Relation between neuronal morphology and electrophysiology in the Kainate lesion model of Alzheimer's Disease

This paper describes a computational and statistical study of the influence of morphological changes on the electrophysiological response of neurons from an animal model of Alzheimer's Disease (AD). We combined experimental morphological data from rat hippocampal CA1 pyramidal cells with a well-established model of active membrane properties. Dendritic morphology and the somatic response to simulated current clamp conditions were then compared for cells from the control and the AD group. The computational approach allowed us to single out the influences of neuromorphology on neuronal response by eliminating the effects of active channel variability. The results did not reveal a simple relationship between morphological changes associated with AD and changes in neural response. However, they did suggest the existence of more complex than anticipated relationships between dendritic morphology and single-cell electrophysiology.

Generation, description and storage of dendritic morphology data

It is generally assumed that the variability of neuronal morphology has an important effect on both the connectivity and the activity of the nervous system, but this effect has not been thoroughly investigated. Neuroanatomical archives represent a crucial tool to explore structure–function relationships in the brain. We are developing computational tools to describe, generate, store and render large sets of three–dimensional neuronal structures in a format that is compact, quantitative, accurate and readily accessible to the neuroscientist. Single–cell neuroanatomy can be characterized quantitatively at several levels. In computer–aided neuronal tracing files, a dendritic tree is described as a series of cylinders, each represented by diameter, spatial coordinates and the connectivity to other cylinders in the tree. This ‘Cartesian’ description constitutes a completely accurate mapping of dendritic morphology but it bears little intuitive information for the neuroscientist. In contrast, a classical neuroanatomical analysis characterizes neuronal dendrites on the basis of the statistical distributions of morphological parameters, e.g. maximum branching order or bifurcation asymmetry. This description is intuitively more accessible, but it only yields information on the collective anatomy of a group of dendrites, i.e. it is not complete enough to provide a precise ‘blueprint’ of the original data. We are adopting a third, intermediate level of description, which consists of the algorithmic generation of neuronal structures within a certain morphological class based on a set of ‘fundamental’, measured parameters. This description is as intuitive as a classical neuroanatomical analysis (parameters have an intuitive interpretation), and as complete as a Cartesian file (the algorithms generate and display complete neurons). The advantages of the algorithmic description of neuronal structure are immense. If an algorithm can measure the values of a handful of parameters from an experimental database and generate virtual neurons whose anatomy is statistically indistinguishable from that of their real counterparts, a great deal of data compression and amplification can be achieved. Data compression results from the quantitative and complete description of thousands of neurons with a handful of statistical distributions of parameters. Data amplification is possible because, from a set of experimental neurons, many more virtual analogues can be generated. This approach could allow one, in principle, to create and store a neuroanatomical database containing data for an entire human brain in a personal computer. We are using two programs, L–NEURON and ARBORVITAE, to investigate systematically the potential of several different algorithms for the generation of virtual neurons. Using these programs, we have generated anatomically plausible virtual neurons for several morphological classes, including guinea pig cerebellar Purkinje cells and cat spinal cord motor neurons. These virtual neurons are stored in an online electronic archive of dendritic morphology. This process highlights the potential and the limitations of the ‘computational neuroanatomy’ strategy for neuroscience databases.

Effects of dendritic morphology on CA3 pyramidal cell electrophysiology: a simulation study

We investigated the effect of morphological differences on neuronal firing behavior within the hippocampal CA3 pyramidal cell family by using three-dimensional reconstructions of dendritic morphology in computational simulations of electrophysiology. In this paper, we report for the first time that differences in dendritic structure within the same morphological class can have a dramatic influence on the firing rate and firing mode (spiking versus bursting and type of bursting). Our method consisted of converting morphological measurements from three-dimensional neuroanatomical data of CA3 pyramidal cells into a computational simulator format. In the simulation, active channels were distributed evenly across the cells so that the electrophysiological differences observed in the neurons would only be due to morphological differences. We found that differences in the size of the dendritic tree of CA3 pyramidal cells had a significant qualitative and quantitative effect on the electrophysiological response. Cells with larger dendritic trees: (1) had a lower burst rate, but a higher spike rate within a burst, (2) had higher thresholds for transitions from quiescent to bursting and from bursting to regular spiking and (3) tended to burst with a plateau. Dendritic tree size alone did not account for all the differences in electrophysiological responses. Differences in apical branching, such as the distribution of branch points and terminations per branch order, appear to effect the duration of a burst. These results highlight the importance of considering the contribution of morphology in electrophysiological and simulation studies.

Numerical convergence of the Block-Maxima approach to the generalized extreme value distribution

In this paper we perform an analytical and numerical study of Extreme Value distributions in discrete dynamical systems. In this setting, recent works have shown how to get a statistics of extremes in agreement with the classical Extreme Value Theory. We pursue these investigations by giving analytical expressions of Extreme Value distribution parameters for maps that have an absolutely continuous invariant measure. We compare these analytical results with numerical experiments in which we study the convergence to limiting distributions using the so called block-maxima approach, pointing out in which cases we obtain robust estimation of parameters. In regular maps for which mixing properties do not hold, we show that the fitting procedure to the classical Extreme Value Distribution fails, as expected. However, we obtain an empirical distribution that can be explained starting from a different observable function for which Nicolis et al. (Phys. Rev. Lett. 97(21): 210602, 2006) have found analytical results.

Extreme value distribution for singular measures

In this paper we perform an analytical and numerical study of Extreme Value distributions in discrete dynamical systems that have a singular measure. Using the block maxima approach described in Faranda et al. [2011] we show that, numerically, the Extreme Value distribution for these maps can be associated to the Generalised Extreme Value family where the parameters scale with the information dimension. The numerical analysis are performed on a few low dimensional maps. For the middle third Cantor set and the Sierpinskij triangle obtained using Iterated Function Systems, experimental parameters show a very good agreement with the theoretical values. For strange attractors like Lozi and H\`enon maps a slower convergence to the Generalised Extreme Value distribution is observed. Even in presence of large statistics the observed convergence is slower if compared with the maps which have an absolute continuous invariant measure. Nevertheless and within the uncertainty computed range, the results are in good agreement with the theoretical estimates.

Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome

BACKGROUND & AIMS: The mechanisms underlying abdominal pain perception in irritable bowel syndrome (IBS) are poorly understood. Intestinal mast cell infiltration may perturb nerve function leading to symptom perception. We assessed colonic mast cell infiltration, mediator release, and spatial interactions with mucosal innervation and their correlation with abdominal pain in IBS patients. METHODS: IBS patients were diagnosed according to Rome II criteria and abdominal pain quantified according to a validated questionnaire. Colonic mucosal mast cells were identified immunohistochemically and quantified with a computer-assisted counting method. Mast cell tryptase and histamine release were analyzed immunoenzymatically. Intestinal nerve to mast cell distance was assessed with electron microscopy. RESULTS: Thirty-four out of 44 IBS patients (77%) showed an increased area of mucosa occupied by mast cells as compared with controls (9.2% +/- 2.5% vs. 3.3 +/- 0.8%, respectively; P < 0.001). There was a 150% increase in the number of degranulating mast cells (4.76 +/- 3.18/field vs. 2.42 +/- 2.26/field, respectively; P = 0.026). Mucosal content of tryptase was increased in IBS and mast cells spontaneously released more tryptase (3.22 +/- 3.48 pmol/min/mg vs. 0.87 +/- 0.65 pmol/min/mg, respectively; P = 0.015) and histamine (339.7 +/- 59.0 ng/g vs. 169.3 +/- 130.6 ng/g, respectively; P = 0.015). Mast cells located within 5 microm of nerve fibers were 7.14 +/- 3.87/field vs. 2.27 +/- 1.63/field in IBS vs. controls (P < 0.001). Only mast cells in close proximity to nerves were significantly correlated with severity and frequency of abdominal pain/discomfort (P < 0.001 and P = 0.003, respectively). CONCLUSIONS: Colonic mast cell infiltration and mediator release in proximity to mucosal innervation may contribute to abdominal pain perception in IBS patients.

Mutamenti politico-istituzionali nella Venezia Giulia e a Trieste tra Tito e gli americani alla luce delle nuove testimonianze documentarie da Washington, 1944-1954

“La questione di Trieste”, ovvero la questione del confine italo-yugoslavo all’indomani della seconda guerra mondiale costituisce da lungo tempo oggetto di attenzione e di esame da parte della storiografia italiana e straniera. Con alcune importanti eccezioni, la ricostruzione complessiva di quelle vicende ha visto il più delle volte il prevalere di un approccio storico-diplomatico che ha reso difficile comprendere con chiarezza i rapporti e le interdipendenze fra contesto locale, contesto nazionale e contesto internazionale. Attraverso la lettura incrociata dell’ampia documentazione proveniente dai fondi dei National Archives Records Administration (NARA) questo studio tenta una rilettura delle varie fasi di sviluppo della questione nel periodo compreso tra il giugno del 1945 e l’ottobre del 1954 secondo una duplice prospettiva: nella prima parte si concentra sulla politica americana a Trieste, guardando nello specifico a due aspetti interni tra loro strettamente correlati, la gestione dell’ordine pubblico e la “strategia” del consenso da realizzarsi mediante il controllo dell’informazione da un lato e la promozione di una politica culturale dall’altro. Sono aspetti entrambi riconducibili al modello del direct rule, che conferiva al governo militare alleato (GMA) piena ed esclusiva autorità di governo sulla zona A della Venezia Giulia, e che ci appaiono centrali anche per cogliere l’interazione fra istituzioni e soggetti sociali. Nella seconda parte, invece, il modificarsi della fonte d’archivio indica un cambiamento di priorità nella politica estera americana relativa a Trieste: a margine dei negoziati internazionali, i documenti del fondo Clare Boothe Luce nelle carte dell’Ambasciata mostrano soprattutto come la questione di Trieste venne proiettata verso l’esterno, verso l’Italia in particolare, e sfruttata – principalmente dall’ambasciatrice – nell’ottica bipolare della guerra fredda per rinforzare il sostegno interno alla politica atlantica. Il saggio, dunque, si sviluppa lungo due linee: dentro e fuori Trieste, dentro 1945-1952, fuori 1953-1954, perché dalle fonti consultate sono queste ad emergere come aree di priorità nei due periodi. Abstract - English The “Trieste question”, or the question regarding the Italian - Yugoslav border after the Second World War, has been the object of careful examination in both Italian and foreign historiography for a long time. With a few important exceptions, the overall reconstruction of these events has been based for the most part on historic and diplomatic approaches, which have sometimes made it rather difficult to understand clearly the relationships and interdependences at play between local, national and international contexts. Through a comparative analysis of a large body of documents from the National Archives and Records Administration (NARA), College Park MD, this essay attempts a second reading of the various phases in which the question developed between June 1945 and October 1954, following a twofold perspective: the first part focuses on American policy for Trieste, specifically looking at two internal and closely linked aspects, on the one hand, the management of ‘law and order’, as well as a ‘strategy’ of consent, to be achieved through the control of all the means of information , and, on the other, the promotion of a cultural policy. Both aspects can be traced back to the ‘direct rule’ model, which gave the Allied Military Government (AMG) full and exclusive governing authority over Venezia Giulia’s Zone A. These issues are also fundamental to a better understanding of the relationships between institutions and social subjects. In the second part of the essay , the change in archival sources clearly indicates a new set of priorities in American foreign policy regarding Trieste: outside any international negotiations for the settlement of the question, the Clare Boothe Luce papers held in the Embassy’s archives, show how the Trieste question was focused on external concerns, Italy in particular, and exploited – above all by the ambassador – within the bi-polar optic of the Cold War, in order to strengthen internal support for Atlantic policies. The essay therefore follows two main lines of inquiry: within and outside Trieste, within in 1945-1952, and outside 1953-1954, since, from the archival sources used, these emerge as priority areas in the two periods.

Neuromantic : from semi-manual to semi-automatic reconstruction of neuron morphology

The ability to create accurate geometric models of neuronal morphology is important for understanding the role of shape in information processing. Despite a significant amount of research on automating neuron reconstructions from image stacks obtained via microscopy, in practice most data are still collected manually. This paper describes Neuromantic, an open source system for three dimensional digital tracing of neurites. Neuromantic reconstructions are comparable in quality to those of existing commercial and freeware systems while balancing speed and accuracy of manual reconstruction. The combination of semi-automatic tracing, intuitive editing, and ability of visualizing large image stacks on standard computing platforms provides a versatile tool that can help address the reconstructions availability bottleneck. Practical considerations for reducing the computational time and space requirements of the extended algorithm are also discussed.

Identification and ranking of extraordinary rainfall events over northwest Italy: the role of Atlantic moisture

An objective identification and ranking of extraordinary rainfall events for Northwest Italy is established using time series of annual precipitation maxima for 1938–2002 at over 200 stations. Rainfall annual maxima are considered for five reference durations (1, 3, 6, 12, and 24 h). In a first step, a day is classified as an extraordinary rainfall day when a regional threshold calculated on the basis of a two-components extreme value distribution is exceeded for at least one of the stations. Second, a clustering procedure taking into account the different rainfall durations is applied to the identified 163 events. Third, a division into six clusters is chosen using Ward's distance criteria. It is found that two of these clusters include the seven strongest events as quantified from a newly developed measure of intensity which combines rainfall intensities and spatial extension. Two other clusters include the weakest 72% historical events. The obtained clusters are analyzed in terms of typical synoptic characteristics. The two top clusters are characterized by strong and persistent upper air troughs inducing not only moisture advection from the North Atlantic into the Western Mediterranean but also strong northward flow towards the southern Alpine ranges. Humidity transports from the North Atlantic are less important for the weaker clusters. We conclude that moisture advection from the North Atlantic plays a relevant role in the magnitude of the extraordinary events over Northwest Italy.