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A novel paradigm to investigate the role of the retrosplenial cortex in spatial learning and memory in freely behaving mice
Get PDFSpatial cognition is vital for the survival of many species, enabling mice and other animals to navigate their environment, locate food resources, and escape from threats. Meanwhile, spatial learning and memory allow an individual to acquire, retain, and recall spatial information. The retrosplenial cortex (RSC) has recently gained attention for its role in spatial cognition and memory, integrating sensory and spatial signals. Despite extensive research on the neural circuits involved in spatial learning through employment of various spatial memory tasks, the specific contributions of the rodent RSC to spatial memory are not fully understood. This gap in knowledge emphasises the need for innovative behavioural paradigms to address previous spatial memory tasks’ limitations. In this thesis, I present a novel behavioural paradigm designed to explore the role of the RSC to spatial learning and memory.
The task I developed investigates mechanisms of spatial memory formation, retrieval, and reversal learning in rodents, wherein mice learn the locations of hidden trigger zones within a circular arena. This spatial memory task stands out for its ability to track mice, their behaviour, and task performance in a three-dimensional environment without any physical constraints on head or body movement. This allows for naturalistic animal behaviour and the simultaneous use of portable neuronal recording devices during training. In this study, I identified key task metrics for quantifying behaviour in the spatial memory task, including error angles and active task engagement, to assess
learning and task performance. Using these parameters, I demonstrate that the goal-directed navigational strategies employed by mice vary significantly whether they are guided by vision or memory. Specifically, mice resort to memory-guided navigation exclusively in the absence of visual landmark cues. Through manipulations of the external landmarks within the animals' environment during spatial memory training, I demonstrate that mice develop a comprehensive cognitive map of the arena and the surrounding space, using allocentric navigation strategies to locate previously learnt goal locations. The results of this study further show that mice can form robust allocentric spatial memories quickly and efficiently, even under conditions where RSC activity is inhibited. Chemogenetic experiments show that inactivating RSC neuronal activity does not impede the formation or retrieval of spatial memories in this task.
Taken together, these findings highlight the effectiveness of this task for investigating allocentric spatial learning and memory in mice. Characterized by rapid acquisition of task proficiency, high trial rates, reliable memory formation and recall, brief pre-training periods, and unrestricted, natural mouse behaviour, this paradigm opens up new avenues for advanced research into the neural substrates of spatial learning and memory with broad applications in RSC research and beyond
Das Reproduktionssystem der Lanzenfliegen (Diptera: Lonchopteridae)
Get PDFDiese aus insgesamt drei Publikationen bzw. Kapiteln bestehende Dissertation soll zum allgemeinen Verständnis der Mechanismen der postkopulatorischen sexuellen Selektion beitragen, die zur Entstehung von Riesenspermien geführt haben. Zu diesem Zweck wurde das Fortpflanzungssystem der Lanzenfliegen (Diptera: Lonchopteridae) eingehender untersucht. Bei den Vertretern dieser Familie gibt es hierbei bemerkenswerte Unterschiede, wobei einige Arten Riesenspermien produzieren und die entsprechenden Weibchen extrem lange Spermatheken besitzen. Mit einer Länge von 7.500 µm und einer Dicke von 1,3 µm gehört das Spermium von Lonchoptera fallax zu den größten bisher bekannten überhaupt. Die Weibchen dieser Art besitzen Spermatheken mit einer Gesamtlänge von etwa 14.000 µm, womit diese etwa viermal so lang wie deren Körper sind.
Anhand von 3D-Rekonstruktionen und Erkenntnissen aus der Elektronenmikroskopie wird in Kapitel I die Morphologie und Ultrastruktur der Spermien der nahe verwandten Art Lonchoptera lutea näher beschrieben. Mit einer Länge von 2.200 μm und einer Dicke von 1,4 μm sind diese zwar deutlich kleiner als die von L. fallax, können aber dennoch als riesig bezeichnet werden. Anders als die typischen Spermien anderer Fliegen haben sie einen stark asymmetrischen Querschnitt mit nur einem, wenn auch sehr großen Mitochondrienderivat und einem Paar massiver akzessorischer Körper, von denen sich aber nur einer über die gesamte Länge des Flagellums erstreckt.
Um die Entstehung von Riesenspermien in dieser Fliegen-Familie näher zu erforschen, wurden für Kapitel II die Körpergröße, die Hodengröße, die Spermiengröße und die Anzahl der Spermien pro Bündel und pro Hoden bei insgesamt elf Lonchoptera-Arten untersucht. Anhand dieser Ergebnisse wird diskutiert, wie diese Merkmale miteinander in Beziehung stehen und wie ihre Entwicklung die Ressourcenverteilung unter den Spermien beeinflusst. Auf Grundlage der Spermienmerkmale und unterstützt durch einen aus DNA-Barcodes abgeleiteten molekularen Stammbaum wird zudem eine phylogenetische Hypothese für die Gattung Lonchoptera formuliert.
Um die postkopulatorischen Prozesse zu verstehen, die zur Entstehung von riesigen Spermien bei Lonchopteridae geführt haben, wurden für Kapitel III die Abmessungen der Spermatheken, die wiederum in vier morphologisch, histologisch und funktionell unterschiedliche Abschnitte unterteilt werden können, bei elf Lonchoptera-Arten untersucht und mit den Maßen der entsprechenden Spermien ins Verhältnis gesetzt. 3D-Rekonstruktionen machten es zudem möglich, das Volumen in diese Überlegungen mit einzubeziehen, was einen neuen Ansatz in diesem Kontext darstellt. Die Ergebnisse zeigen, dass die Spermatheken immer deutlich länger sind als die entsprechenden Spermien und dass ein hochsignifikanter, positiv linearer Zusammenhang zwischen beiden Größen besteht, was auf einen zugrundeliegenden koevolutiven Prozess hindeutet. Auf Grundlage aller Ergebnisse werden einige evolutive Szenarien inklusive eines neuen Ansatzes zu den selektiven Vorteilen längerer Spermien aufgezeigt, um zu diskutieren, wie Spermien- und Spermathekenlänge bei Lonchopteridae abhängig voneinander entstanden sein könnten
Investigations on multilateration of ionoacoustic signals for localisation of the bragg peak in pre-clinical research
Get PDFRadiation therapy is one of the most typically used treatments in cancer care, with around 60% of patients undergoing this form of treatment. While X-rays and gamma rays (photon therapy) are the standard approach, proton therapy has emerged as a valuable alternative. Proton therapy is renowned for its ability to provide a more conformal dose delivery. Proton therapy’s superiority over photon therapy is due to protons depositing their maximum energy directly within the tumour while sparing surrounding healthy tissues. However, proton therapy is highly sensitive to range uncertainties.
Range uncertainties in proton therapy arise primarily because we cannot precisely determine where the proton beam will stop, leading to the risk of overshooting or undershooting the target. Thus, there is a need for in vivo range verification methods to reduce range uncertainties. The two methods nearing routine clinical use are positron emission tomography (PET) and prompt gamma imaging (PGI).
Range verification relies on monitoring nuclear reaction products along proton beams for these methods. However, PET and PGI methods do not directly correlate the measurable signal, beam range, or Bragg peak (BP) position. Additionally, their equipment is bulky and not cost-effective. Therefore, the research conducted during this work proposes a range verification method that is both cost-effective and establishes a direct correlation between the proton beam and ionoacoustic (IA) signals.
At present, only two commercial platforms support small animal photon radiotherapy, though their imaging systems can be adapted for research beamlines. Proton therapy offers distinct advantages over photon therapy, which led to the development of the Small Animal Proton Irradiator for Research in Molecular Image-guided Radiation-Oncology (SIRMIO) project. It was led by Prof. Dr. Katia Parodi at Ludwig Maximilians-Universit¨at (LMU) Munich and funded by the European Research Council (ERC) under grant agreement 725539. SIRMIO aimed to create the first portable, imageguided research platform for small animal proton therapy. As part of this effort, different range verification methods are investigated. One of these methods is the one studied in this thesis, which is based on localising the BP using IA signals.
The research presented here investigates BP localisation using IA signals, aiming to determine the BP position in both two-dimensional (2D) and three-dimensional (3D) space. The localisation was performed in homogenous and heterogenous media via time-of-flight (ToF) estimation from different sensor spatial locations. The localisation of the BP was assessed using a technique called multilateration. The initial studies were performed in-silico, using ideal point sources that emulated the BP position and evaluated the robustness of two numerical optimisation algorithms: Nelder-Mead Simplex and Levenberg Marquardt. Secondly, the robustness of the multilateration technique was assessed for two localisation methods: time-of-arrival (TOA) and time-difference-of-arrival (TDOA). By modelling random and systematic uncertainties in the geometrical ToF, the robustness of both TOA and TDOA was evaluated. Random uncertainties aimed to model the speed of sound variations, inaccurate knowledge of the sensor spatial location and errors on the ToF. On the other hand, the objective of modelling systematic uncertainties was to simulate the inaccurate knowledge of the measurement starting time from a proton beam accelerator. After fully understanding the numerical optimisation methods and the impact of uncertainties on TOA and TDOA, the localisation focus was addressed to a realistic simulation case using a pre-clinical beam with an energy of 20 MeV. The multilateration of the BP position was performed with a sensor network of 843 ideal point sensors arranged in a semi-circular configuration with a diameter of 60 mm. Similarly, the impact of different ToF extraction methods on BP localisation was evaluated.
Moreover, the studies were further expanded to investigate the impact of the number of sensors on the ToF estimation and, consequently, their impact on the accuracy of the BP localisation.
Experimental campaigns were conducted to benchmark the localisation of the BP using pre-knowledge gained from the simulation studies. These experimental studies retrieved the BP position in the Tandem accelerator with two different beam energies (20 and 22 MeV). The first experimental campaign aimed to localise the BP using 3 transducers. Furthermore, two different techniques were implemented to localise the spatial location of the transducers. The second experimental campaign aimed to localise the BP using 5 transducers. Moreover, the spatial locations of the transducers were estimated experimental using a single approach based on the measurement performed with an optical tracking system. For the SIRMIO case, a dedicated localisation setup with a 50 MeV beam energy was considered. This setup aimed to localise the BP under various conditions, including different proton beam time profiles, beam spatial locations, and numbers of sensors. The first step involved studying the error in ToF as a function of the proton time profiles and then assessing multilateration accuracy based on thesame proton time profiles. After identifying the optimal proton time profile, the BP was localised by keeping the proton time profile constant while varying the number of sensors.
For the numerical methods, the Levenberg-Marquardt method demonstrated greater robustness compared to the Nelder-Mead Simplex method, with failure rates (FR) of 0.22% and 0% when localising the emulated BP positions with TOA and 1.12% and 4.85% when localising the source with TDOA, respectively. Considering ideal point sources, both localisation methods were equivalent in 2D. A mean error in localisation of 7.4×10^−4 mm and 7.8×10^−4 mm for TOA and TDOA was obtained. In 3D, the localisation error varied from 7.8×10^−4 mm and 1.0×10^−3 mm for TOA and TDOA. The speed of sound varies in vivo depending on the tissue type, which is expected to reduce the BP localisation accuracy. With a conservative assumption of a 5% error in the average speed of sound along the acoustic path (modelled by random uncertainties), it was observed that the localisation error after multilateration increased by around 2 mm for the examined geometry. The lowest error on the ToF estimation is obtained for the maximum-envelope extraction method when considering IA signals. Therefore, through optimal sensor positioning to minimise ToF errors, the BP could be localised in-silico with an accuracy exceeding 90 μm (equivalent to a 2% error). The BP was localised for the first experimental setup with errors ranging from 0.43 mm to 0.48 mm, depending on the sensor arrangement. The localisation was performed with a total dose of 1.69 Gy with a single shot. In the second experimental setup, the localisation was performed with 50 IA signals and a total dose of 29 Gy, achieving a localisation error of 1 mm. For both setups, the primary sources of localisation errors were inaccuracies in sensor positioning and low signal-to-noise ratio (SNR) due to the weak and directional nature of the IA emissions. The studies conducted for the SIRMIO beamline demonstrated that the proton time profile significantly impacts the ToF estimation, influencing the accuracy of BP localisation. The optimal localisation accuracy was achieved with proton time profiles ranging from 1 μs to 4 μs. In this setup, the BP was localised for different beam offsets along the x,y, and z axes. When applying offsets along the beam axis (x-axis), the maximum error was found to be 0.48 mm. Conversely, a maximum error of 1.23 mm was obtained for a transverse beam offset (z-axis).
In conclusion, this work introduces a range verification method using IA signals within the framework of the SIRMIO project. Additionally, further discussions explore the potential for transitioning the studies presented in this thesis toward real-time range verification applications
Sensorische Testungen zur Charakterisierung chronischer Schmerzerkrankungen und der Effekte nicht-medikamentöser Schmerztherapieverfahren
Get PDFMechanism-based psychotherapy for acute psychosis
Get PDFImproving psychotherapeutic inpatient care for acute patients with psychotic symptoms is a key issue for national and international health care services. However, most studies of psychotherapy for psychosis have primarily focused on outpatient settings, leaving a knowledge gap regarding effective interventions for acute inpatients. Furthermore, recent systematic reviews and meta-analyses of the effectiveness of guideline-recommended cognitive behavioural therapy for psychosis (CBTp) in acute settings have reported rather disappointing results. Nevertheless, there is increasing evidence for mechanism-based third-wave therapies, such as the Acceptance and Commitment Therapy, and third-wave-inspired approaches, such as the Metacognitive. However, although promising, few of these mechanism-based interventions have been specifically developed or adapted for acute psychiatric settings. Therefore, the current research aimed to develop and test a novel mechanism-based and needs-oriented psychological intervention (MEBASp) for acute inpatients with psychotic symptoms.
Intervention Mapping (IM), a six-step structured methodological framework for scientific intervention design, was used to guide both the rigorous development process of MEBASp in Stage I (Publication I) and the subsequent feasibility study in Stage II (Publication II). The MEBASp intervention designed in Stage I consists of a three-module, low-threshold, experiential, and destigmatizing group intervention focusing on different aspects of metacognitive change mechanisms. Modules I and II focus on enhancing cognitive insight to alleviate acute symptoms, while Module III emphasizes cognitive defusion to reduce participants' distress. In Stage II, a sample of 37 participants with psychotic symptoms (ICD-10 codes F20-39: schizophrenia, schizotypal, delusional and psychotic mood disorders) was recruited from the locked acute ward of the Max Planck Institute of Psychiatry (MPI) in Munich, Germany, and received up to nine sessions of MEBASp. Primary outcome measures were feasibility (recruitment, retention and session attendance rates) and acceptability (participant satisfaction with treatment). Secondary outcome measures included general psychopathology, psychotic symptoms, global functioning, symptom distress, and symptom severity assessed at baseline and post-intervention. Measures of the hypothesized mechanisms of change were administered before and after each module.
High feasibility was demonstrated by a recruitment rate of 78.8%, retention rate of 89.2% and attendance rate of 86.5%. 80% of participants rated their overall satisfaction with the treatment as the highest possible, further indicating a high level of acceptability. In addition to the primary outcome measures, the feasibility and acceptability of MEBASp were supported by secondary outcome measures and qualitative data. Although the feasibility study was not designed or powered to assess clinical effectiveness, there was evidence of significant pre-post effects on all secondary clinical outcomes and hypothesized mechanisms of change. The results of the two-stage MEBASp research project provide compelling evidence for the feasibility and acceptability of a group intervention based on a meta-cognitive model for patients with psychosis in acute inpatient settings. The positive outcomes observed in terms of clinical improvements and mechanisms of change warrant further investigation in a randomized controlled trial
Collaborative Care für Patienten mit PTBS im hausärztlichen Setting – eine systematische Übersichtsarbeit mit Metaanalyse
Get PDFUnveiling novel features of HPV-related cancers through in silico and in vitro approaches
Get PDFHigh-risk HPV has the potential to induce carcinogenesis in epithelial cells through diverse pathways. Although primary and secondary prevention has been promoted by the WHO over the past two decades, HPV-related cancers still demonstrate considerable global incidence rates and economic impacts and treatment options for patients with advanced HPV-related cancers still remain limited. To develop novel therapeutic drugs and more effectively address the challenges posed by HPV-related cancers, it is essential to explore these cancers from new perspectives. The advancements in bioinformatics technology provide a possibility for this, and with validations through in vitro experiments, its reliability limitations could be com-pensated.
In our studies, we utilized both bioinformatic analysis and in vitro experiments to investigate HPV-related cancers. Main findings in these studies involves the establishment of gene risk models for survival and relapse in patients with HPV-related cancers, the identification of the pivotal role played by CDC42 in cancer progression, and the screening of afatinib as a poten-tial therapeutic drug, which unveiled novel features of these cancers and laid the foundation for the development of novel targeted therapy in the future
Fraktionierung als effiziente, kostengünstige und nachhaltige Methode zur Probenaufbereitung von Milch im Labor
Get PDFDie vorliegende Arbeit geht der Frage nach, ob ein Fraktionierungsverfahren zur „just-in-time“-Probenvorbereitung von Rohmilchproben für die Rückstandsanalytik eingesetzt werden kann. Um das Fraktionierungsverfahren in eine Laboranwendung umzusetzen, ist eine Fraktionierungseinheit in Zusammenarbeit mit der Sartorius Lab Instruments GmbH konzipiert worden, die als FraMiTrACR (Fractionation of Milk for Trace Analysis of Contaminants and Residues) bezeichnet wird. Der FraMiTrACR ermöglicht eine passive und extraktionsmittelfreie Trennung von komplexen Probenmatrices in einem ein-Schritt-Verfahren mittels Zentrifugation. Eine der beiden Fraktionen kann nach der Zentrifugation direkt zur weiteren Analyse zum Beispiel mittels Flüssigchromatographie mit Massenspektrometrie-Kopplung (LC-MS/MS) genutzt werden. Neben der grundsätzlichen Fragestellung der Machbarkeit sollte im Rahmen der vorliegenden Arbeit am Milchprüfring Baden-Württemberg e.V. auch geprüft werden, ob die Fraktionierung gleichwertige Analyseergebnisse wie das QuEChERS- oder QuPPe-Verfahren ermöglicht. Zusätzlich sollte betrachtet werden, welche Unterschiede diese drei Methoden hinsichtlich der Arbeitsabläufe und der Arbeitskosten eines Labors aufweisen. Neben diesen rein wirtschaftlichen Aspekten sollten wegen der völlig neuen Prozesscharakteristika, nämlich der Eliminierung aller Chemikalienzusätze im Verlauf der Probenaufarbeitung wie auch der drastischen Verkürzung der Prozesszeiten, auch Fragen der Auswirkungen auf die Umwelt geklärt und nach neuen Möglichkeiten für just-in-time Monitoringkonzepte mit Green Chemistry Ansatz gesucht werden.This study investigates whether a fractionation process can be used for the “just-in-time” sample preparation of raw milk samples for residue analysis. In order to implement the fractionation process in a laboratory application, a fractionation unit has been designed in cooperation with Sartorius Lab Instruments GmbH, which is referred to as FraMiTrACR (Fractionation of Milk for Trace Analysis of Contaminants and Residues). The FraMiTrACR enables a passive and extractant-free separation of complex sample matrices in a one-step process using centrifugation. After centrifugation, one of the two fractions can be used directly for further analysis, for example by liquid chromatography with mass spectrometry coupling (LC-MS/MS). In addition to the fundamental question of feasibility, the present work at Milchprüfring Baden-Württemberg e.V. was also intended to examine whether fractionation provides equivalent analysis results to the QuEChERS or QuPPe method. In addition, the differences between these three methods in terms of laboratory workflows and labor costs should be considered. In addition to these purely economic aspects, the completely new process characteristics, namely the elimination of all chemical additives during sample preparation and the drastic shortening of process times, should also clarify questions of environmental impact and search for new possibilities for just-in-time monitoring concepts with a green chemistry approach
