Complex Neuronal Networks Research Articles

Chipping away at memory

Inverse power-law behavior is known to be characteristic of adaptation, learning, and memory. Herein, we propose a phenomenological model of forgetting based on renewal theory that introduces a new psychophysical concept, chipping; discrete events that chip away at chunks of memory and thereby produce forgetting. The neural mechanism producing these chips is the 1/f-noise that is generically produced in complex neuronal networks.

Heterogeneous neuronal firing patterns during interictal epileptiform discharges in the human cortex

Epileptic cortex is characterized by paroxysmal electrical discharges. Analysis of these interictal discharges typically manifests as spike-wave complexes on electroencephalography, and plays a critical role in diagnosing and treating epilepsy. Despite their fundamental importance, little is known about the neurophysiological mechanisms generating these events in human focal epilepsy. Using three different systems of microelectrodes, we recorded local field potentials and single-unit action potentials during interictal discharges in patients with medically intractable focal epilepsy undergoing diagnostic workup for localization of seizure foci. We studied 336 single units in 20 patients. Ten different cortical areas and the hippocampus, including regions both inside and outside the seizure focus, were sampled. In three of these patients, high density microelectrode arrays simultaneously recorded between 43 and 166 single units from a small (4 mm x 4 mm) patch of cortex. We examined how the firing rates of individual neurons changed during interictal discharges by determining whether the firing rate during the event was the same, above or below a median baseline firing rate estimated from interictal discharge-free periods (Kruskal-Wallis one-way analysis, P<0.05). Only 48% of the recorded units showed such a modulation in firing rate within 500 ms of the discharge. Units modulated during the discharge exhibited significantly higher baseline firing and bursting rates than unmodulated units. As expected, many units (27% of the modulated population) showed an increase in firing rate during the fast segment of the discharge (+ or - 35 ms from the peak of the discharge), while 50% showed a decrease during the slow wave. Notably, in direct contrast to predictions based on models of a pure paroxysmal depolarizing shift, 7.7% of modulated units recorded in or near the seizure focus showed a decrease in activity well ahead (0-300 ms) of the discharge onset, while 12.2% of units increased in activity in this period. No such pre-discharge changes were seen in regions well outside the seizure focus. In many recordings there was also a decrease in broadband field potential activity during this same pre-discharge period. The different patterns of interictal discharge-modulated firing were classified into more than 15 different categories. This heterogeneity in single unit activity was present within small cortical regions as well as inside and outside the seizure onset zone, suggesting that interictal epileptiform activity in patients with epilepsy is not a simple paroxysm of hypersynchronous excitatory activity, but rather represents an interplay of multiple distinct neuronal types within complex neuronal networks.

Sensor Mechanism and Afferent Signal Transduction of the Urinary Bladder: Special Focus on transient receptor potential Ion Channels.

In the urine storage phase, mechanical stretch stimulates bladder afferents. These urinary bladder afferent sensory nerves consist of small diameter Aδ- and C-fibers running in the hypogastic and pelvic nerves. Neuroanatomical studies have revealed a complex neuronal network within the bladder wall. The exact mechanisms that underline mechano-sensory transduction in bladder afferent terminals remain ambiguous; however, a wide range of ion channels (e.g. TTX-resistant Na(+) channels, Kv channels and hyperpolarization-activated cyclic nucleotidegated cation channels, degenerin/epithelial Na+ channel), and receptors (e.g. TRPV1, TRPM8, TRPA1, P2X2/3, etc.) have been identified at bladder afferent terminals and have implicated in the generation and modulation of afferent signals, which are elcited by a wide range of bladder stimulations including physiological bladder filling, noxious distension, cold, chemical irritation and inflammation. The mammalian transient receptor potential (TRP) family consists of 28 channels that can be subdivided into six different classes: TRPV (Vanilloid), TRPC (Canonical), TRPM (Melastatin), TRPP (Polycystin), TRPML (Mucolipin), and TRPA (Ankyrin). TRP channels are activated by a diversity of physical (voltage, heat, cold, mechanical stress) or chemical (pH, osmolality) stimuli and by binding of specific ligands, enabling them to act as multifunctional sensors at the cellular level. TRPV1, TRPV2, TRPV4, TRPM8, and TRPA1 have been described in different parts of the urogenital tract. Although only TRPV1 among TRPs has been extensively studied so far, more evidence is slowly accumulating about the role of other TRP channels, ion channels, and receptors in the pathophysiology of the urogenital tract, and may provide a new strategy for the treatment of bladder dysfunction.

Delay-aided stochastic multiresonances on scale-free FitzHugh–Nagumo neuronal networks

The stochastic resonance in paced time-delayed scale-free FitzHugh–Nagumo (FHN) neuronal networks is investigated. We show that an intermediate intensity of additive noise is able to optimally assist the pacemaker in imposing its rhythm on the whole ensemble. Furthermore, we reveal that appropriately tuned delays can induce stochastic multiresonances, appearing at every integer multiple of the pacemaker's oscillation period. We conclude that fine-tuned delay lengths and locally acting pacemakers are vital for ensuring optimal conditions for stochastic resonance on complex neuronal networks.

Netrins guide migration of distinct glial cells in the Drosophila embryo

Development of the nervous system and establishment of complex neuronal networks require the concerted activity of different signalling events and guidance cues, which include Netrins and their receptors. In Drosophila, two Netrins are expressed during embryogenesis by cells of the ventral midline and serve as attractant or repellent cues for navigating axons. We asked whether glial cells, which are also motile, are guided by similar cues to axons, and analysed the influence of Netrins and their receptors on glial cell migration during embryonic development. We show that in Netrin mutants, two distinct populations of glial cells are affected: longitudinal glia (LG) fail to migrate medially in the early stages of neurogenesis, whereas distinct embryonic peripheral glia (ePG) do not properly migrate laterally into the periphery. We further show that early Netrin-dependent guidance of LG requires expression of the receptor Frazzled (Fra) already in the precursor cell. At these early stages, Netrins are not yet expressed by cells of the ventral midline and we provide evidence for a novel Netrin source within the neurogenic region that includes neuroblasts. Later in development, most ePG transiently express uncoordinated 5 (unc5) during their migratory phase. In unc5 mutants, however, two of these cells in particular exhibit defective migration and stall in, or close to, the central nervous system. Both phenotypes are reversible in cell-specific rescue experiments, indicating that Netrin-mediated signalling via Fra (in LG) or Unc5 (in ePG) is a cell-autonomous effect.

Fast optical imaging of human brain function.

Great advancements in brain imaging during the last few decades have opened a large number of new possibilities for neuroscientists. The most dominant methodologies (electrophysiological and magnetic resonance-based methods) emphasize temporal and spatial information, respectively. However, theorizing about brain function has recently emphasized the importance of rapid (within 100 ms or so) interactions between different elements of complex neuronal networks. Fast optical imaging, and in particular the event-related optical signal (EROS, a technology that has emerged over the last 15 years) may provide descriptions of localized (to sub-cm level) brain activity with a temporal resolution of less than 100 ms. The main limitations of EROS are its limited penetration, which allows us to image cortical structures not deeper than 3 cm from the surface of the head, and its low signal-to-noise ratio. Advantages include the fact that EROS is compatible with most other imaging methods, including electrophysiological, magnetic resonance, and trans-cranial magnetic stimulation techniques, with which can be recorded concurrently. In this paper we present a summary of the research that has been conducted so far on fast optical imaging, including evidence for the possibility of recording neuronal signals with this method, the properties of the signals, and various examples of applications to the study of human cognitive neuroscience. Extant issues, controversies, and possible future developments are also discussed.

Neurokinin 3 Receptor Immunoreactivity in the Septal Region, Preoptic Area and Hypothalamus of the Female Sheep: Colocalisation in Neurokinin B Cells of the Arcuate Nucleus but not in Gonadotrophin‐Releasing Hormone Neurones

Recent evidence has implicated neurokinin B (NKB) in the complex neuronal network mediating the effects of gonadal steroids on the regulation of gonadotrophin-releasing hormone (GnRH) secretion. Because the neurokinin 3 receptor (NK3R) is considered to mediate the effects of NKB at the cellular level, we determined the distribution of immunoreactive NK3R in the septal region, preoptic area (POA) and hypothalamus of the ewe. NK3R cells and/or fibres were found in areas including the bed nucleus of the stria terminalis, POA, anterior hypothalamic and perifornical areas, dopaminergic A15 region, dorsomedial and lateral hypothalamus, arcuate nucleus (ARC) and the ventral premammillary nucleus. We also used dual-label immunocytochemistry to determine whether a neuroanatomical basis for direct modulation of GnRH neurones by NKB was evident. No GnRH neurones at any rostral-caudal level were observed to contain NK3R immunoreactivity, although GnRH neurones and fibres were in proximity to NK3R-containing fibres. Because NKB fibres formed close contacts with NKB neurones in the ARC, we determined whether these NKB neurones also contained immunoreactive NK3R. In luteal-phase ewes, 64% +/- 11 of NKB neurones colocalised NK3R. In summary, NK3R is distributed in areas of the sheep POA and hypothalamus known to be involved in the control of reproductive neuroendocrine function. Colocalisation of NK3R in NKB neurones of the ARC suggests a potential mechanism for the autoregulation of this subpopulation; however, the lack of NK3R in GnRH neurones suggests that the actions of NKB on GnRH neurosecretory activity in the ewe are mediated indirectly via other neurones and/or neuropeptides.

Endogenous Retroviruses: Thierry Heidmann wins the 2009 Retrovirologyprize

Thierry Heidmann wins the 2009 Retrovirology prize.

Noninvasive dynamic imaging of seizures in epileptic patients.

Epileptic seizures are due to abnormal synchronized neuronal discharges. Techniques measuring electrical changes are commonly used to analyze seizures. Neuronal activity can be also defined by concomitant hemodynamic and metabolic changes. Simultaneous electroencephalogram (EEG)-functional MRI (fMRI) measures noninvasively with a high-spatial resolution BOLD changes during seizures in the whole brain. Until now, only a static image representing the whole seizure was provided. We report in 10 focal epilepsy patients a new approach to dynamic imaging of seizures including the BOLD time course of seizures and the identification of brain structures involved in seizure onset and discharge propagation. The first activation was observed in agreement with the expected location of the focus based on clinical and EEG data (three intracranial recordings), thus providing validity to this approach. The BOLD signal preceded ictal EEG changes in two cases. EEG-fMRI may detect changes in smaller and deeper structures than scalp EEG, which can only record activity form superficial cortical areas. This method allowed us to demonstrate that seizure onset zone was limited to one structure, thus supporting the concept of epileptic focus, but that a complex neuronal network was involved during propagation. Deactivations were also found during seizures, usually appearing after the first activation in areas close or distant to the activated regions. Deactivations may correspond to actively inhibited regions or to functional disconnection from normally active regions. This new noninvasive approach should open the study of seizure generation and propagation mechanisms in the whole brain to groups of patients with focal epilepsies.

Helix neuronal ensembles with controlled cell type composition and placement develop functional polysynaptic circuits on Micro-Electrode Arrays

Neuronal cell cultures on Micro-Electrode Arrays (MEAs) provide an essential experimental tool for studying the connectivity and long-term activity of complex neuronal networks. MEA studies are generally based on the analysis of mixed neuronal populations constituted by a large number of cultured cells with cell type composition and connectivity patterns which are quite unpredictable a priori. In this work, we propose a different approach which consists of assembling on MEAs neuronal circuits formed by individually identifiable C1, C3, and B2 Helix neurons. Cells were plated under conditions of controlled number and position to form neuronal networks of defined composition. We performed multi-site electrophysiological recordings, and we characterized the firing dynamics. By means of cross-correlation analysis, we studied the electrophysiological properties of MEA-coupled microcircuits and characterized their activity patterns. We showed how the synaptic connectivity, actually observed in polysynaptic circuits of C1, C3 and B2 neurons, correlates well with the expected connectivity of C1–B2, B2–B2 and B2–C3 cell pairs as previously reported in conventional electrophysiological studies in culture.

Worms With a Single Functional Sensory Cilium Generate Proper Neuron-Specific Behavioral Output

Studying the development and mechanisms of sensory perception is challenging in organisms with complex neuronal networks. The worm Caenorhabditis elegans possesses a simple neuronal network of 302 neurons that includes 60 ciliated sensory neurons (CSNs) for detecting external sensory input. C. elegans is thus an excellent model in which to study sensory neuron development, function, and behavior. We have generated a genetic rescue system that allows in vivo analyses of isolated CSNs at both cellular and systemic levels. We used the RFX transcription factor DAF-19, a key regulator of ciliogenesis. Mutations in daf-19 result in the complete absence of all sensory cilia and thus of external sensory input. In daf-19 mutants, we used cell-specific rescue of DAF-19 function in selected neurons, thereby generating animals with single, fully functional CSNs. Otherwise and elsewhere these animals are completely devoid of any environmental input through cilia. We demonstrated the rescue of fully functional, single cilia using fluorescent markers, sensory behavioral assays, and calcium imaging. Our technique, functional rescue in single sensory cilia (FRISSC), can thus cell-autonomously and cell-specifically restore the function of single sensory neurons and their ability to respond to sensory input. FRISSC can be adapted to many different CSNs and thus constitutes an excellent tool for studying sensory behaviors, both in single animals and in populations of worms. FRISSC will be very useful for the molecular dissection of sensory perception in CSNs and for the analysis of the developmental aspects of ciliogenesis.

Arbitrary multisite two-photon excitation in four dimensions

We demonstrate dynamic and arbitrary multisite two-photon excitation in three dimensions using the holographic projection method. Rapid response (fourth dimension) is achieved through high-speed noniterative calculation of the hologram using a video graphics accelerator board. We verify that the projected asymmetric spot configurations have sufficient spatiotemporal photon density for localized two-photon excitation. This system is a significant advance and can be applied to time-resolved photolysis of caged compounds in biological cells and complex neuronal networks, nonlinear microfabrication and volume holographic optical storage.

Synchronization transitions on scale-free neuronal networks due to finite information transmission delays

We investigate front propagation and synchronization transitions in dependence on the information transmission delay and coupling strength over scale-free neuronal networks with different average degrees and scaling exponents. As the underlying model of neuronal dynamics, we use the efficient Rulkov map with additive noise. We show that increasing the coupling strength enhances synchronization monotonously, whereas delay plays a more subtle role. In particular, we found that depending on the inherent oscillation frequency of individual neurons, regions of irregular and regular propagating excitatory fronts appear intermittently as the delay increases. These delay-induced synchronization transitions manifest as well-expressed minima in the measure for spatial synchrony, appearing at every multiple of the oscillation frequency. Larger coupling strengths or average degrees can broaden the region of regular propagating fronts by a given information transmission delay and further improve synchronization. These results are robust against variations in system size, intensity of additive noise, and the scaling exponent of the underlying scale-free topology. We argue that fine-tuned information transmission delays are vital for assuring optimally synchronized excitatory fronts on complex neuronal networks and, indeed, they should be seen as important as the coupling strength or the overall density of interneuronal connections. We finally discuss some biological implications of the presented results.

Towards Reproducible Descriptions of Neuronal Network Models

Progress in science depends on the effective exchange of ideas among scientists. New ideas can be assessed and criticized in a meaningful manner only if they are formulated precisely. This applies to simulation studies as well as to experiments and theories. But after more than 50 years of neuronal network simulations, we still lack a clear and common understanding of the role of computational models in neuroscience as well as established practices for describing network models in publications. This hinders the critical evaluation of network models as well as their re-use.We analyze here 14 research papers proposing neuronal network models of different complexity and find widely varying approaches to model descriptions, with regard to both the means of description and the ordering and placement of material. We further observe great variation in the graphical representation of networks and the notation used in equations. Based on our observations, we propose a good model description practice, composed of guidelines for the organization of publications, a checklist for model descriptions, templates for tables presenting model structure, and guidelines for diagrams of networks. The main purpose of this good practice is to trigger a debate about the communication of neuronal network models in a manner comprehensible to humans, as opposed to machine-readable model description languages.We believe that the good model description practice proposed here, together with a number of other recent initiatives on data-, model-, and software-sharing, may lead to a deeper and more fruitful exchange of ideas among computational neuroscientists in years to come. We further hope that work on standardized ways of describing—and thinking about—complex neuronal networks will lead the scientific community to a clearer understanding of high-level concepts in network dynamics, and will thus lead to deeper insights into the function of the brain.

Ion channel and receptor mechanisms of bladder afferent nerve sensitivity

Sensory nerves of the urinary bladder consist of small diameter A δ and C fibers running in the hypogastic and pelvic nerves. Neuroanatomical studies have revealed a complex neuronal network within the bladder wall. Electrophysiological recordings in vitro and in vivo have revealed several distinct classes of afferent fibers that may signal a wide range of bladder stimulations including physiological bladder filling, noxious distension, cold, chemical irritation and inflammation. The exact mechanisms that underline mechanosensory transduction in bladder afferent terminals remain ambiguous; however, a wide range of ion channels (e.g., TTX-resistant Na + channels, Kv channels and hyperpolarization-activated cyclic nucleotide-gated cation channels) and receptors (e.g., TRPV1, TRPM8, TRPA1, P2X 2/3, etc) have been identified at bladder afferent terminals and implicated in the generation and modulation of afferent signals. Experimental investigations have revealed that expression and/or function of these ion channels and receptors may be altered in animal models and patients with overactive and painful bladder disorders. Some of these ion channels and receptors may be potential therapeutic targets for bladder diseases.

Interplay among enteric neurons, interstitial cells of Cajal, resident and not resident connective tissue cells

Interplay among enteric neurons, interstitial cells of Cajal, resident and not resident connective tissue cells

Role of dorsal raphe nucleus 5-HT 1A and 5-HT 2 receptors in tonic immobility modulation in guinea pigs

Tonic immobility (TI) is an innate defensive behavior characterized by a state of physical inactivity and diminished responsiveness to environmental stimuli. Behavioral adaptations to changes in the external and internal milieu involve complex neuronal network activity and a large number of chemical neurotransmitters. The TI response is thought to be influenced by serotonin (5-HT) activity in the central nervous system (CNS) of vertebrates, but the neuronal groups involved in the mechanisms underlying this behavior are poorly understood. Owing to its extensive afferents and efferents, the dorsal raphe nucleus (DRN) has been implicated in a great variety of physiological and behavioral functions. In the current study, we investigated the influence of serotonergic 5-HT 1A and 5-HT 2 receptor activity within the DRN on the modulation of TI behavior in the guinea pig. Microinjection of a 5-HT 1A receptor agonist (8-OH-DPAT, 0.01 and 0.1 μg) decreased TI behavior, an effect blocked by pretreatment with WAY-100635 (0.033 μg), a 5-HT 1A antagonist. In contrast, activation of 5-HT 2 receptors within the DRN (α-methyl-5-HT, 0.5 μg) increased the TI duration, and this effect could be reversed by pretreatment with an ineffective dose (0.01 μg) of ketanserine. Since the 5-HT 1A and 5-HT 2 agonists decreased and increased, respectively, the duration of TI, different serotonin receptor subtypes may play distinct roles in the modulation of TI in the guinea pig.

Coordinated changes in energy intake and expenditure following hypothalamic administration of neuropeptides involved in energy balance

ObjectiveThe hypothalamic control of energy balance is regulated by a complex network of neuropeptide-releasing neurons. Whilst the effect of these neuropeptides on individual aspects of energy homeostasis has been studied, the coordinated response of these effects has not been comprehensively investigated. We have simultaneously monitored a number of metabolic parameters following ICV administration of 1nmol and 3nmol of neuropeptides with established roles in the regulation of feeding, activity and metabolism. Ad libitum fed rats received the orexigenic neuropeptides neuropeptide Y (NPY), agouti-related protein (AgRP), melanin-concentrating hormone (MCH) or orexin-A. Overnight food deprived rats received an ICV injection of the anorectic peptides α-MSH, corticotrophin releasing factor (CRF) or neuromedin U (NMU).ResultsOur results reveal the temporal sequence of the effects of these neuropeptides on both energy intake and expenditure, highlighting key differences in their function as mediators of energy balance. NPY and AgRP increased feeding and decreased oxygen consumption, with the effects of AgRP being more prolonged. In contrast, orexin-A increased both feeding and oxygen consumption, consistent with an observed increase in activity. The potent anorexigenic effects of CRF were accompanied by a prolonged increase in activity whilst NMU injection resulted in significant but short-lasting inhibition of food intake, ambulatory activity and oxygen consumption. Alpha-MSH injection resulted in significant increases in both ambulatory activity and oxygen consumption, and reduced food intake following administration of 3nmol of the peptide.ConclusionWe have for the first time, simultaneously measured several metabolic parameters following hypothalamic administration of a number of neuropeptides within the same experimental system. This work has demonstrated the interrelated effects of these neuropeotides on activity, energy expenditure and food intake thus facilitating comparison between the different hypothalamic systems.

Delay-induced multiple stochastic resonances on scale-free neuronal networks

We study the effects of periodic subthreshold pacemaker activity and time-delayed coupling on stochastic resonance over scale-free neuronal networks. As the two extreme options, we introduce the pacemaker, respectively, to the neuron with the highest degree and to one of the neurons with the lowest degree within the network, but we also consider the case when all neurons are exposed to the periodic forcing. In the absence of delay, we show that an intermediate intensity of noise is able to optimally assist the pacemaker in imposing its rhythm on the whole ensemble, irrespective to its placing, thus providing evidences for stochastic resonance on the scale-free neuronal networks. Interestingly thereby, if the forcing in form of a periodic pulse train is introduced to all neurons forming the network, the stochastic resonance decreases as compared to the case when only a single neuron is paced. Moreover, we show that finite delays in coupling can significantly affect the stochastic resonance on scale-free neuronal networks. In particular, appropriately tuned delays can induce multiple stochastic resonances independently of the placing of the pacemaker, but they can also altogether destroy stochastic resonance. Delay-induced multiple stochastic resonances manifest as well-expressed maxima of the correlation measure, appearing at every multiple of the pacemaker period. We argue that fine-tuned delays and locally active pacemakers are vital for assuring optimal conditions for stochastic resonance on complex neuronal networks.

Systems Biology and Addiction

The onset of addiction is marked with drug induced positive experiences that keep being repeated. During that time, adaptation occurs and addiction is stabilized. Interruption of those processes induces polysymptomatic withdrawal syndromes. Abstinence is accompanied by risks of relapse. These features of addiction suggest adaptive brain dynamics with common pathways in complex neuronal networks. Addiction research has used animal models, where some of those phenomena could be reproduced, to find correlates of addictive behavior. The major thrust of those approaches has been on the involvement of genes and proteins. Recently, an enormous amount of data has been obtained by high throughput technologies in these fields. Therefore, (Computational) "Systems Biology" had to be implemented as a new approach in molecular biology and biochemistry. Conceptually, Systems Biology can be understood as a field of theoretical biology that tries to identify patterns in complex data sets and that reconstructs the cell and cellular networks as complex dynamic, self-organizing systems. This approach is embedded in systems science as an interdisciplinary effort to understand complex dynamical systems and belongs to the field of theoretical neuroscience (Computational Neuroscience). Systems biology, in a similar way as computational neuroscience is based on applied mathematics, computer-based computation and experimental simulation. In terms of addiction research, building up "computational molecular systems biology of the (addicted) neuron" could provide a better molecular biological understanding of addiction on the cellular and network level. Some key issues are addressed in this article.