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Network oscillatory dynamics accompany cerebral bioenergetic defence in hypoxia.

A network physiology framework investigated how coordinated interactions among multiple organ systems collectively support the preservation of cerebral bioenergetic function and better distinguish adaptive from maladaptive responses to hypoxia. Twelve healthy males were passively exposed to 6 h of normoxia (21% O2) and hypoxia (12% O2) in a randomised, single-blind, crossover design. Venous blood was assayed for oxidative-nitrosative stress (OXNOS, spectroscopy/chemiluminescence) and neurovascular unit (hs-ELISA) biomarkers. Global cerebral delivery of O2 and glucose were determined by duplex ultrasound. Clinical acute mountain sickness (AMS+) was diagnosed in five participants. Cerebral substrate delivery was well maintained in both hypoxia and AMS+ (p < 0.05 vs normoxia and AMS-) despite marked arterial hypoxemia. Bioenergetic defence coincided with pronounced elevations in the spectral amplitude and phase synchronisation of very low-frequency oscillations (VLFOs, 0.03-0.06 Hz), which were evident across multiple organ systems and most prominent within the cerebral network. Systemic VLFOs were further exaggerated and more functionally connected in AMS+ in the absence of exaggerated systemic OXNOS or structural damage/destabilisation of the neurovascular unit (both p < 0.05 vs normoxia and AMS-). Collectively, these findings suggest that AMS, while characterised by debilitating symptomatology, may reflect a neuroprotective adaptive as opposed to pathologically maladaptive phenotype.

Humans↗

Differential involvement of Ca(2+) channels in survival and neurite outgrowth of cultured embryonic cockroach brain neurons.

The contribution of voltage-gated calcium channels (VGCC) to the development of cultured embryonic cockroach brain neurons was assessed using pharmacological agents. VGCC currents were recorded using the patch-clamp technique and were found to be blocked dose-dependently by micromolar concentrations of mibefradil. The activation and inactivation properties of the calcium channels enable a sizeable calcium current to flow at rest (about -30 and -20 mV in high-potassium culture media). As expected, the cytoplasmic-free calcium concentration was found to rise when the extracellular potassium concentration was raised from 3 to 15 and 30 mM. The effects of VGCC blockers and calcium chelators were different in fresh and in mature cultures in which the neurons were connected to each other to form a defined network. In fresh cultures, the two non-selective VGCC blockers (verapamil and mibefradil) induced a dose-dependent cell death that was proportional to their blocking effect on I(Ba). This effect could not be prevented by addition of fetal calf serum to the culture medium. A similar effect was obtained using intra- or extracellular calcium chelating agents (10 microM BAPTA-AM or 10 mM EGTA). Quite unexpectedly, blockade of the P/Q-like (omega-Aga WA-sensitive) component of the calcium current by 500 nM of omega-AgaTx IVA had no lethal effect, suggesting that the corresponding channels are not involved in the survival mechanism. As expected from their lack of effect on I(Ba), isradipine, nifedipine, and omega-CgTx GVIA did not induce cell death. When the neurons started growing neurites, their sensitivity to calcium channel blockade by mibefradil decreased, indicating a correlation between neurite outgrowth and resistance to calcium depletion. In mature cultures, the neurons became resistant to mibefradil, verapamil, and BAPTA-AM. However, these agents, as well as omega-AgaTx IVA, had a significant inhibitory effect on the increase in diameter of the connectives that linked adjacent clusters of neurons. This effect has been shown to result, in the case of mibefradil, from an inhibition of neurite outgrowth characterized by a significant reduction of the number of primary neurites and secondary branchings but not to a significant modification of the diameter of individual neurites. These results support the view that, as in vertebrates, calcium influx through VGCC plays an important role in survival and neurite outgrowth of cultured embryonic insect neurons. The differential contribution of the P/Q-like and R-like (omega-Aga WA-sensitive) calcium channels in these processes is discussed.

Animals↗

Morphological characteristics and distribution pattern of the arterial vessels in human cerebral cortex: a scanning electron microscope study.

BACKGROUND: The human cerebral cortex is supplied by vessels that arise from the pial arteries. These vessels give rise to a dense vascular network that is highly interconnected. Cortical arteries have been classified in different categories. Both their angioarchitectonic pattern and anatomical structures involved in their regulation are not fully understood. METHODS: Twelve fresh human brains were studied by scanning electron microscopy of vascular corrosion casts. RESULTS: Four types of arterial vessels in the cerebral cortex--short, middle, long, and transcortical--were identified. The cortical vascular network was formed by several interconnected clusters of vessels, which were arranged in four vascular layers parallel to the pial surface and characterized by different vascular densities. The greatest vascular density corresponded to the middle and deep vascular layers. Circular constrictions were found at the origin of cortical arteries and at their branching sites, probably related to vascular sphincters. Connections between cortical arteries were observed at their initial course. Plastic strips, occasionally related to constrictions, were observed around both middle and long cortical arteries. Other plastic structures, morphologically similar to pericytes, were found around capillary vessels. CONCLUSIONS: The blood supply to the human cerebral cortex depends on the short, middle, and long cortical arteries, which give rise to a highly anastomosed capillary network. There exist vascular connections between pial arteries and occasionally between cortical arteries. Blood flow autoregulation is probably mediated by smooth muscle cells at the arteriolar level and by pericytes at the capillary level, through endothelial connections.

Adult↗

Inhibitory circuits in sensory maps develop through excitation.

Inhibitory and excitatory connections are equal partners in determining neuronal response properties. Although the development and plasticity of excitatory networks have been heavily studied, little is known about how inhibitory circuits develop. In a recent study, Gunsoo Kim and Karl Kandler have shown that, as in the development of excitatory circuits, synapse elimination and strengthening are important processes for the development of well-organized inhibitory circuits.

Animals↗

Elman topology with sigma-pi units: an application to the modeling of verbal hallucinations in schizophrenia.

The development of neural network models has greatly enhanced the comprehension of cognitive phenomena. Here, we show that models using multiplicative processing of inputs are both powerful and simple to train and understand. We believe they are valuable tools for cognitive explorations. Our model can be viewed as a subclass of networks built on sigma-pi units and we show how to derive the Kronecker product representation from the classical sigma-pi unit. We also show how the connectivity requirements of the Kronecker product can be relaxed considering statistical arguments. We use the multiplicative network to implement what we call an Elman topology, that is, a simple recurrent network (SRN) that supports aspects of language processing. As an application, we model the appearance of hallucinated voices after network damage, and show that we can reproduce results previously obtained with SRNs concerning the pathology of schizophrenia.

Brain↗

Early development of the serotonergic and dopaminergic nervous system in Spisula solidissima (surf clam) larvae.

We have defined the development of the serotonergic and dopaminergic components of the central nervous system in the early Spisula solidissima (surf clam) embryo using HPLC and immunocytochemistry. HPLC analysis reveals norepinephrine, dopamine, and serotonin are present at 24 h post-fertilization. Immunocytochemistry shows that the serotonergic nervous system emerges during the late trochophore stage with the development of a single serotonergic cell, C/A1, in the cerebral/apical ganglion. After 48 h, a second serotonergic cell forms, C/A2, which is connected to C/A1 by two serotonergic processes, and a single serotonergic cell emerges in the visceral ganglion, V1. At 72 h, a new serotonergic cell body develops in the cerebral/apical ganglion, C/A3. After 96 h, the cerebral/apical ganglion and visceral ganglion are connected by a serotonergic process. Expression of the dopamine receptor, D2, begins by 24 h with a generalized expression in the region of the developing gut. D2 expression in the gut ceases by 48 h. At 48 h, a network of fibers forms dorsolateral to the mouth. By 72 h, D2 expressing projections emerge from this network.

Animals↗

An emotional mediation theory of differential age effects in episodic and semantic memories.

Although there is a large decrement in central episodic memory processes as adults age, there is no appreciable decrement in central semantic memory processes (Allen et al., Journal of Gerontology: Psychological Sciences, 57B, P173-P186, 2002; Allen et al., Experimental Aging Research, 28, 111-142, 2002; Mitchell, Journal of Experimental Psychology: Learning, Memory, and Cognition, 15, 31-49, 1989). The authors develop a theory of episodic memory's connections to cognitive, emotional, and motivational systems to explain these differential age effects. The theory is discussed within the context of the cognitive neuroscience research regarding limbic system connectivity in conjunction with Damasio's notion of somatic markers (Descartes' error: Emotion, reason, and the human brain, New York: Grosset/Putnam, 1994). The central hypothesis is that elements of limbic system circuitry, including portions of the medial temporal lobes and frontal cortex, are associated with both working and long-term episodic memory performance, and by extension, with the capacity to engage in emotion-guided, self-regulatory processes that depend heavily on episodic memory. In contrast, the semantic memory system may have less shared interface with episodic and affective networks (i.e., the limbic-related system), and therefore remain independent of neurocognitive changes impacting emotional states and episodic-type memory processes. Accordingly, this framework may account for the pattern of age-related declines in episodic relative to semantic memory, particularly if older adults experience less emotional activation, and therefore fewer somatic markers, than younger adults. An initial empirical examination of this emotional mediation theory is presented, using preexisting data that include indicators of age, chronic tendency to focus on negative emotional stimuli (neuroticism), and working memory performance.

Adolescent↗

Simulation of paleocortex performs hierarchical clustering.

Simulations were performed of layers I and II of olfactory paleocortex, as connected to its primary input structure, olfactory bulb. Induction of synaptic long-term potentiation by means of repetitive sampling of inputs caused the simulation to organize encodings of learned cues into a hierarchical memory that uncovered statistical relationships in the cue environment, corresponding to the performance of hierarchical clustering by the biological network. Simplification led to characterization of those parts of the network responsible for the mechanism, resulting in a novel, efficient algorithm for hierarchical clustering. The hypothesis is put forward that these corticobulbar networks and circuitry of similar design in other brain regions contain computational elements sufficient to construct perceptual hierarchies for use in recognizing environmental cues.

Animals↗

Control of cricket stridulation by a command neuron: efficacy depends on the behavioral state.

Crickets use different song patterns for acoustic communication. The stridulatory pattern-generating networks are housed within the thoracic ganglia but are controlled by the brain. This descending control of stridulation was identified by intracellular recordings and stainings of brain neurons. Its impact on the generation of calling song was analyzed both in resting and stridulating crickets and during cercal wind stimulation, which impaired the stridulatory movements and caused transient silencing reactions. A descending interneuron in the brain serves as a command neuron for calling-song stridulation. The neuron has a dorsal soma position, anterior dendritic processes, and an axon that descends in the contralateral connective. The neuron is present in each side of the CNS. It is not activated in resting crickets. Intracellular depolarization of the interneuron so that its spike frequency is increased to 60-80 spikes/s reliably elicits calling-song stridulation. The spike frequency is modulated slightly in the chirp cycle with the maximum activity in phase with each chirp. There is a high positive correlation between the chirp repetition rate and the interneuron's spike frequency. Only a very weak correlation, however, exists between the syllable repetition rate and the interneuron activity. The effectiveness of the command neuron depends on the activity state of the cricket. In resting crickets, experimentally evoked short bursts of action potentials elicit only incomplete calling-song chirps. In crickets that previously had stridulated during the experiment, short elicitation of interneuron activity can trigger sustained calling songs during which the interneuron exhibits a spike frequency of approximately 30 spikes/s. During sustained calling songs, the command neuron activity is necessary to maintain the stridulatory behavior. Inhibition of the interneuron stops stridulation. A transient increase in the spike frequency of the interneuron speeds up the chirp rate and thereby resets the timing of the chirp pattern generator. The interneuron also is excited by cercal wind stimulation. Cercal wind stimulation can impair the pattern of chirp and syllable generation, but these changes are not reflected in the discharge pattern of the command neuron. During wind-evoked silencing reactions, the activity of the calling-song command neuron remains unchanged, but under these conditions, its activity is no longer sufficient to maintain stridulation. Therefore stridulation can be suppressed by cercal inputs from the terminal ganglia without directly inhibiting the descending command activity.

Action Potentials↗

New thoughts on female precocious puberty.

Much effort has been devoted in recent years to unravel the neuroendocrine mechanisms responsible for the initiation of mammalian puberty. The concept that has emerged is that puberty results from the unfolding of a centrally originated process involving the concerted influence of neuronal systems that utilize excitatory and inhibitory amino acids as transmitters and astroglial networks that produce growth factors able to affect LHRH secretion. We discuss the idea that an isolated alteration of each of these components may result in the precocious activation of pulsatile LHRH release, and thus lead to idiopathic sexual precocity. According to this notion, such a premature activation of LHRH neuronal function would be neither associated with structural damage of the neuroendocrine brain system, nor related to a generalized activation of the neuronal-glial mechanisms underlying the onset of puberty. On the contrary, localized activation of discrete cellular subsets functionally connected to LHRH neurons would suffice to promote an increase in LHRH release of sufficient magnitude and duration to initiate the pubertal process.

Child↗

Brain areas involved in medial temporal lobe seizures: a principal component analysis of ictal SPECT data.

The study describes brain areas involved in medial temporal lobe (mTL) seizures of 12 patients. All patients showed so-called oro-alimentary behavior within the first 20 s of clinical seizure manifestation characteristic of mTL seizures. Single photon emission computed tomography (SPECT) images of regional cerebral blood flow (rCBF) were acquired from the patients in ictal and interictal phases and from normal volunteers. Image analysis employed categorical comparisons with statistical parametric mapping and principal component analysis (PCA) to assess functional connectivity. PCA supplemented the findings of the categorical analysis by decomposing the covariance matrix containing images of patients and healthy subjects into distinct component images of independent variance, including areas not identified by the categorical analysis. Two principal components (PCs) discriminated the subject groups: patients with right or left mTL seizures and normal volunteers, indicating distinct neuronal networks implicated by the seizure. Both PCs were correlated with seizure duration, one positively and the other negatively, confirming their physiological significance. The independence of the two PCs yielded a clear clustering of subject groups. The local pattern within the temporal lobe describes critical relay nodes which are the counterpart of oro-alimentary behavior: (1) right mesial temporal zone and ipsilateral anterior insula in right mTL seizures, and (2) temporal poles on both sides that are densely interconnected by the anterior commissure. Regions remote from the temporal lobe may be related to seizure propagation and include positively and negatively loaded areas. These patterns, the covarying areas of the temporal pole and occipito-basal visual association cortices, for example, are related to known anatomic paths.

Adolescent↗

Functional holography analysis: simplifying the complexity of dynamical networks.

We present a novel functional holography (FH) analysis devised to study the dynamics of task-performing dynamical networks. The latter term refers to networks composed of dynamical systems or elements, like gene networks or neural networks. The new approach is based on the realization that task-performing networks follow some underlying principles that are reflected in their activity. Therefore, the analysis is designed to decipher the existence of simple causal motives that are expected to be embedded in the observed complex activity of the networks under study. First we evaluate the matrix of similarities (correlations) between the activities of the network's components. We then perform collective normalization of the similarities (or affinity transformation) to construct a matrix of functional correlations. Using dimension reduction algorithms on the affinity matrix, the matrix is projected onto a principal three-dimensional space of the leading eigenvectors computed by the algorithm. To retrieve back information that is lost in the dimension reduction, we connect the nodes by colored lines that represent the level of the similarities to construct a holographic network in the principal space. Next we calculate the activity propagation in the network (temporal ordering) using different methods like temporal center of mass and cross correlations. The causal information is superimposed on the holographic network by coloring the nodes locations according to the temporal ordering of their activities. First, we illustrate the analysis for simple, artificially constructed examples. Then we demonstrate that by applying the FH analysis to modeled and real neural networks as well as recorded brain activity, hidden causal manifolds with simple yet characteristic geometrical and topological features are deciphered in the complex activity. The term "functional holography" is used to indicate that the goal of the analysis is to extract the maximum amount of functional information about the dynamical network as a whole unit.

Algorithms↗

Biomimetic approaches to the control of underwater walking machines.

We have developed a biomimetic robot based on the American lobster. The robot is designed to achieve the performance advantages of the animal model by adopting biomechanical features and neurobiological control principles. Three types of controllers are described. The first is a state machine based on the connectivity and dynamics of the lobster central pattern generator (CPG). The state machine controls myomorphic actuators based on shape memory alloys (SMAs) and responds to environmental perturbation through sensors that employ a labelled-line code. The controller supports a library of action patterns and exteroceptive reflexes to mediate tactile navigation, obstacle negotiation and adaptation to surge. We are extending this controller to neuronal network-based models. A second type of leg CPG is based on synaptic networks of electronic neurons and has been adapted to control the SMA actuated leg. A brain is being developed using layered reflexes based on discrete time map-based neurons.

Animals↗

Spindle-like thalamocortical synchronization in a rat brain slice preparation.

We obtained rat brain slices (550-650 microm) that contained part of the frontoparietal cortex along with a portion of the thalamic ventrobasal complex (VB) and of the reticular nucleus (RTN). Maintained reciprocal thalamocortical connectivity was demonstrated by VB stimulation, which elicited orthodromic and antidromic responses in the cortex, along with re-entry of thalamocortical firing originating in VB neurons excited by cortical output activity. In addition, orthodromic responses were recorded in VB and RTN following stimuli delivered in the cortex. Spontaneous and stimulus-induced coherent rhythmic oscillations (duration = 0.4-3.5 s; frequency = 9-16 Hz) occurred in cortex, VB, and RTN during application of medium containing low concentrations of the K(+) channel blocker 4-aminopyridine (0.5-1 microM). This activity, which resembled electroencephalograph (EEG) spindles recorded in vivo, disappeared in both cortex and thalamus during application of the excitatory amino acid receptor antagonist kynurenic acid in VB (n = 6). By contrast, cortical application of kynurenic acid (n = 4) abolished spindle-like oscillations at this site, but not those recorded in VB, where their frequency was higher than under control conditions. Our findings demonstrate the preservation of reciprocally interconnected cortical and thalamic neuron networks that generate thalamocortical spindle-like oscillations in an in vitro rat brain slice. As shown in intact animals, these oscillations originate in the thalamus where they are presumably caused by interactions between RTN and VB neurons. We propose that this preparation may help to analyze thalamocortical synchronization and to understand the physiopathogenesis of absence attacks.

4-Aminopyridine↗

Multivariate autoregressive modeling of fMRI time series.

We propose the use of multivariate autoregressive (MAR) models of functional magnetic resonance imaging time series to make inferences about functional integration within the human brain. The method is demonstrated with synthetic and real data showing how such models are able to characterize interregional dependence. We extend linear MAR models to accommodate nonlinear interactions to model top-down modulatory processes with bilinear terms. MAR models are time series models and thereby model temporal order within measured brain activity. A further benefit of the MAR approach is that connectivity maps may contain loops, yet exact inference can proceed within a linear framework. Model order selection and parameter estimation are implemented by using Bayesian methods.

Algorithms↗

Comparison of impaired subcortico-frontal metabolic networks in normal aging, subcortico-frontal dementia, and cortical frontal dementia.

Normal aging, progressive supranuclear palsy (PSP), and frontotemporal dementia (FTD) are characterized by different degrees of decline in frontal lobe functions. We used (18)FDG-PET and statistical parametric mapping (SPM96) to compare relative subcorticofrontal metabolic impairment at rest in 21 healthy elderly subjects (HES), 20 PSP patients, and 6 FTD patients. When HES were compared to 22 healthy young subjects, widespread decrease in metabolism was observed in bilateral medial prefrontal areas including anterior cingulate cortices, in dorsolateral prefrontal areas, in left lateral premotor area, in Broca's area, and in left insula. In PSP compared to the 43 healthy subjects (HS), we observed subcorticofrontal metabolic impairment including both motor and cognitive neural networks. Impairment of functional connections between midbrain tegmentum and cerebellar, temporal and pallidal regions was demonstrated in PSP as compared to HS. When comparing FTD to HS, glucose uptake was primarily reduced in dorsolateral and ventrolateral prefrontal cortices and in frontopolar and anterior cingulate regions. There was also bilateral anterior temporal, right inferior parietal, and bilateral striatal hypometabolism. Finally, FTD showed more severe striatofrontal metabolic impairment than PSP, while mesencephalothalamic involvement was only observed in PSP. Our data suggest that subcorticofrontal metabolic impairment is distributed in distinct subcorticocortical networks in normal aging, PSP, and FTD. Subcorticofrontal dementia in PSP is related to hypometabolism in discrete frontal areas, which are probably disconnected from certain subcortical structures. The concept of subcortical dementia is reinforced by our data, which show disrupted functional connections between mesencephalon and cerebellar cortex, inferior and medial temporal regions, and pallidum.

Adult↗

Microscopical and ultrastructural investigations on the development of the blood-brain barrier in the chick embryo optic tectum.

The formation of a blood-brain barrier to horseradish peroxidase was microscopically and ultrastructurally investigated in the tectum opticum of the chick during development of the intraneural blood vessel network from the 6th incubation day to hatching, and in adult specimens. Extravasation of the circulating marker, apparently unimpeded during early stages of vasculogenesis, starts to diminish from the 14th incubation day (i.d.) and is prevented after the 18th i.d. The tracer seems to get out of the vessel lumina through the sites of reciprocal contact between adjacent endothelial cells, and the differentiation of tight junctions there hinders the passage of peroxidase particles. The formation of numerous endothelial vacuoles during early vasculogenesis and the setting of the blood-brain barrier are discussed in connection with the mechanisms of transendothelial transport, and respectively, the processes of moulding of the growing endothelia.

Animals↗

A role for sleep in the processing of memory traces. Contribution of functional neuroimaging in humans.

Sleep is thought to participate in the consolidation of recent memory traces. We tested this hypothesis in humans, using functional neuroimaging (functional magnetic resonance imaging and positron emission tomography). First, following the training on a procedural visuo-motor learning task (pursuit task), total sleep deprivation on the first post-training night significantly deteriorates the gain in performance, which is usually observed after one complete night of sleep. In parallel, sleep deprivation hampers the changes in functional segregation and connectivity, which underpin the gain in performance usually observed in subjects allowed to sleep on the first post-training night. Second, following the training on an implicit memory task (probabilistic serial reaction time task), some brain areas are reactivated during REM sleep on the first post-training night. The reactivation was shown to be related to the processing of high-level material and to be modulated by the amount of learning achieved during the training session. These changes in activity do not involve isolated brain areas but entire macroscopic cortico-subcortical networks. Taken together, the results suggest an off-line processing of recent memory traces during sleep.

Brain↗