Replay of spike sequences can be seen during sharp wave – ripple population burst activity in the hippocampus. It is thought that this activity, which occurs during rest and sleep, is involved in memory consolidation. The cellular mechanisms underlying the initiation of these replay events are not well understood. To investigate this, a hippocampal slice model, showing spontaneous sharp wave – ripple activity, and a combination of planar multi-electrode array recordings and whole-cell patch-clamp recordings of anatomically identified hippocampal neurons were used. Firstly, the spatial and temporal profile of sharp waves in vitro was analysed in detail. Sharp waves were generated by changing subpopulations of pyramidal neurons in the CA3 region and had characteristics similar to those found in vivo. Secondly, four major receptor types present in hippocampal CA3, namely NMDA, AMPA, GABAA and GABAB receptors, were investigated for their involvement in sharp wave generation. Surprisingly, not only AMPA receptor-mediated events, but also phasic GABAA receptor-mediated inhibition, were necessary for sharp wave generation. Thirdly, single perisomatic-targeting interneurons were activated. This experiment showed that induced spiking activity of an individual perisomatic-targeting interneuron can both suppress and subsequently enhance local sharp wave generation. Spiking activity of other neuron types (i.e. pyramidal neurons, dendritic-targeting interneurons and interneuron-selective interneurons) had no significant effect on sharp wave incidence. Finally, it is suggested that this post-inhibitory enhancement of sharp wave generation can be mediated by a transient increase in the ratio of excitation to inhibition in the local network. In conclusion, these results suggest a new role for perisomatic-targeting interneurons in controlling the local initiation of sharp waves by selectively suppressing and subsequently enhancing recruitment of a subpopulation of pyramidal neurons. These results further imply that interneurons may play an integral part in the local information processing that takes place in the hippocampal network.

Traditional methods of studying underground coal mine explosions are limited to observations and data collected during experimental explosions. These experiments are expensive, time-consuming, and require major facilities, such as the Lake Lynn Experimental Mine. The development of computational fluid dynamics (CFD) modeling of explosions can help minimize the need for large-scale testing. This thesis utilized the commercial CFD software, SC/Tetra, to examine three case studies. The first case study modeled the combustion of methane in a scaled shock tube, measuring approximately 1 foot by 1 foot, by 20.5 feet long, with a methane cloud of 2.5 feet in length, at a concentration of 9% methane. The numerical results from the CFD model were in good agreement with experimental data gathered, with all pressure peaks within 0.25 psi of the recorded pressure data. However, the model had an extensive run-time of 16 hours to reach the peak pressures. The second case study modeled the same explosion, but utilized a total pressure boundary condition at the location of the membrane, instead of the combustion of methane. A pressure-time curve was assigned to this boundary, recreating the release of pressure by the explosion. This was made possible with the knowledge of the experimental data. The numerical results from the CFD model were in excellent agreement with experimental data gathered, with all pressure peaks within 0.07 psi of the recorded pressure data. Alternatively, this model had a run-time of 40 minutes. The third case study modeled a methane explosion in a large shock tube, measuring 8 feet by 8 feet, by 40 feet long, with a methane cloud of 4 feet in length, at a concentration of 9% methane. The bursting balloon technique was employed, which did not model the combustion of methane, but instead the equivalent energy release. The numerical results from the CFD model were in good agreement with the experimental data gathered, with all pressure peaks within 0.025 psi of the recorded pressure data. Additionally, the numerical results modeled the negative pressure phenomenon observed in the experimental results, caused by suction or negative pressure created by the blast wave, immediately following the positive wave. This model had a run-time of 20 minutes. The results of this researched provided validation that there are alternative ways to successfully model methane explosion, without having to model the chemical reactions involved in the combustion of methane, providing quicker run-times and in this case, more accurate results.

Crohn’s disease is a chronic inflammatory bowel disease with unknown origin. This study investigates the combined use of surgery and immuno modulation in Crohn’s disease. The outcome of medication and surgery in 371 operations on 237 patients between 1989 and 2006 were evaluated. Moreover the effects of prednisolone, azathioprine and infliximab on the healing of colo-colonic anastomosis in 84 mice with or without colitis were evaluated. The use of thiopurines after abdominal surgery in selected cases of severe Crohn’s disease was found to prolong the time to clinical relapse of the disease from 24 to 53 months. Patients on postoperative maintenance therapy with azathioprine had a decreased symptomatic load over time and needed fewer steroid courses. The use of thiopurines was found to be a risk factor of anastomotic complications in abdominal surgery for Crohn’s disease together with pre-operative intra-abdominal sepsis and colo-colonic anastomosis. The risk for anastomotic complications increased from 4 % in those without any of these risk factors to 13 % in those with any one and 24 % if two or three risk factors were present. In patients with two or more of these, or previously established, risk factors prior to surgery one should consider refraining from anastomosis or doing a proximal diverting stoma. Another possibility is to use a split stoma in which both ends of a future delayed anastomosis are brought out in the same ostomy hole of the abdominal wall. This method was found to significantly decrease the number of risk factors prior to the actual anastomosis as well as decreasing the risk of anastomotic complications, without increasing the number of operations or the time spent in hospital. In the animal model all three medications had an ameliorating effect on the colitis compared with placebo. Only prednisolone was found to interfere with the healing of the colo-colonic anastomoses with significantly decreased bursting pressure compared with placebo as well as azathioprine and infliximab. The association between azathioprine therapy and anastomotic complications may be due to a subgroup of patients with a more severe form of the disease who have an increased risk of such complications and also are more prone to receive intense pharmacological therapy. / Crohns sjukdom är en kronisk inflammatorisk tarmsjukdom av oklar orsak. Huvudsyftet med denna avhandling var att undersöka den kombinerade behandlingen med kirurgi och immunhämmare vid Crohns sjukdom. Utfallet av medicinsk och kirurgisk behandling vid 371 operationer på 237 patienter mellan 1989 och 2006 utvärderades. Därutöver studerades effekterna av kortison, immunhämmare och behandling med inflammationsdämpande antikroppar på läkning av tjocktarms-skarv på 84 möss med eller utan inflammation i tarmen. Vid utvalda fall med svårare form av Crohns sjukdom visade sig förebyggande behandling med immunhämmare efter kirurgi förlänga tiden till återfall av symptom från 24 till 53 månader. Patienter med immunhämmare som underhållsbehandling hade också minskade symptom under uppföljningstiden med ett minskat behov av kortison. Immunhämmande behandling inför kirurgi visade sig, liksom pågående infektion i bukhålan och sydd skarv på tjocktarmen, vara en riskfaktor för att drabbas av komplikationer vid bukkirurgi på grund av Crohns sjukdom. Risken för infektionskomplikationer i bukhålan ökade från 4 % hos dem utan någon av dessa riskfaktorer till 13 % hos dem med någon och 24 % hos dem med två eller tre riskfaktorer inför operationen. Hos patienter med två eller fler kända riskfaktorer bör man överväga att avstå från att sy en skarv på tarmen vid kirurgi eller möjligen skydda skarven med en avlastande stomi. Ett alternativ till detta är att anlägga en delad stomi där bägge ändarna av den framtida skarven tas ut genom en och samma stomiöppning i bukväggen. Denna metod med en fördröjd skarv på tarmen visade sig minska antalet kirurgiska riskfaktorer inför själva skarvningen och dessutom minska risken för tidiga infektiösa komplikationer i bukhålan, utan att vare sig öka antalet kirurgiska ingrepp eller förlänga vårdtiden på sjukhus. I en djurmodell visade sig alla tre läkemedlen ha en lindrande effekt på tarminflammation jämfört med placebo. Endast kortison visade sig påverka läkningen negativt med en sänkning av bristningstrycket i den sydda skarven på tjocktarmen, jämfört med placebo såväl som med immunhämmare och antikropps-behandling. Kopplingen mellan immunhämmare och komplikationer efter sydda skarvar på tarmen behöver alltså inte vara en direkt läkemedelseffekt. Orsaken kan istället vara att en undergrupp av Crohnpatienter har en svårare sjukdomsform som ger både ökad komplikationsrisk och större behov av intensiv medicinsk behandling.

Networks of neurons, which form central pattern generators (CPGs), are important for controlling animal behaviors. Of special interest are configurations or CPG motifs composed of reciprocally inhibited neurons, such as half-center oscillators (HCOs). Bursting rhythms of HCOs are shown to include stable synchrony or in-phase bursting. This in-phase bursting can co-exist with anti-phase bursting, commonly expected as the single stable state in HCOs that are connected with fast non-delayed synapses. The finding contrasts with the classical view that reciprocal inhibition has to be slow or time-delayed to synchronize such bursting neurons. Phase-locked rhythms are analyzed via Lyapunov exponents estimated with variational equations, and through the convergence rates estimated with Poincar\'e return maps. A new mechanism underlying multistability is proposed that is based on the spike interactions, which confer a dual property on the fast non-delayed reciprocal inhibition; this reveals the role of spikes in generating multiple co-existing phase-locked rhythms. In particular, it demonstrates that the number and temporal characteristics of spikes determine the number and stability of the multiple phase-locked states in weakly coupled HCOs. The generality of the multistability phenomenon is demonstrated by analyzing diverse models of bursting networks with various inhibitory synapses; the individual cell models include the reduced leech heart interneuron, the Sherman model for pancreatic beta cells, the Purkinje neuron model and Fitzhugh-Rinzel phenomenological model. Finally, hypothetical and experiment-based CPGs composed of HCOs are investigated. This study is relevant for various applications that use CPGs such as robotics, prosthetics, and artificial intelligence.

The co-existence of bursting activity and silence is a common property of various neuronal models. We describe a novel mechanism explaining the co-existence of and the transition between these two regimes. It is based on the specific homoclinic and Andronov-Hopf bifurcations of the hyper- and depolarized steady states that determine the co-existence domain in the parameter space of the leech heart interneuron models: canonical and simplified. We found that a sub-critical Andronov-Hopf bifurcation of the hyperpolarized steady state gives rise to small amplitude sub-threshold oscillations terminating through the secondary homoclinic bifurcation. Near the corresponding boundary the system can exhibit long transition from bursting oscillations into silence, as well as the bi-stability where the observed regime is determined by the initial state of the neuron. The mechanism found is shown to be generic for the simplified 4D and the original 14D leech heart interneuron models.

No description available.

Population-wide synchronized rhythmic bursts of electrical activity are present in a variety of neural circuits. The proposed general mechanisms for rhythmogenesis are often attributed to intrinsic and synaptic properties. For example, the recurrent excitation through excitatory synaptic connections determines burst initiation, and the slower kinetics of ionic currents or synaptic depression results in burst termination. In such theories, a slow recovery process is essential for the slow dynamics associated with bursting. This thesis presents a new hypothesis that depends on the connectivity pattern among neurons rather than a slow kinetic process to achieve the network-wide bursting. The thesis begins with an introduction of bursts of electrical activity in a purely excitatory neural network and existing theories explaining this phenomenon. It then covers the small-world approach, which is applied to modify the network structure in the simulation, and the Morris-Lecar (ML) neuron model, which is used as the component cells in the network. Simulation results of the dependence of bursting activity on network connectivity, as well as the inherent network properties explaining this dependence are described. This work shows that the network-wide bursting activity emerges in the small-world network regime but not in the regular or random networks, and this small-world bursting primarily results from the uniform random distribution of long-range connections in the network, as well as the unique dynamics in the ML model. Both attributes foster progressive synchronization in firing activity throughout the network during a burst, and this synchronization may terminate a burst in the absence of an obvious slow recovery process. The thesis concludes with possible future work.

No description available.

The plasma membrane electrical activities of neurons that secrete gonadotropin releasing hormone (GnRH), referred to as GnRH neurons hereafter, have been studied extensively. A couple of mathematical models have been developed previously to explain different aspects of these activities including spontaneous spiking and responses to stimuli such as current injections, GnRH, thapsigargin (Tg) and apamin. The goal of this paper is to develop one single, minimal model that accounts for the experimental results reproduced by previously existing models and results that were not accounted for by these models. The latter includes two types of membrane potential bursting mechanisms and the associated calcium oscillations in the cytosol. One of them has not been reported in experimental literatures on GnRH neurons and is thus regarded as a model prediction. Other improvements achieved in this model include the incorporation of a more detailed description of calcium dynamics in a three dimensional cell body with the ion channels evenly distributed on the cell surface. Although the model is mainly based on data collected in cultured GnRH cell lines, we show that it is capable of explaining some properties of GnRH neurons observed in several of other preparations including mature GnRH neurons in hypothalamic slices. One potential explanation is suggested. A phenomenological reduction of this model into a simplified form is presented. The simplified model will facilitate the study of the roles of plasma membrane electrical activities on the pulsatile release of GnRH by these neurons when it is coupled with a model of pulsatile GnRH release based on the autoregulation mechanism.

A multifunctional central pattern generator (CPG) can produce bursting polyrhythms that determine locomotive activity in an animal: for example, swimming and crawling in a leech. Each rhythm corresponds to a specific attractor of the CPG. We employ a Hodgkin-Huxley type model of a bursting leech heart interneuron, and connect three such neurons by fast inhibitory synapses to form a ring. This network motif exhibits multistable co-existing bursting rhythms. The problem of determining rhythmic outcomes is reduced to an analysis of fixed points of Poincare mappings and their attractor basins, in a phase plane defined by the interneurons' phase differences along bursting orbits. Using computer assisted analysis, we examine stability, bifurcations of attractors, and transformations of their basins in the phase plane. These structures determine the global bursting rhythms emitted by the CPG. By varying the coupling synaptic strength, we examine the dynamics and patterns produced by inhibitory networks.