Neurodegenerative diseases are hallmarked by protein inclusions and cell loss in disease-related brain regions, but the molecular mechanisms that lead to the pathological and symptomatic hallmarks... Show moreNeurodegenerative diseases are hallmarked by protein inclusions and cell loss in disease-related brain regions, but the molecular mechanisms that lead to the pathological and symptomatic hallmarks of neurodegeneration are still not fully understood. In this thesis, we make use of bioinformatics approaches to analyze a high-resolution spatial gene expression atlas of the healthy human brain generated by the Allen Institute of Brain Science. Spatial transcriptomics allows examining the molecular and functional organization of the human brain and can be combined with neuroimaging data to identify brain regions and anatomical structures that are vulnerable to cell loss in neurodegenerative diseases. By combining both data modalities, we examined healthy molecular functions in brain regions associated with disease vulnerability based on neuroimaging features, namely gray matter loss within brain networks in individuals with Parkinson’s disease, Huntington’s disease, and individuals at risk of schizophrenia. With this thesis, we have shown that by applying data-driven computational methods we can explore the whole genome and find gene expression patterns informative of regional brain vulnerability in neurodegenerative diseases. Our methods can similarly be applied to unravel the molecular mechanisms in other neurodegenerative diseases, and potentially even reveal shared mechanisms between neurological disorders. Show less
In this thesis, we have studied the potential of the zebrafish larval model in studying the ECS, as a complementary model to the existing rodent models. More specifically, we have looked at the... Show moreIn this thesis, we have studied the potential of the zebrafish larval model in studying the ECS, as a complementary model to the existing rodent models. More specifically, we have looked at the role of the ECS in regulating locomotion and anxiety, and its interaction with the hypothalamic-pituitary-interrenal (HPI) axis, or stress axis. This study has provided us with an interesting animal model which allows for pharmacological screening of Cnr1 agonists, and their involvement in the CNS, as shown by a change in locomotion, anxiety-like behavior and HPI axis activity. The zebrafish larval model can be used as a complementary model to the existing rodent animal models, to study the ECS. The zebrafish larval model brings several interesting features, such as optical transparency and possibilities for high-throughput screening. Furthermore, a complete ECS is present, there is lack of endogenous activity, allowing for exogenous compound screening, and zebrafish data is generally in line with rodent literature. Since the ECS is involved in many diseases, more research of this system may result in the discovery of novel drugs and drug targets. Show less
The locus coeruleus, a small brainstem nucleus, is the main source of the chemical norepineprine in the brain and is involved in a number of cognitive functions as well as several neurological and... Show moreThe locus coeruleus, a small brainstem nucleus, is the main source of the chemical norepineprine in the brain and is involved in a number of cognitive functions as well as several neurological and psychiatric disorders. In this dissertation we study the human LC-NE system, the anatomy of this tiny brainstem nucleus and the involvement of the LC-NE system in stress, arousal, cognitive flexibility and physiology (hormones & pupil responses). To date, the LC-NE system has been studied in animals or ex vivo (dead donors). This dissertation is among the first ones to study and visualize the LC-NE system in humans in vivo (alive volunteers) and to approach the human cognition and the study of the LC-NE system in a holistic manner: from central neuromodulators to hormones that are secreted in the body, from anatomy to physiology and cognition. To this end, all chapters were written by taking into consideration theoretical knowledge about the LC-NE system with regard to brain anatomy, cognitive functions, neuromodulation, physiological responses, and clinical applications. Chapters 2 and 3 deal mainly with the anatomy of the LC, while Chapters 4, 5 and 6 concentrate on cognition and human physiology. Additionally Chapters 5 and 6 take also a clinical approach. Show less
