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Traumatic brain injury
Full text linkTraumatic brain injury (TBI) is a current economical and societal burden affecting around 70 million individuals worldwide. Traumatic brain injury is categorised in different severity level, being mild, moderate and severe, mild traumatic brain injury (mild TBI) representing 80% of all TBI cases.
The heterogeneity displayed by patient undergoing a TBI has made it difficult for the clinician as well as for the scientist to give the appropriate diagnosis and care and develop the adequate therapy and treatment to alleviate the impact of such a trauma. Moderate and severe TBI, which are invasive injury, are rather straightforward in the display of their repercussion as compared to mild TBI (or concussion) which have displayed no macroscopic changes but rather specific microscopic alterations. Behavioural impairments have also been detected and the extent of the impairments is dependent on the injury severity level. In this thesis, we will tackle different aspects of TBI and investigate the consequences and mechanisms of TBI.
In the first study of this thesis, I introduce an innovative automated analysis tool named Automated Limb Motion Analysis (ALMA), tailored for evaluating locomotion and paw placement in mice afflicted with various neurological disorders. ALMA uses pose estimation derived from DeepLabCut with a user-friendly graphical interface to automate the computation of kinematic parameters, footfall detection, kinematic data analysis, and visualization of gait kinematics.
Interestingly, in this study, we used ALMA to analyze, among others, motor dysfunction following TBI. While motor dysfunction is always difficult to quantify following TBI, ALMA allows an in-depth access to gait parameters and can capture small but important impairments and recovery following trauma to the brain.
The second study of my thesis delves into the intricate structural and functional changes occurring in the contralesional cortex following TBI. Despite initial neuronal cell loss and circuit disruption leading to behavioural and cognitive deficits, both clinical observations and animal models indicate a potential for spontaneous recovery, implicating neuronal circuit plasticity. In order to clarify the circuit rearrangements occurring in the contralesional cortex after traumatic brain injury (TBI), the study uses a comprehensive methodology that combines selective labelling of neuronal subpopulations, structural and functional in vivo imaging techniques, and mono-synaptic circuit tracing approaches. Results highlight specific adaptations of callosal neurons and their input circuits, shedding light on the mechanisms underlying cortical plasticity and recovery following TBI. This investigation not only advances our understanding of cortical plasticity but also provides crucial insights into potential therapeutic targets for enhancing recovery mechanisms in TBI patients. Concussive injuries represent the majority of TBI and pose a significant health risk to the victims. While symptoms often dissipate shortly after a single impact, repetitive concussions, particularly prevalent in sports, lead to enduring acute and chronic deficits.
This third and last study aimed to establish a mouse model of concussive head injury to examine differences in behaviour and anatomy between single and repetitive injuries. Our results demonstrate that the consequences of a single concussion in term of synaptic changes or microglial structure and function are less severe than following repetitive injury. In particular, I showed that repetitive concussions result in a specific cortical and hippocampal loss of excitatory synapses, below the concussion site, associated to a chronic heightened microglial activation and increased engulfment of presynaptic excitatory synapses. These alterations coincide with a temporary deterioration in spatial memory followed by changes in fear and anxiety-related behaviours. This study underscores the significance of concussion repetition in initiating pathological processes affecting excitatory synapses, attributed to enhanced microglial engulfment function.
By integrating the findings from these three studies, my thesis offers a comprehensive understanding of behavioral deficits, cortical plasticity, mechanisms initiating the impairments following different severity of TBIs
Untersuchung der antifibrotischen Wirkung biokompatibler Beschichtungen von Cochlea-Implantat-Elektrodenträgern im Meerschweinchen-Modell mittels Histologie, Impedanzmessung und Elektrophysiologie
Full text linkNierentransplantation zur Verbesserung der durch eine chronische Niereninsuffizienz verursachte Herzfunktionsstörung im Rattenmodell
Full text linkBackground: Chronic kidney disease (CKD) causes congestive heart failure (CHF) with systolic dysfunction and left ventricular hypertrophy (LVH), which is a major contributor to increased mortality in CKD patients. It remains unclear whether cardiovascular changes that occur during the course of CKD can be reversed when renal function is restored by transplantation.
Methods: To investigate this, chronic kidney disease was established in F344 rats by subtotal nephrectomy (SNx) for 8 weeks, followed by transplantation of a functional kidney from an isogenic F344 donor. SNx rats without transplantation and sham-operated animals served as controls. Renal function was assessed before and throughout the experiment. In addition, cardiac ultrasound was performed at weeks 0, 8, 12 and 16. At the end of the experiment, intra-arterial blood pressure was measured and kidneys and hearts were histologically and molecularly examined.
Results: Eight weeks after SNx, rats developed marked renal dysfunction associated with significant glomerulosclerosis and tubulointerstitial fibrosis, but also an increase in left ventricular mass. After transplantation, renal function normalized but relative heart weight and ventricular mass as assessed by ultrasound scans showed no reduction compared with SNx controls. However, left ventricular wall thickness, fractional shortening and ejection fraction was normalized by renal transplantation. At 8 weeks after kidney transplantation, cardiac expression of BNP and FGF23 was also at levels comparable to healthy controls, whereas these factors were significantly increased in SNx rats. Cardiac
fibrosis, as measured by fibronectin mRNA expression, was completely normalized, whereas cardiac fibronectin protein was still slightly but not significantly increased in transplanted animals compared to controls. In addition, the myofibroblast marker collagen 1, as assessed by immunohistochemistry, was significantly increased in SNx rats and also normalized by renal transplantation. Interestingly, CD68+ macrophages were significantly reduced in the hearts of SNx rats and in transplanted animals at slightly higher levels compared to controls.
Conclusion: Restoration of renal function by kidney transplantation normalized early cardiac changes at most functional and molecular levels, but did not completely reverse LVH. However, further studies are needed to determine whether restoration of renal function can also reverse LVH at a later time point
Untersuchung der strukturellen Plastizität hippokampaler Somatostatin exprimierender Interneurone am Tiermodell der N-methyl-D-aspartat-Rezeptor Autoimmunenzephalitis
Full text linkIn vitro Untersuchungen zur Biokompatibilität dentaler Schienenmaterialien für die additive Fertigung
Full text linkEvaluation der Toxizität der Selektiven Internen Radiotherapie (SIRT) bei Patienten mit hepatisch metastasierten Neuroendokrinen Tumoren im GEPNET-KUM Tumorzentrum und der Effektivität unter Berücksichtigung der Somatostatin-Rezeptor PET/CT
Full text linkKorrelation des Anti-Müller-Hormons in der Läufigkeit der Hündin mit der Fertilität
Full text linkDer Einfluss der orthodontischen Therapie mit selbstligierenden Brackets auf die Achsenposition der Zähne im Hinblick auf Inklination und Angulation
Full text linkSystematische Entschlüsselung kontextabhängiger Tumor-Vulnerabilitäten zur Verbesserung der Therapie kindlicher Krebserkrankungen
Full text linkEntwicklung und Anwendung analytischer Methoden zum Nachweis von Spurenelementen am Arbeitsplatz und in der Umwelt
Full text linkDer Nachweis von Spurenelementen am Arbeitsplatz und in der Umwelt ist für die Beurteilung der Exposition und einer hieraus resultierenden potenziellen Gefährdung von großer Bedeutung. Anhand der in dieser Habilitationsschrift vorgestellten Studien ist erkennbar, dass die dafür angewendeten Methoden an die jeweils vorliegenden Gegebenheiten angepasst werden müssen. Eine „One-fits-all“-Methode ist eine wünschenswerte Idealvorstellung, jedoch sind die Eigenschaften der einzelnen Spurenelemente und der Matrices z.T. sehr unterschiedlich. Gleichzeitig schreiten die technischen Möglichkeiten der Spurenelementanalytik immer weiter voran, so dass ein Nachweis auch in Microsamples, also sehr geringen Probenvolumina, möglich ist. Die hier präsentierten Ergebnisse sollen helfen, den Arbeits- und Umweltschutz zu verbessern und Zusammenhänge zwischen Exposition und Erkrankung zu verstehen. Weiterhin soll das Monitoring von Spurenelementen durch die Entwicklung neuer Methoden vereinfacht werden, damit ein möglichst breiter Zugang zu diesen Technologien erfolgen kann.The detection of trace elements in the workplace and in the environment is of great importance for assessing the exposure and the potential health effects. The studies presented in this thesis show that the methods used for this purpose must be adapted to the circumstances at hand. A one-size-fits-all method is a desirable ideal, but the properties of the individual trace elements and matrices can vary greatly. At the same time, the technical possibilities of trace element analysis are advancing rapidly, making detection possible even in very small sample volumes. The results presented here are intended to help improve occupational safety and environmental protection and to understand the links between exposure and disease. Furthermore, the development of new methods should simplify the monitoring of trace elements so that these technologies can be made as widely accessible as possible