THE ROLE OF SPINDLES FOR SLEEP: MANIPULATING OSCILLATORY ACTIVITY IN THE THALAMOCORTICAL NETWORK

Modern urban lifestyle encourages the prolongation of wakefulness, leaving less and less time for sleep. Although the exact functions of sleep remain one of the biggest mysteries in neuroscience, the society is well aware of the negative consequences of sleep loss on human physical and mental health and performance. Enhancing sleep's recuperative functions might allow shortening sleep duration while preserving the beneficial effects of sleep. During sleep, brain activity oscillates across a continuum of frequencies. Individual oscillations have been suggested to underlie distinct functions for sleep and cognition. Gaining control about individual oscillations might allow boosting their specific functions. Sleep spindles are 11 - 15 Hz oscillations characteristic for light non-rapid-eye-movement sleep (NREMS) and have been proposed to play a role in memory consolidation and sleep protection against environmental stimuli. The reticular thalamic nucleus (nRt) has been identified as the major pacemaker of spindles. Intrinsic oscillatory burst discharge in nRt neurons, arising from the interplay of low-threshold (T-type) Ca2+ channels (T channels) and small conductance type 2 (SK2) K+ channels (SK2 channels), underlies this pacemaking function. In the present work we investigated the impact of altered nRt bursting on spindle generation during sleep by studying mutant mice for SK2 channels and for CaV3.3 channels, a subtype of T channels. Using in vitro electrophysiology I showed that nRt bursting was abolished in CaV3.3 knock out (CaV3.3 KO) mice. In contrast, in SK2 channel over-expressing (SK2-OE) nRt cells, intrinsic repetitive bursting was prolonged. Compared to wildtype (WT) littermates, altered nRt burst discharge lead to weakened thalamic network oscillations in vitro in CaV3.3 KO mice, while oscillatory activity was prolonged in SK2-OE mice. Sleep electroencephalographic recordings in CaV3.3 KO and SK2-OE mice revealed that reduced or potentiated nRt bursting respectively weakened or prolonged sleep spindle activity at the NREMS - REMS transition. Furthermore, SK2-OE mice showed more consolidated NREMS and increased arousal thresholds, two correlates of good sleep quality. This thesis work suggests that CaV3.3 and SK2 channels may be targeted in order to modulate sleep spindle activity. Furthermore, it proposes a novel function for spindles in NREMS consolidation. Finally, it provides evidence that sleep quality may be improved by promoting spindle activity, thereby supporting the hypothesis that sleep quality can be enhanced by modulating oscillatory activity in the brain. Le style de vie moderne favorise la prolongation de l'��veil, laissant de moins en moins de temps pour le sommeil. M��me si le r��le exact du sommeil reste un des plus grands myst��res des neurosciences, la soci��t�� est bien consciente des cons��quences n��gatives que provoque un manque de sommeil, �� la fois sur le plan de la sant�� physique et mentale ainsi qu'au niveau des performances cognitives. Augmenter les fonctions r��cup��ratrices du sommeil pourrait permettre de raccourcir la dur��e du sommeil tout en en conservant les effets b��n��fiques. Durant le sommeil, on observe des oscillations �� travers un continuum de fr��quences. Il a ��t�� propos�� que chaque oscillation pourrait ��tre �� l'origine de fonctions sp��cifiques pour le sommeil et la cognition. Pouvoir de contr��ler les oscillations individuelles permettrait d'augmenter leurs fonctions respectives. Les fuseaux sont des oscillations de 11 �� 15 Hz caract��ristiques du sommeil �� ondes lentes l��ger et il a ��t�� sugg��r�� qu'elles jouent un r��le majeur pour la consolidation de la m��moire ainsi que dans la protection du sommeil contre les stimuli environnementaux. Le nucleus r��ticulaire du thalamus (nRt) a ��t�� identifi�� en tant que g��n��rateur de rythme des fuseaux. Les bouff��es oscillatoires intrins��ques des neurones du nRt, provenant de l'interaction de canaux calciques �� bas seuil de type T (canaux T) et de canaux potassiques �� faible conductance de type 2 (canaux SK2), sont �� l'origine de la fonction de g��n��rateur de rythme. Dans ce travail, j'ai ��tudi�� l'impact de la modulation de bouff��es de nRT sur la g��n��ration des fuseaux pendant le sommeil en investiguant des souris g��n��tiquement modifi��es pour les canaux SK2 et les canaux CaV3.3, un sous-type de canaux T. En utilisant l'��lectrophysiologie in vitro j'ai d��montr�� que les bouff��es du nRT ��taient abolies dans les souris knock-out du type CaV3.3 (CaV3.3 KO). D'autre part, dans les cellules nRT sur-exprimant les canaux SK2 (SK2-OE), les bouff��es oscillatoires intrins��ques ��taient prolong��es. Par rapport aux souris wild type, les souris CaV3.3 KO ont montr�� un affaiblissement des oscillations thalamiques en r��ponse �� un changement des bouff��es de nRT, alors que l'activit�� oscillatoire ��tait prolong��e dans les souris SK2-OE. Des enregistrements EEG du sommeil dans des souris de type CaV3.3 KO et SK2-OE ont r��v��l�� qu'une r��duction ou augmentation des bouff��es nRT ont respectivement affaibli ou prolong�� l'activit�� des fuseaux durant les transitions du sommeil �� ondes lentes au sommeil paradoxal. De plus, les souris SK2-OE ont montr�� des signes de consolidation du sommeil �� ondes lentes et un seuil augment�� pour le r��veil, deux mesures qui corr��lent avec une bonne qualit�� du sommeil. Le travail de cette th��se propose que les canaux CaV3.3 et SK2 pourrait ��tre cibl��s pour moduler l'activit�� des fuseaux. De plus, je propose une fonction nouvelle pour les fuseaux dans la consolidation du sommeil �� ondes lentes. Finalement je sugg��re que la qualit�� du sommeil peut ��tre am��lior��e en promouvant l'activit�� des fuseaux, soutenant ainsi l'id��e que la qualit�� du sommeil peut ��tre am��lior��e en modulant l'activit�� oscillatoire dans le cerveau.

Network-guided analysis of genes with altered somatic copy number and gene expression reveals pathways commonly perturbed in metastatic melanoma.

Cancer genomes frequently contain somatic copy number alterations (SCNA) that can significantly perturb the expression level of affected genes and thus disrupt pathways controlling normal growth. In melanoma, many studies have focussed on the copy number and gene expression levels of the BRAF, PTEN and MITF genes, but little has been done to identify new genes using these parameters at the genome-wide scale. Using karyotyping, SNP and CGH arrays, and RNA-seq, we have identified SCNA affecting gene expression ('SCNA-genes') in seven human metastatic melanoma cell lines. We showed that the combination of these techniques is useful to identify candidate genes potentially involved in tumorigenesis. Since few of these alterations were recurrent across our samples, we used a protein network-guided approach to determine whether any pathways were enriched in SCNA-genes in one or more samples. From this unbiased genome-wide analysis, we identified 28 significantly enriched pathway modules. Comparison with two large, independent melanoma SCNA datasets showed less than 10% overlap at the individual gene level, but network-guided analysis revealed 66% shared pathways, including all but three of the pathways identified in our data. Frequently altered pathways included WNT, cadherin signalling, angiogenesis and melanogenesis. Additionally, our results emphasize the potential of the EPHA3 and FRS2 gene products, involved in angiogenesis and migration, as possible therapeutic targets in melanoma. Our study demonstrates the utility of network-guided approaches, for both large and small datasets, to identify pathways recurrently perturbed in cancer.

A semantic model of selective dissemination of information for digital libraries

In this paper we present the theoretical and methodologicalfoundations for the development of a multi-agentSelective Dissemination of Information (SDI) servicemodel that applies Semantic Web technologies for specializeddigital libraries. These technologies make possibleachieving more efficient information management,improving agent���user communication processes, andfacilitating accurate access to relevant resources. Othertools used are fuzzy linguistic modelling techniques(which make possible easing the interaction betweenusers and system) and natural language processing(NLP) techniques for semiautomatic thesaurus generation.Also, RSS feeds are used as ���current awareness bulletins���to generate personalized bibliographic alerts.

2004 Annual Report of the Iowa Communications Network, 2004

This is the Annual Report for Fiscal Year 2004 (July 1, 2003-June 30, 2004) for the Iowa Communications Network.

A regulatory network for coordinated flower maturation.

For self-pollinating plants to reproduce, male and female organ development must be coordinated as flowers mature. The Arabidopsis transcription factors AUXIN RESPONSE FACTOR 6 (ARF6) and ARF8 regulate this complex process by promoting petal expansion, stamen filament elongation, anther dehiscence, and gynoecium maturation, thereby ensuring that pollen released from the anthers is deposited on the stigma of a receptive gynoecium. ARF6 and ARF8 induce jasmonate production, which in turn triggers expression of MYB21 and MYB24, encoding R2R3 MYB transcription factors that promote petal and stamen growth. To understand the dynamics of this flower maturation regulatory network, we have characterized morphological, chemical, and global gene expression phenotypes of arf, myb, and jasmonate pathway mutant flowers. We found that MYB21 and MYB24 promoted not only petal and stamen development but also gynoecium growth. As well as regulating reproductive competence, both the ARF and MYB factors promoted nectary development or function and volatile sesquiterpene production, which may attract insect pollinators and/or repel pathogens. Mutants lacking jasmonate synthesis or response had decreased MYB21 expression and stamen and petal growth at the stage when flowers normally open, but had increased MYB21 expression in petals of older flowers, resulting in renewed and persistent petal expansion at later stages. Both auxin response and jasmonate synthesis promoted positive feedbacks that may ensure rapid petal and stamen growth as flowers open. MYB21 also fed back negatively on expression of jasmonate biosynthesis pathway genes to decrease flower jasmonate level, which correlated with termination of growth after flowers have opened. These dynamic feedbacks may promote timely, coordinated, and transient growth of flower organs.

Iowa Communications Network, Independent Auditor's Reports, Basic Financial Statements and Supplementary Information, Schedule of Findings, June 30, 2004

State Agency Audit Report

A WiMAX-based implementation of network MIMO for indoor wireless systems

It is well known that multiple-input multiple-output (MIMO) techniques can bring numerous benefits, such as higher spectral efficiency, to point-to-point wireless links. More recently, there has been interest in extending MIMO concepts tomultiuser wireless systems. Our focus in this paper is on network MIMO, a family of techniques whereby each end user in a wireless access network is served through several access points within its range of influence. By tightly coordinating the transmission and reception of signals at multiple access points, network MIMO can transcend the limits on spectral efficiency imposed by cochannel interference. Taking prior information-theoretic analyses of networkMIMO to the next level, we quantify the spectral efficiency gains obtainable under realistic propagation and operational conditions in a typical indoor deployment. Our study relies on detailed simulations and, for specificity, is conducted largely within the physical-layer framework of the IEEE 802.16e Mobile WiMAX system. Furthermore,to facilitate the coordination between access points, we assume that a high-capacity local area network, such as Gigabit Ethernet,connects all the access points. Our results confirm that network MIMO stands to provide a multiple-fold increase in spectralefficiency under these conditions.

Free-and open source software for a course on network management: authoring and enactment of scripts based on collaborative learning strategies

This paper describes a Computer-Supported Collaborative Learning (CSCL) case study in engineering education carried out within the context of a network management course. The case study shows that the use of two computing tools developed by the authors and based on Free- and Open-Source Software (FOSS) provide significant educational benefits over traditional engineering pedagogical approaches in terms of both concepts and engineering competencies acquisition. First, the Collage authoring tool guides and supports the course teacher in the process of authoring computer-interpretable representations (using the IMS Learning Design standard notation) of effective collaborative pedagogical designs. Besides, the Gridcole system supports the enactment of that design by guiding the students throughout the prescribed sequence of learning activities. The paper introduces the goals and context of the case study, elaborates onhow Collage and Gridcole were employed, describes the applied evaluation methodology, anddiscusses the most significant findings derived from the case study.

FY04 Enrich Iowa: State Funding for Iowa Libraries, 2004

In accordance with 2004 IOWA ACTS Chapter 182 (5)(5)(b), the State Library of Iowa submits this report on the uses and impact of state funding provided to Iowa libraries through the Enrich Iowa Program.

2005 Annual Report of the Iowa Communications Network

This is the Annual Report for Fiscal Year 2005 (July 1, 2004-June 30, 2005) for the Iowa Communications Network.

Iowa Communications Network Performance Report, FY 2004

Agency Performance Report

Iowa Communications Network Performance Report, FY 2005

Agency Performance Report