Oxygen can be limited at the environmental (e.g. flood-prone burrows) or cellular (e.g. stroke, heart attack) levels. O2 deprivation in nervous tissue depolarizes cell membranes, incrementing extracellular potassium concentration ([K+]o). Consequently, [K+]o can be used to assess neural failure during anoxia. The effect of temperature on the maintenance of brain [K+]o homeostasis in male and female Drosophila melanogaster (W1118) was assessed during repeated anoxic comas induced by N2 gas. Brain [K+]o was continuously monitored using K+-sensitive microelectrodes while body temperature was gradually increased/decreased using a Peltier plate. Once the desired temperature was reached (16°C/17°C, 23°C or 29°C/30°C), it was maintained for the rest of the experiment and the fly was subjected to repeated anoxic bouts. Repetitive anoxia resulted in a loss of the ability to maintain [K+]o baseline at ~10 mM. In both sexes, the total [K+]o baseline variation (D[K+]o) was augmented at 30°C (D[K+]o male = 119.2 ± 21.9 mM; D[K+]o female = 51.2 ± 8.1 mM), whereas 16°C stabilized [K+]o baseline for the duration of the experiment (D[K+]o male = 17.5 ± 4.1 mM; D[K+]o female = 16.9 ± 6.8 mM). Additionally, D[K+]o in males was significantly greater (114.3 ± 10.5 mM ) than in females (36.1 ± 10.5 mM) at 23°C. Under reduced dehydration, experiments performed only in males showed the same trends although the D[K+]o values where considerably reduced at 17°C (D[K+]o male = -1.0 ± 1.3 mM) and 23°C (D[K+]o male = 17.3 ± 1.5 mM) and increased at 29°C (D[K+]o male = 332.7 ± 83.0 mM). It was concluded that 1) N2-delivery patterns consisting of long anoxia, short normoxia and high cycle frequency increased disruption of brain [K+]o baseline maintenance, 2) males were more susceptible to repeated anoxia than females at room temperature, and 3) hypothermia had a protective effect on brain K+ homeostasis during repetitive anoxia. Male flies are suggested as a useful model for examining deleterious consequences of O2 reperfusion with extensive application on therapeutical treatment of stroke or heart attack. / Thesis (Master, Biology) -- Queen's University, 2012-01-30 13:03:10.913

No / Cortical spreading depression (CSD) is a transient disruption of local ionic homeostasis that may promote migraine attacks and the progression of stroke lesions. We reported previously that the local inhibition of nitric oxide (NO) synthesis with N¿-nitro-L-arginine methyl ester (L-NAME) delayed markedly the initiation of the recovery of ionic homeostasis from CSD. Here we describe a novel method for selective, controlled generation of exogenous NO in a functioning brain region. It is based on microdialysis perfusion of the NO donor, 2-(N,N-diethylamino)-diazenolate-2-oxide (DEA/NO). As DEA/NO does not generate NO at alkaline pH, and as the brain has a strong acid-base buffering capacity, DEA/NO was perfused in a medium adjusted at alkaline (but unbuffered) pH. Without DEA/NO, such a microdialysis perfusion medium did not alter CSD. DEA/NO (1, 10 and 100 ¿M) had little effect on CSD by itself, but it reversed in a concentration-dependent manner the effects of NOS inhibition by 1 mM L-NAME. These data demonstrate that increased formation of endogenous NO associated with CSD is critical for subsequent, rapid recovery of cellular ionic homeostasis. In this case, the molecular targets for NO may be located either on brain cells to suppress mechanisms directly involved in CSD genesis, or on local blood vessels to couple flow to the increased energy demand associated with CSD

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Dans cette thèse nous avons utilisé des méthodes de systèmes dynamiques et des simulations numériques pour étudier les mécanismes d'oscillations d'épilepsie associés à des concentrations d’ions dynamiques et au comportement bimodal des cellules Purkinje du cervelet. Le propos général de ce travail est l'interaction entre les propriétés intrinsèques des neurones simple et la structure d'entrée synaptique contrôlant l'excitabilité neuronale. Dans la première partie de la thèse nous avons développé un modèle de transition de crise épileptique dans le lobe temporal du cerveau. Plus précisément nous nous sommes concentrés sur le rôle du cotransporteur KCC2, qui est responsable de la maintenance du potassium extracellulaire et du chlorure intracellulaire dans les neurones. Des données expérimentales récentes ont montré que cette molécule est absente dans un groupe significatif de cellules pyramidales dans le tissue neuronal de patients épileptiques suggérant son rôle épileptogène. Nous avons trouvé que l'addition d’une quantité critique de cellules pyramidale KCC2 déficient au réseau de subiculum, avec une connectivité réaliste, peut provoquer la génération d’oscillations pathologiques, similaire aux oscillations enregistrées dans des tranches de cerveau épileptogène humaines. Dans la seconde partie de la thèse, nous avons étudié le rôle du bruit synaptique dans les cellules de Purkinje. Nous avons étudié l'effet de l'inhibition de la génération du potentiel d’action provoquée par injection de courant de bruit, un phénomène connu comme résonance stochastique inverse (RSI). Cet effet a déjà été trouvé dans des modèles neuronaux, et nous avons fournis sa première validation expérimentale. Nous avons trouvé que les cellules de Purkinje dans des tranches de cerveau peuvent être efficacement inhibées par des injectionsde bruit de courant. Cet effet est bien reproduit par le modèle phénoménologique adapté pour différentes cellules. En utilisant des méthodes de la théorie de l'information, nous avons montré que RSI prend en charge une transmission efficace de l'information des cellules de Purkinje simples suggérant son rôle pour les calculs du cervelet. / In this thesis we used dynamical systems methods and numericalsimulations to study the mechanisms of epileptic oscillations associated with ionconcentration changes and cerebellar Purkinje cell bimodal behavior. The general issue in this work is the interplay between single neuron intrinsicproperties and synaptic input structure controlling the neuronal excitability. In the first part of this thesis we focused on the role of the cellular intrinsicproperties, their control over the cellular excitability and their response to thesynaptic inputs. Specifically we asked the question how the cellular changes ininhibitory synaptic function might lead to the pathological neural activity. We developed a model of seizure initiation in temporal lobe epilepsy. Specifically we focused on the role of KCC2 cotransporter that is responsible for maintaining the baseline extracellular potassium and intracellular chloride levels in neurons. Recent experimental data has shown that this cotransporter is absent in the significant group of pyramidal cells in epileptic patients suggesting its epileptogenic role. We found that addition of the critical amount of KCC2-deficient pyramidal cells to the realistic subiculum network can switch the neural activity from normal to epileptic oscillations qualitatively reproducing the activity recorded in human epileptogenic brain slices. In the second part of this thesis we studied how synaptic noise might control the Purkinje cell excitability. We investigated the effect of spike inhibition caused by noise current injection, so-called inverse stochastic resonance (ISR). This effect has been previously found in single neuron models while we provided its first experimental evidence. We found that Purkinje cells in brain slices could be efficiently inhibited by current noise injections. This effect is well reproduced by the phenomenological model fitted for different cells. Using methods of information theory we showed that ISR supports an efficient information transmission of single Purkinje cells suggesting its role for cerebellar computations.