Realistic spiking neural network: Non-synaptic mechanisms improve convergence in cell assembly.

Learning in neural networks inspired by brain tissue has been studied for machine learning applications. However, existing works primarily focused on the concept of synaptic weight modulation, and other aspects of neuronal interactions, such as non-synaptic mechanisms, have been neglected. Non-synaptic interaction mechanisms have been shown to play significant roles in the brain, and four classes of these mechanisms can be highlighted: (i) electrotonic coupling; (ii) ephaptic interactions; (iii) electric field effects; and iv) extracellular ionic fluctuations. In this work, we proposed simple rules for learning inspired by recent findings in machine learning adapted to a realistic spiking neural network. We show that the inclusion of non-synaptic interaction mechanisms improves cell assembly convergence. By including extracellular ionic fluctuation represented by the extracellular electrodiffusion in the network, we showed the importance of these mechanisms to improve cell assembly convergence. Additionally, we observed a variety of electrophysiological patterns of neuronal activity, particularly bursting and synchronism when the convergence is improved.

Gold Nanoparticles for X-ray Microtomography of Neurons.

Commonly used methods to visualize the biological structure of brain tissues at subcellular resolution are confocal microscopy and two-photon microscopy. Both require slicing the sample into sections of a few tens of micrometers. The recent developments in X-ray microtomography enable three-dimensional imaging at sub-micrometer and isotropic resolution with larger biological samples. In this work, we developed and compared original microtomography methods and staining protocols to improve the contrast for in vitro mouse neuron imaging. Using Golgi's method to stain neurons randomly, we imaged the whole set of mouse brain structures. For specific and nonrandom neuron labeling, we conjugated 20 nm gold nanoparticles to antibodies used in the immunohistochemistry (IHC) method, using anti-NeuN to label specifically neuronal nuclei. We applied an original subtraction dual-energy method for microtomography in the vicinity of the Au L-III absorption edge and compared image reconstructions to confocal microscopy images acquired on the same samples. The results show the possibility to characterize the 3D entire brain structure of mice. They demonstrated a high contrast and neuron detection improvement by applying the dual-energy method coupled to IHC staining.

Robust Network Inhibition and Decay of Early-Phase LTP in the Hippocampal CA1 Subfield of the Amazon Rodent Proechimys.

Background: Diverse forms of long-term potentiation (LTP) have been described, but one of the most investigated is encountered in the glutamatergic synapses of the hippocampal cornu Ammonis (CA1) subfield. However, little is known about synaptic plasticity in wildlife populations. Laboratory animals are extremely inbred populations that have been disconnected from their natural environment and so their essential ecological aspects are entirely absent. Proechimys are small rodents from Brazil's Amazon rainforest and their nervous systems have evolved to carry out specific tasks of their unique ecological environment. It has also been shown that long-term memory duration did not persist for 24-h in Proechimys, in contrast to Wistar rats, when both animal species were assessed by the plus-maze discrimination avoidance task and object recognition test. Methods: In this work, different protocols, such as theta burst, single tetanic burst or multiple trains of high frequency stimulation (HFS), were used to induce LTP in hippocampal brain slices of Proechimys and Wistar rats. Results: A protocol-independent fast decay of early-phase LTP at glutamatergic synapses of the CA1 subfield was encountered in Proechimys. Long-term depression (LTD) and baseline paired-pulse facilitation (PPF) were investigated but no differences were found between animal species. Input/output (I/O) relationships suggested lower excitability in Proechimys in comparison to Wistar rats. Bath application of d-(-)-2-amino-5-phosphonopentanoicacid (D-AP5) and CNQX prevented the induction of LTP in both Proechimys and Wistar. However, in marked contrast to Wistar rats, LTP induction was not facilitated by the GABAA antagonist in the Amazon rodents, even higher concentrations failed to facilitate LTP in Proechimys. Next, the effects of GABAA inhibition on spontaneous activity as well as evoked field potentials (FPs) were evaluated in CA1 pyramidal cells. Likewise, much lower activity was detected in Proechimys brain slices in comparison to those of the Wistar rats. Conclusions: These findings suggest a possible high inhibitory tone in the CA1 network mediated by GABAA receptors in the Amazon rodents. Currently, neuroscience research still seeks to reveal molecular pathways that control learning and memory processes, Proechimys may prove useful in identifying such mechanisms in complement to traditional animal models.

GABAa excitation and synaptogenesis after Status Epilepticus - A computational study.

The role of GABAergic neurotransmission on epileptogenesis has been the subject of speculation according to different approaches. However, it is a very complex task to specifically consider the action of the GABAa neurotransmitter, which, in its dependence on the intracellular level of Cl-, can change its effect from inhibitory to excitatory. We have developed a computational model that represents the dentate gyrus and is composed of three different populations of neurons (granule cells, interneurons and mossy cells) that are mutually interconnected. The interconnections of the neurons were based on compensation theory with Hebbian and anti-Hebbian rules. The model also incorporates non-synaptic mechanisms to control the ionic homeostasis and was able to reproduce ictal discharges. The goal of the work was to investigate the hypothesis that the observed aberrant sprouting is promoted by GABAa excitatory action. Conjointly with the abnormal sprouting of the mossy fibres, the simulations show a reduction of the mossy cells connections in the network and an increased inhibition of the interneurons as a response of the neuronal network to control the activity. This finding contributes to increasing the changes in the connectivity of the neuronal circuitry and to increasing the epileptiform activity occurrences.

Modification of the natural progression of epileptogenesis by means of biperiden in the pilocarpine model of epilepsy.

Brain injuries are often associated with the later development of epilepsy. Evidence suggests that morphological and functional changes occur in the remaining neural tissue during a silent (or latent) period in which no seizures are expressed. It is believed that this silent (reorganization) period may provide a therapeutic window for modifying the natural history of disease progression. Here we provide evidence that biperiden, a muscarinic anticholinergic agent, is able to alter disease progression in an animal model of epilepsy. We observed that biperiden was capable of slowing the manifestation of the first spontaneous epileptic seizure and effectively reduced the severity and number of recurrent, spontaneous epileptic seizures during the animals' lifespan. Biomolecular (microdialysis) and electrophysiological (extracellular field recordings) studies determined that biperiden was capable of elevating the threshold of hippocampal excitability, thereby making the hippocampal glutamatergic pathways less responsive to stimuli when high concentrations of potassium were used in vivo or in vitro. Notably, there was no hindrance of long-term memory or learning (a potential problem given the amnestic nature of biperiden). We conclude that biperiden has antiepileptogenic potential and may represent an opportunity for the prevention of post-traumatic epilepsy.

Fish Oil Supplementation Reduces Heart Levels of Interleukin-6 in Rats with Chronic Inflammation due to Epilepsy.

Sudden unexpected death in epilepsy (SUDEP) is a major cause of premature death related to epilepsy. The causes of SUDEP remain unknown, but cardiac arrhythmias and asphyxia have been suggested as a major mechanism of this event. Inflammation has been implicated in the pathogenesis of both epilepsy and ventricular arrhythmia, with interleukin-6 (IL-6) being recognized as a crucial orchestrator of inflammatory states. Our group previously reported that levels of IL-6 were increased in the hearts of epileptic rats. In this scenario, anti-inflammatory actions are among the beneficial effects of fish oil dietary supplementation. This investigation revealed that elevated levels of IL-6 in the heart were markedly reduced in epileptic rats that were treated in the long-term with fish oil, suggesting protective anti-inflammatory actions against dangerously high levels of IL-6. Based on these findings, our results suggest beneficial effects of long-term intake of fish oil in reducing the inflammation associated with chronic epilepsy.

pH during non-synaptic epileptiform activity-computational simulations.

The excitability of neuronal networks is strongly modulated by changes in pH. The origin of these changes, however, is still under debate. The high complexity of neural systems justifies the use of computational simulation to investigate mechanisms that are possibly involved. Simulated neuronal activity includes non-synaptic epileptiform events (NEA) induced in hippocampal slices perfused with high-K(+) and zero-Ca(2+), therefore in the absence of the synaptic circuitry. A network of functional units composes the NEA model. Each functional unit represents one interface of neuronal/extracellular space/glial segments. Each interface contains transmembrane ionic transports, such as ionic channels, cotransporters, exchangers and pumps. Neuronal interconnections are mediated by gap-junctions, electric field effects and extracellular ionic fluctuations modulated by extracellular electrodiffusion. Mechanisms investigated are those that change intracellular and extracellular ionic concentrations and are able to affect [H(+)]. Our simulations suggest that the intense fluctuations in intra and extracellular concentrations of Na(+), K(+) and Cl(-) that accompany NEA are able to affect the combined action of the Na(+)/H(+) exchanger (NHE), [HCO(-)(3)]/Cl(-) exchanger (HCE), H(+) pump and the catalytic activity of intra and extracellular carbonic anhydrase. Cellular volume changes and extracellular electrodiffusion are responsible for modulating pH.

Zoological techniques parameters of Proechimys guyannensis(Rodentia, Echimydae) bred in captivity / Parâmetros zootécnicos de Proechimys guyannensis (Rodentia, Echimydae) criados em cativeiro

The rodents Proechimys guyannensis have led a great interest because they are considered as hosts to several pathogens causing zoological diseases. Therefore, it is important to know their biological and physiological parameters. The age at first cubs delivery and the average of birth interval per female were evaluated. The estimated age at puberty was 83 days. The number of pups born per delivery did not differ significantly when associated with the female mating age. However, an increase in the average mortality rate correlated with the increase in delivery number per female was detected. There is no statistical difference neither in the litter size in different seasons of the year, nor in the body weight between sexes for all ages. Differences were found in the daily water consumption and in the feed intake in animals with approximately 100 days of age, perhaps owing to the increased need for energy intake due to sexual activity or even because they had not reached adult weight yet. The parameters assessed in the present study are of relevance for maintaining this species in captivity as a laboratory animal.

Roedores da espécie Proechimys guyannensis têm motivado grande interesse por serem frequentementeconsiderados como hospedeiros de diversos agentes patogênicos causadores de doenças. É importanteestabelecer seus parâmetros biológicos e fisiológicos; neste contexto, foram avaliadas a idade ao primeiroparto e a média de intervalo de natalidade por fêmea. A idade à puberdade foi estimada em 83 dias.O número de filhotes nascidos por parto não diferiu significativamente com a idade das fêmeas aoacasalarem. Observou-se aumento da taxa média de mortalidade de acordo com o aumento do númerode partos por fêmea. Não houve diferença estatística no tamanho da ninhada em diferentes estações doano; tampouco houve diferença de peso entre os sexos. Foram detectadas diferenças no consumo diáriode água e no consumo de ração em animais com menos e mais de 100 dias de idade, talvez em funçãode aumento da necessidade de consumo de energia pela atividade sexual ou mesmo por ainda não teremalcançado o peso corporal de adulto. Os parâmetros apresentados são relevantes para a futura manutençãodesta espécie em cativeiro como animal de laboratório.

Alcohol abuse promotes changes in non-synaptic epileptiform activity with concomitant expression changes in cotransporters and glial cells.

Non-synaptic mechanisms are being considered the common factor of brain damage in status epilepticus and alcohol intoxication. The present work reports the influence of the chronic use of ethanol on epileptic processes sustained by non-synaptic mechanisms. Adult male Wistar rats administered with ethanol (1, 2 e 3 g/kg/d) during 28 days were compared with Control. Non-synaptic epileptiform activities (NEAs) were induced by means of the zero-calcium and high-potassium model using hippocampal slices. The observed involvement of the dentate gyrus (DG) on the neurodegeneration promoted by ethanol motivated the monitoring of the electrophysiological activity in this region. The DG regions were analyzed for the presence of NKCC1, KCC2, GFAP and CD11b immunoreactivity and cell density. The treated groups showed extracellular potential measured at the granular layer with increased DC shift and population spikes (PS), which was remarkable for the group E1. The latencies to the NEAs onset were more prominent also for the treated groups, being correlated with the neuronal loss. In line with these findings were the predispositions of the treated slices for neuronal edema after NEAs induction, suggesting that restrict inter-cell space counteracts the neuronal loss and subsists the hyper-synchronism. The significant increase of the expressions of NKCC1 and CD11b for the treated groups confirms the existence of conditions favorable to the observed edematous necrosis. The data suggest that the ethanol consumption promotes changes on the non-synaptic mechanisms modulating the NEAs. For the lower ethanol dosage the neurophysiological changes were more effective suggesting to be due to the less intense neurodegenertation.

Effect of co-transporter blockers on non-synaptic epileptiform activity-computational simulation.

The important role of cation-chloride co-transporters in epilepsy is being supported by an increasing number of investigations. However, enormous complexity is involved since the action of these co-transporters has effects on the ionic homeostasis influencing directly the neuronal excitability and the tissue propensity to sustain seizure. To unravel the complex mechanisms involving the co-transporters action during seizure, this paper shows simulations of non-synaptic epileptiform activity and the effect of the blockage of the two different types of cation-chloride co-transporters present in the brain: Na, K and 2Cl co-transporter (NKCC) and K and Cl co-transporter (KCC). The simulations were performed with an electrochemical model representing the non-synaptic structure of the granule cell layer of the dentate gyrus (DG) of the rat hippocampus. The simulations suggest: (i) the potassium clearance is based on the systemic interplay between the Na/K pump and the NKCC co-transporters; (ii) the simultaneous blockage of the NKCC of the neurons and KCC of glial cells acts efficiently suppressing the epileptiform activities; and (iii) the simulations show that depending on the combined blockage of the co-transporters, the epileptiform activities may be suppressed or enhanced.