinal cord to examine the origin, trajectory, and effects of descending supraspinal pathways on lumbosacral motor activity. The in vitro preparation remained viable for < or 24 h and was sufficiently stable for electrophysiological, pharmacological, and neuroanatomic examination. In this preparation, as in the isolated spinal cord, spontaneous episodes of both forelimb and hindlimb motor activity occur in the absence of phasic afferent input. Motor activity can also be evoked by brain stem electrical stimulation or modulated by the introduction of neurochemicals to the independently perfused brain stem. 2. At embryonic day (E)6, lumbosacral motor activity could be evoked by brain stem electrical stimulation. At E5, neither brain stem nor spinal cord stimulation evoked activity in the lumbosacral spinal cord, although motoneurons did express spontaneous activity. 3. Lesion and electrophysiological studies indicated that axons traveling in the ventral cord mediated the activation of lumbosacral networks by brain stem stimulation. 4. Partition of the preparation into three separately perfused baths, using a zero-Ca2+ middle bath that encompassed the cervical spinal cord, demonstrated that the brain stem activation of spinal networks could be mediated by long-axoned pathways connecting the brain stem and lumbosacral spinal cord. 5. Using retrograde tracing from the spinal cord combined with brain stem stimulation, we found that the brain stem regions from which spinal activity could be evoked lie in the embryonic reticular formation close to neurons that send long descending axons to the lumbosacral spinal cord. The cells giving rise to these descending pathways are found in the ventral pontine and medullary reticular formation, a region that is the source of reticulospinal neurons important for motor activity in adult vertebrates. 6. Electrical recordings from this region revealed that the activity of some brain stem neurons was synchronized with the electrical activity of lumbosacral motoneurons during evoked or spontaneous episodes of rhythmic motor activity. 7. Both brain stem and spinal cord activity could be modulated by selective application of the glutamate agonist N-methyl-D-aspartate to the brain stem, supporting the existence of functionally active descending projections from the brain stem to the spinal cord. It is not yet clear what role the brain stem activity carried by these pathways has in the genesis and development of spinal cord motor activity.

Animals↗

Solving the binding problem of the brain with bi-directional functional connectivity.

We propose a neural network model which gives one solution to the binding problem on the basis of 'functional connectivity' and bidirectional connections. Here, 'functional connectivity' is dynamic neuronal connectivity peculiar to temporal spike coding neural networks with coincidence detector neurons. The model consists of a single primary map and two higher modules which extract two different features shown on the primary map. There exist three layers in each higher module and the layers are connected bi-directionally. An object in the outer world is represented by a 'global dynamical cell assembly' which is organized across the primary map and the two higher modules. Detailed, but spatially localized, information is coded in the primary map, whereas coarse, but spatially extracted information or globally integrated information is coded in the higher modules. Computer simulations of the proposed model show that multiple cell assemblies sharing the same neurons partially can co-exist. Furthermore, we introduce a three-dimensional J-PSTH (Joint-Peri Stimulus Time Histogram) which is capable of tracking such cell assemblies, altering its constituent neurons as in our proposed model.

Action Potentials↗

Hebb's concept of cell assemblies and the psychophysiology of word processing.

Hebb's brain-theoretical approach suggests that tightly connected networks of neurons, Hebbian cell assemblies, are the building blocks of cognitive functions. These assemblies are not necessarily restricted to a small cortical locus but may be dispersed over distant cortical areas. Assemblies with different topographies can be postulated for different kinds of words, such as meaningful content versus grammatical function words or words eliciting motor versus visual associations. Evidence from evoked potentials and gamma-band electrocortical responses elicited by lexical material supports a cell assembly model of language and other higher cognitive functions.

Brain↗

New approaches for exploring anatomical and functional connectivity in the human brain.

Information processing in the primate brain is based on the complementary principles of modular and distributed information processing. The former emphasizes the specialization of functions within different brain areas. The latter emphasizes the massively parallel nature of brain networks and the fact that function also emerges from the flow of information between brain areas. The localization of function to specific brain areas ("functional segregation") is the commonest approach to investigating function; however, an emerging, complementary approach ("functional integration") describes function in terms of the information flow across networks of areas. Here, we highlight recent advances in neuroimaging methodology that have made it possible to investigate the anatomical architecture of networks in the living human brain with diffusion tensor imaging (DTI). We also highlight recent thinking on the ways in which functional imaging can be used to characterize information transmission across networks in the human brain (functional and effective connectivity).

Animals↗

Cerebral mechanisms of prosodic integration: evidence from connected speech.

Using functional Magnetic Resonance Imaging (fMRI) and long connected speech stimuli, we addressed the question of neuronal networks involved in prosodic integration by comparing (1) differences in brain activity when hearing connected speech stimuli with high and low degrees of prosodic expression; (2) differences in brain activity in two different diotic listening conditions (normal speech delivery to both ears, i.e., NN; and low-pass-filtered speech delivery to both ears, i.e., FF); and (3) effects of high and low degrees of prosodic information in the NN and FF conditions. Twelve right-handed French men listened passively to the stimuli. Each stimulus induced a specific cerebral network, the flat one weakening activations, which were mainly reduced to the bilateral STG for both listening conditions. High degrees of prosodic information were found to trigger right specific activations in a wider neuronal network involved in speech integration (such as BA44, BA21-22 and BA39-40) than low degrees of prosodic information did. More precisely, the right BA44 was found to be specifically involved in the process of F(0) modulations, which are the main acoustic correlate of prosody. Not only do the results achieved in the present experiment using 30-s-long connected speech stimuli show the involvement of a bilateral neuronal network but they also strongly suggest that high degrees of prosodic information elicit activations in a wider neuronal network involved in speech perception than low degrees of prosodic information do.

Acoustic Stimulation↗

Electroencephalographic evidence of cortical network disruption preceding overt cardioinhibition during tilt-induced reflex syncope.

OBJECTIVE: Reflex syncope is a common cause of transient loss of consciousness. However, the early cerebral mechanisms underlying cardiovascular changes remain poorly understood. Our objective was to investigate early cerebral changes by quantitatively analyzing EEG activity preceding overt cardioinhibition during tilt-induced reflex syncope. METHODS: EEG recordings from patients undergoing tilt testing were retrospectively analyzed. Patients who experienced reflex syncope were compared to those who did not. Spectral and functional connectivity analyses were performed across baseline, pre-cardioinhibition, and syncopal phases. RESULTS: Prior to the onset of cardioinhibitory pathological reflex, a significant increase in theta-band spectral power was observed in the right temporal region, accompanied by a widespread increase in functional connectivity within the same frequency band. These findings suggest the involvement of brain networks before cardioinhibition. CONCLUSIONS: EEG changes in the theta band (power and functional connectivity) were observed before overt cardioinhibition during tilt-induced reflex syncope. SIGNIFICANCE: Our findings support the hypothesis of cortical processing preceding cardioinhibition in reflex syncope. EEG may represent a valuable complementary tool for improving the understanding and diagnosis of these events.

Humans↗