In humans, damage to the mammillothalamic tract (MTT) as a result of localised strokes, tumours or alcohol abuse has consistently been implicated in the severe anterograde amnesia evident in these patients. This small neural pathway, which connects the mammillary bodies (MB) to the anterior thalamic nuclei (ATN), is thought to provide one important link in a larger extended hippocampal circuit involved in encoding and retrieval of episodic memory. Brain damage in clinical cases is, however, typically diffuse and contributions from additional sites of pathology cannot be ruled out. There are also inconsistencies within a limited animal literature on MTT lesions. The current study made MTT lesions in female rats and used multiple „episodic - like‟ memory tasks relevant to the proposed importance of this pathway. The project also intended to test whether enrichment reduces any impairments after MTT lesions. None of the lesions resulted in complete bilateral disconnection of the MTT, but many had moderate to large bilateral (n = 6) (81% to 50%), or unilateral MTT damage (n = 4). Rats with bilateral lesions were compared to controls (n = 14, including 4 other lesion rats in which no lesion occurred). The severe working memory deficit in the water maze expected for rats with MTT lesion was not found and only a slight deficit in reference memory in the water maze was observed (so enrichment was not implemented). Although none of the bilateral MTT lesions were complete, they are also often incomplete in clinical cases and previous research has shown that lesions to the ATN in excess of 50% are sufficient to induce severe behavioural deficits in rats. Therefore, if the MTT is critical to memory then substantial but not total bilateral disconnection should be sufficient to induce profound deficits in rats, at least on spatial working memory. Taken together these findings suggest a less crucial role for the MTT in memory than previously suggested. Future research needs to resolve the inconsistencies observed in the animal literature by repeating the present study, using larger MTT lesions and both male and female rats.

Alternative splicing (AS) is a major source of biological diversity and a crucial determinant of cell fate and identity. Characterizing the role of AS regulatory networks in physiological and pathological processes remains challenging. The work presented here addresses this challenge using systems biology analyses of AS regulatory networks in programmed cell death and neurological disorders. The first study describes a genome-wide screen based on splicing-sensitive reporters to identify factors that affect the AS of apoptosis regulators Bclx and Mcl1. The screen identified over 150 factors that affect apoptosis through modulating the pro- and anti-apoptotic splicing variants of these apoptosis regulators. This screen revealed a new functional connection between apoptosis regulation and cell-cycle control through an AS network. It also unearthed many disease-associated factors as AS effectors. The second study describes the functions of the Polyglutamine-binding protein 1 (PQBP1)-mediated AS regulatory network in neurological disorders. PQBP1 is a factor linked to intellectual disability and was unexpectedly identified as an AS effector from the screen described above. We found that PQBP1 influences the splicing of many mRNAs and is associated with a wide range of splicing factors. Depletion of PQBP1 in mouse primary cortical neurons caused defects in neurite outgrowth and altered AS of mRNAs enriched for functions in neuron projection regulation. Disease-mutants of PQBP1 lose associations with splicing factors and cannot complement the aberrant AS patterns and neuron morphology defects in PQBP1 depleted-neurons. This study revealed a novel function of PQBP1 in AS regulation associated with neurite outgrowth and indicated that aberrant AS underlies the pathology of PQBP1-related neurological disorders. A final study examines the dynamics of the Drosophila Sex-lethal AS regulation network using a combination of experimental tools and mathematical modeling. This study demonstrates that the features of Sxl AS regulation have great potentials in building synthetic memory circuits in mammalian cells to track cell fate. Collectively, this work describes the landscape of three diverse AS regulatory networks in various biological processes. The results and methods presented here contribute to our rapidly advancing knowledge of AS regulation in biology and human disease.

In dieser Arbeit werden Speichertransistoren mit Oxid-Nitrid-Oxid-Speicherschicht und lokaler Ladungsspeicherung untersucht, die zur nichtflüchtigen Speicherung von Informationen genutzt werden. Charakteristisch für diese Transistoren ist, dass an beiden Enden des Transistorkanals innerhalb der Isolationsschicht Informationen in Form von Ladungspaketen unabhängig und getrennt voneinander gespeichert werden. Für das Auslesen, Programmieren und Löschen der Speichertransistoren werden die physikalischen Hintergründe diskutiert und grundlegende Algorithmen zur Implementierung dieser Operationen auf einer typischen Speicherfeldarchitektur aufgezeigt. Für Standard-MOS-Transistoren wird ein Kurzkanal-Schwellspannungsmodell abgeleitet und analytisch gelöst. Anhand dieser Modellgleichung werden die bekannten Kurzkanaleffekte betrachtet. Weiterhin wird ein Modell zur Berechnung des Drainstroms von Kurzkanaltransistoren im Subthreshold-Arbeitsbereich abgeleitet und gezeigt, dass sich die Drain-Source-Leckströme bei Kurzkanaltransistoren vergrößern. Die Erweiterung des Schwellspannungsmodells für Standard-MOS-Transistoren auf den Fall der lokalen Ladungsspeicherung innerhalb der Isolationsschicht erlaubt die Ableitung eines Schwellspannungsmodells für Oxid-Nitrid-Oxid-Transistoren mit lokaler Ladungsspeicherung. Dieses Modell gestattet die qualitative und quantitative Diskussion der Erhöhung der Schwellspannung durch die lokale Injektion von Ladungsträgern beim Programmiervorgang. Weiterhin ist es mit diesem Modell möglich, die Trennung der an beiden Kanalenden des Transistors gespeicherten Informationen beim Auslesevorgang qualitativ zu erklären und diese Bittrennung in Abhängigkeit von der Drainspannung zu berechnen. Für Langkanalspeichertransistoren wird eine analytische Näherungslösung des Schwellspannungsmodells angegeben, während das Kurzkanalverhalten durch die numerische Lösung der Modellgleichung bestimmt werden kann. Für Langkanalspeichertransistoren wird ein Subthreshold-Modell zur Berechnung des Drainstroms abgeleitet. Dieses Modell zeigt, dass sich die Leckströme von programmierten Speichertransistoren im Vergleich zu Standard-MOS-Transistoren gleicher Schwellspannung vergrößern. Die Ursache dieses Effekts, die Verringerung der Subthreshold-Steigung von Transistoren im programmierten Zustand, wird analysiert. Für einige praktische Beispiele wird die Anwendung der hergeleiteten Modellgleichungen beim Entwurf von Flash-Speichern demonstriert. / In this work, memory transistors with an oxide-nitride-oxide trapping-layer and local charge storage, which are used for non-volatile information storage, are examined. Characteristic for these transistors is an independent and separated storage of information by charge packages, located at both sides of the transistor channel, in the insulation layer. The physical backgrounds for reading, programming and erasing the memory transistors are discussed, and basic algorithms are shown for implementing these operations on a typical memory array architecture. For standard MOS-transistors a short channel threshold model is derived and solved analytically. By using these model equations, the known short channel effects are considered. Further, a model for calculating the drain current of short channel transistors in the subthreshold operation region is derived. This model is used to show the increase of drain-source leakage currents in short channel transistors. By extending the standard MOS-transistor threshold voltage model for local charge storage in the insulation layers, the derivation of a threshold voltage model for oxide-nitride-oxide transistors with local charge storage is enabled. This model permits the quantitative and qualitative discussion of the increase in threshold voltage caused by local injection of charges during programming. Furthermore, with this model, the separation of the information, which are stored at both sides of the transistor channel, in the read-out operation is explained qualitatively, and the bit separation is calculated dependent on the drain voltage. For long channel memory transistors an analytical approximation of the threshold voltage model is given, whereas the short channel behaviour can be determined by solving the model equation numerically. For long channel memory transistors, a subthreshold model for calculating the drain current is derived. This model shows the increase in leakage current of programmed memory transistors in comparision to standard MOS-transistors. The root cause of this effect, the reduced subthreshold swing of transistors in the programmed state, is analysed. The application of the derived model equations for the development of flash memories is demonstrated with some practical examples.

In dieser Arbeit werden Speichertransistoren mit Oxid-Nitrid-Oxid-Speicherschicht und lokaler Ladungsspeicherung untersucht, die zur nichtflüchtigen Speicherung von Informationen genutzt werden. Charakteristisch für diese Transistoren ist, dass an beiden Enden des Transistorkanals innerhalb der Isolationsschicht Informationen in Form von Ladungspaketen unabhängig und getrennt voneinander gespeichert werden. Für das Auslesen, Programmieren und Löschen der Speichertransistoren werden die physikalischen Hintergründe diskutiert und grundlegende Algorithmen zur Implementierung dieser Operationen auf einer typischen Speicherfeldarchitektur aufgezeigt. Für Standard-MOS-Transistoren wird ein Kurzkanal-Schwellspannungsmodell abgeleitet und analytisch gelöst. Anhand dieser Modellgleichung werden die bekannten Kurzkanaleffekte betrachtet. Weiterhin wird ein Modell zur Berechnung des Drainstroms von Kurzkanaltransistoren im Subthreshold-Arbeitsbereich abgeleitet und gezeigt, dass sich die Drain-Source-Leckströme bei Kurzkanaltransistoren vergrößern. Die Erweiterung des Schwellspannungsmodells für Standard-MOS-Transistoren auf den Fall der lokalen Ladungsspeicherung innerhalb der Isolationsschicht erlaubt die Ableitung eines Schwellspannungsmodells für Oxid-Nitrid-Oxid-Transistoren mit lokaler Ladungsspeicherung. Dieses Modell gestattet die qualitative und quantitative Diskussion der Erhöhung der Schwellspannung durch die lokale Injektion von Ladungsträgern beim Programmiervorgang. Weiterhin ist es mit diesem Modell möglich, die Trennung der an beiden Kanalenden des Transistors gespeicherten Informationen beim Auslesevorgang qualitativ zu erklären und diese Bittrennung in Abhängigkeit von der Drainspannung zu berechnen. Für Langkanalspeichertransistoren wird eine analytische Näherungslösung des Schwellspannungsmodells angegeben, während das Kurzkanalverhalten durch die numerische Lösung der Modellgleichung bestimmt werden kann. Für Langkanalspeichertransistoren wird ein Subthreshold-Modell zur Berechnung des Drainstroms abgeleitet. Dieses Modell zeigt, dass sich die Leckströme von programmierten Speichertransistoren im Vergleich zu Standard-MOS-Transistoren gleicher Schwellspannung vergrößern. Die Ursache dieses Effekts, die Verringerung der Subthreshold-Steigung von Transistoren im programmierten Zustand, wird analysiert. Für einige praktische Beispiele wird die Anwendung der hergeleiteten Modellgleichungen beim Entwurf von Flash-Speichern demonstriert. / In this work, memory transistors with an oxide-nitride-oxide trapping-layer and local charge storage, which are used for non-volatile information storage, are examined. Characteristic for these transistors is an independent and separated storage of information by charge packages, located at both sides of the transistor channel, in the insulation layer. The physical backgrounds for reading, programming and erasing the memory transistors are discussed, and basic algorithms are shown for implementing these operations on a typical memory array architecture. For standard MOS-transistors a short channel threshold model is derived and solved analytically. By using these model equations, the known short channel effects are considered. Further, a model for calculating the drain current of short channel transistors in the subthreshold operation region is derived. This model is used to show the increase of drain-source leakage currents in short channel transistors. By extending the standard MOS-transistor threshold voltage model for local charge storage in the insulation layers, the derivation of a threshold voltage model for oxide-nitride-oxide transistors with local charge storage is enabled. This model permits the quantitative and qualitative discussion of the increase in threshold voltage caused by local injection of charges during programming. Furthermore, with this model, the separation of the information, which are stored at both sides of the transistor channel, in the read-out operation is explained qualitatively, and the bit separation is calculated dependent on the drain voltage. For long channel memory transistors an analytical approximation of the threshold voltage model is given, whereas the short channel behaviour can be determined by solving the model equation numerically. For long channel memory transistors, a subthreshold model for calculating the drain current is derived. This model shows the increase in leakage current of programmed memory transistors in comparision to standard MOS-transistors. The root cause of this effect, the reduced subthreshold swing of transistors in the programmed state, is analysed. The application of the derived model equations for the development of flash memories is demonstrated with some practical examples.