No description available.

In order to understand the diverse and complex functions of the Human brain, the temporal relationships of vast quantities of multi-dimensional spike train data must be analysed. A number of statistical methods already exist to analyse these relationships. However, as a result of expansions in recording capability hundreds of spike trains must now be analysed simultaneously. In addition to the requirements for new statistical analysis methods, the need for more efficient data representation is paramount. The computer science field of Information Visualization is specifically aimed at producing effective representations of large and complex datasets. This thesis is based on the assumption that data analysis can be significantly improved by the application of Information Visualization principles and techniques. This thesis discusses the discipline of Information Visualization, within the wider context of visualization. It also presents some introductory neurophysiology focusing on the analysis of multidimensional spike train data and software currently available to support this problem. Following this, the Toolbox developed to support the analysis of these datasets is presented. Subsequently, three case studies using the Toolbox are described. The first case study was conducted on a known dataset in order to gain experience of using these methods. The second and third case studies were conducted on blind datasets and both of these yielded compelling results.

GABAA receptors mediate the majority of fast synaptic inhibition in the adult mammalian brain, and play a critical role in controlling neuronal excitability during development. The functional properties and stability of cell-surface GABAA receptors are key determinants of the efficacy of GABAergic neurotransmission. I therefore employed a broad spectrum of biochemical, and cell and molecular biological techniques to identify molecular interactions that may be involved in regulating the activity and number of GABAA receptors at the neuronal surface. In this thesis, I identified a novel interaction between the GABAA receptor and the calcium/calmodulin-dependent protein kinase II (CaMKII). Affinity-purification assays revealed that CaMKII forms a native complex with the GABAA receptor in brain, and that the kinase binds non-selectively to the major intracellular domain (ICD) of various GABAA receptor subunits. The interaction between CaMKII and the receptor β subunits was found to be dependent upon phosphorylation of the kinase at T286, but appeared to be independent of subunit phosphorylation. Furthermore, a CaMKII binding site was identified in the ICD of the receptor β subunits, between residues 304 and 323. Further work demonstrated that CaMKII selectively phosphorylates the ICDs of the receptor β and γ subunits, and identified protein phosphatases that dephosphorylate the receptor β3 subunit at the CaMKII sites. Depolarisation of cultured immature cortical neurons was found to increase the level of enzymatically-active CaMKII that associates with the ICD of the receptor β3 subunit, and to trigger CaMKII-dependent phosphorylation of the receptor β3 subunit at both the S408 and S409 residues. Work presented in this thesis also identified multivalent interactions between GABAA receptor y subunits and the AP2 adaptor complex, a major component of the endocytic machinery. The ICD of each receptor y subunit was found to interact with the native AP2 complex from brain, and to bind selectively and directly to the u2- adaptin of AP2. Two distinct binding sites for jx2-adaptin were identified in the ICD of the y2S subunit. The N-terminal half of the ICD was found to interact with sub- domain B of u2-adaptin via a putative basic-rich motif. In contrast, the C-terminal half of the ICD was found to bind sub-domain A of u2-adaptin, likely via a tyrosine- based motif. Both u2-adaptin binding motifs were found to be common to all the y subunit isoforms.

No description available.

This thesis was focused on theoretical models of synchronization to cortical dynamics as measured by magnetoencephalography (MEG). Dynamical systems theory was used in both identifying relevant variables for brain coordination and also in devising methods for their quantification. We presented a method for studying interactions of linear and chaotic neuronal sources using MEG beamforming techniques. We showed that such sources can be accurately reconstructed in terms of their location, temporal dynamics and possible interactions. Synchronization in low-dimensional nonlinear systems was studied to explore specific correlates of functional integration and segregation. In the case of interacting dissimilar systems, relevant coordination phenomena involved generalized and phase synchronization, which were often intermittent. Spatially-extended systems were then studied. For locally-coupled dissimilar systems, as in the case of cortical columns, clustering behaviour occurred. Synchronized clusters emerged at different frequencies and their boundaries were marked through oscillation death. The macroscopic mean field revealed sharp spectral peaks at the frequencies of the clusters and broader spectral drops at their boundaries. These results question existing models of Event Related Synchronization and Desynchronization. We re-examined the concept of the steady-state evoked response following an AM stimulus. We showed that very little variability in the AM following response could be accounted by system noise. We presented a methodology for detecting local and global nonlinear interactions from MEG data in order to account for residual variability. We found crosshemispheric nonlinear interactions of ongoing cortical rhythms concurrent with the stimulus and interactions of these rhythms with the following AM responses. Finally, we hypothesized that holistic spatial stimuli would be accompanied by the emergence of clusters in primary visual cortex resulting in frequency-specific MEG oscillations. Indeed, we found different frequency distributions in induced gamma oscillations for different spatial stimuli, which was suggestive of temporal coding of these spatial stimuli.

Sensory gating is a mechanism by which irrelevant sensory information is filtered in the brain, enabling efficient information processing. The auditory conditioning-test paradigm, an index of sensory gating, measures the reduction in the auditory-evoked response (AER) produced by a test stimulus following an initial conditioning stimulus. Schizophrenic patients demonstrate a lack of attenuation of the test response measured in the P50 component of the cortical auditory-evoked potential. The N2/N40 auditory-evoked potential recorded from rat hippocampus is considered homologous to the human P50 wave. Altered glutamatergic neurotransmission and the endocannabinoid system have been implicated in the pathogenesis of schizophrenia with structural and functional abnormalities in the hippocampus and the medial prefrontal cortex (mPFC). The current study examined sensory gating using auditory conditioning-test paradigm in the dentate gyrus (DG) and the CA3 region of the hippocampus and in the medial prefrontal cortex (mPFC) before and after administration of N-Methyl- D-Aspartate (NMDA) receptor antagonist phencyclidine (PCP; 1 mg/kg, i.p) or the cannabinoid agonist WIN55,212-2 (1.2mg/kg, i.p). Electrophysiological recordings were conducted in Lister hooded rats, under isoflurane anaesthesia, during the presentation of paired auditory stimuli. Extracellular action potential spikes and local field potentials (LFPs) were recorded simultaneously using multi-electrode arrays and the effects of acute administration of PCP (1 mg/kg, i.p) or WIN55,212-2 (1.2mg/kg, i.p) was determined. Gating of the N2 wave was assessed by measuring the ratio of the Test to Conditioning response amplitude (T/C ratio); T/C ratio ≤ 50% was indicative of gating. Robust auditory-evoked potentials were recorded from the hippocampal CA3 and DG regions and the mPFC; some rats demonstrated auditory gating while others failed to. In rats that demonstrated gating of N2, mPFC showed higher T/C ratios and shorter conditioning response latencies compared to DG and CA3. PCP disrupted auditory gating in all three areas with a significant increase in test response amplitudes in the gating rats. PCP had no effect on T/C ratios in the non-gating rats. The atypical antipsychotic clozapine (5mg/kg, i.p) prevented PCP induced disruption of gating in the CA3, DG and mPFC. WIN55,212-2 disrupted auditory gating with a significant increase in test response amplitudes in the gating rats. WIN55,212-2 had no effect on T/C ratios in the non-gating rats. The cannabinoid receptor (CB1) antagonist SR141716A (1mg/kg, i.p) prevented WIN55,212-2 induced disruption of gating. Neither clozapine nor SR141716A had any effects on the non-gating rats. Both PCP and WIN55,212- 2 disrupted gating of the single-unit responses in the CA3, DG and mPFC, effects which were prevented by the pre- administration of clozapine or SR141716A. The non-gating rats may model some inhibitory deficits observed in schizophrenic patients. Administration of PCP disrupted auditory gating which was prevented by clozapine; similar deficits are observed in schizophrenic patients. Furthermore, cannabinoid receptor activation disrupted auditory gating which was prevented by CB1 receptor antagonism, suggesting the endocannabinoid system as a potential target for future clinical research in the treatment in schizophrenia.

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Η ΒΥΠ διαθέτει αντίτυπο της διατριβής σε έντυπη μορφή στο βιβλιοστάσιο διδακτορικών διατριβών που βρίσκεται στο ισόγειο του κτιρίου της. / Ακριβής και πλήρης αναλυτική λύση για το ευθύ πρόβλημα του Βιομαγνητισμού του ανθρώπινου εγκεφάλου είναι γνωστή για την περίπτωση που η πηγή του μετρούμενου μαγνητικού πεδίου θεωρείται σημειακό διπολικό ρεύμα εντός σφαιρικού ομογενούς αγωγού. Στην παρούσα διατριβή το ευθύ πρόβλημα του Βιοηλεκτρομαγνητισμού επιλύεται για το πλέον ρεαλιστικό πρότυπο του ομογενούς ελλειψοειδούς εγκεφάλου. Οι πρώτοι όροι προσέγγισης του ηλεκτρικού δυναμικού στο εσωτερικό και στο εξωτερικό του αγωγού παράγονται, καθώς και ο τετραπολικός όρος του πολυπολικού αναπτύγματος του εξωτερικού πεδίου μαγνητικής επαγωγής, κατά τρόπον ώστε να προβάλλεται ο ανισότροπος χαρακτήρας της ελλειψοειδούς γεωμετρίας, αλλά και η δομή της εξάρτησης των πεδίων από τη Φυσική και τη Γεωμετρία.Η επίλυση των αντίστοιχων προβλημάτων στη σφαιρική γεωμετρία καθώς και η επίπονη διαδικασία της αναγωγής των αποτελεσμάτων του ελλειψοειδούς προτύπου στα αντίστοιχα αποτελέσματα του σφαιροειδούς και του σφαιρικού προτύπου, απέδωσε χρήσιμα ποιοτικά συμπεράσματα ως προς τη σύγκριση των χρησιμοποιούμενων γεωμετρικών προτύπων. Ειδικότερα, όπως αποδείχτηκε, η αύξηση της ανισοτροπίας του προτύπου αντιστοιχεί στην εμφάνιση στα αποτελέσματα για τα εξωτερικά πεδία, της συνοριακής επιφάνειας του αγωγού, η οποία απουσιάζει από τα αντίστοιχα αποτελέσματα του πλήρως ισότροπου σφαιρικού αγωγού.Επιπλέον προσδιορίστηκε ο τρόπος με τον οποίο η πηγή εισέρχεται στον τετραπολικό όρο της μαγνητικής επαγωγής στα τρία πρότυπα, μέσω της ροπής, τροποποιημένης όπου χρειάζεται, και της θέσης της. Συνέπεια τούτου ήταν ο προσδιορισμός των μαγνητικά σιωπηλών πηγών σε κάθε πρότυπο, όπου αποδείχτηκε ότι μία πηγή που έχει προσανατολισμό κάθετο στην επιφάνεια του εκάστοτε αγωγού στο σημείο που ορίζει το διάνυσμα θέσης της, είναι σιωπηλή, δηλαδή δεν παράγει μαγνητικό πεδίο μετρήσιμο εξωτερικά του αγωγού.Τέλος, η διατριβή περιλαμβάνει μελέτη της ελλειψοειδούς γεωμετρίας και ανάλυσης του ελλειψοειδούς συστήματος συντεταγμένων, καθώς και εμβάθυνση στη διαδικασία αναγωγής αυτής της γεωμετρίας στη σφαιροειδή και στη σφαιρική. Ειδικά μελετώνται γεωμετρικές και αναλυτικές σχέσεις σύνδεσης του ελλειψοειδούς με το σφαιρικό σύστημα συντεταγμένων, με σκοπό την βαθύτερη κατανόηση των αποτελεσμάτων της διατριβής στα αντίστοιχα πρότυπα, αλλά και των δυνατοτήτων εκμετάλλευσης τους στη μελλοντική αντιμετώπιση των αντιστρόφων προβλημάτων του Βιοηλεκτρομαγνητισμού. / An exact and complete analytic solution for the forward problem, in the theory of Biomagnetics of the human brain, is known only for the case where the source of the measured magnetic field, in the exterior of a homogeneous sphere, is considered to be a point current dipole. It is also known for special directions of the source inside a spheroidal homogeneous conductor. In the present thesis the corresponding problem for the more realistic ellipsoidal brain model is solved up to its first multipole term. The leading terms of the electric potential in the interior and the exterior of the conductor , as well as the leading quadrupolic term of the multipole expansion of the exterior magnetic induction field, are obtained. The results are given in a form that exhibits the anisotropic character of the ellipsoidal geometry and the structure of the dependence of the fields on Physics and Geometry. The solution of the corresponding problems in spherical geometry as well as the laborious task of reducing the ellipsoidal results in the corresponding spheroidal and spherical cases, has brought up useful conclusions concerning these three geometrical models. In particular it has been proved that, as the anisotropy of the model is increased, the corresponding results for the exterior fields incorporate the boundary of the conductor, which is totally absent in the corresponding results of the isotropic spherical model. Furthermore, the way that the source enters in the quadrupolic term of the magnetic induction field is identified as the vector product of its moment, modified when needed, by its position vector. Consequently, the magnetic silent sources for each model, i.e. sources that produce non detectable exterior magnetic field, are also characterized. Actually, a source that is oriented normally to the boundary of the conductor in the direction of its location, is shown to be always silent. Finally, the present thesis includes a study of ellipsoidal geometry and of the related ellipsoidal coordinate system, as well as a thorough examination of its reduction process to the spheroidal and spherical system. Geometric and analytic connection relations between the ellipsoidal and the spherical system are obtained, aiming to a better understanding of the results of the present thesis. Furthermore this study sets the basis for broadening the possibilities of solving some of the inverse problems of Bioelectromagnetics.

Στην παρούσα εργασία ο πρώτος στόχος είναι η μελέτη των πρωτεϊνικών επιπέδων της υπομονάδας NR2B του υποδοχέα NMDA. Σε προηγούμενη εργασία του εργαστηρίου μας παρατηρήθηκε αύξηση των επιπέδων έκφρασης στο mRNA της υπομονάδας NR2B στο ραβδωτό σώμα των μυών weaver ηλικίας έξι μηνών. Η αύξηση του mRNA δεν ακολουθείται πάντα από αύξηση της πρωτεΐνης καθώς το mRNΑ μπορεί να καταστρέφεται προτού οδηγήσει στη δημιουργία νέων πρωτεϊνικών μορίων. Δεύτερος στόχος της εργασίας είναι η μελέτη της επίδρασης της ντοπαμινεργικής εννεύρωσης στη φωσφορυλίωση της υπομονάδας NR2B του υποδοχέα NMDA. Επιλέχθηκε η μελέτη της φωσφορυλίωση της υπομονάδας NR2B του υποδοχέα NMDA στη σερίνη 1303 λόγω του ότι στη συγκεκριμένη θέση φωσφορυλιώνεται από την ασβεστιοεξαρτώμενη κινάση της καλμοδουλίνης (CaMKII). H CaMKII εμπλέκεται στο LTP και στο LTD και στο μοντέλο της 6-OHDA φαίνεται να επηρεάζεται από την ντοπαμινεργική ανεπάρκεια. Αλλαγές, συνεπώς, στα επίπεδα φωσφορυλίωσης στη σερίνη 1303 είναι πιθανό να απορρέουν από αλλαγές στα επίπεδα της CaMKII, οδηγώντας σε μεταβολή της συναπτικής πλαστικότητας του ραβδωτού σε ντοπαμινεργική ανεπάρκεια. / -

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