Neuroreceptor imaging of mood disorder related systems

Hoogendijk, W.J.G. [Promotor]Lammertsma, A.A. [Promotor]Veltman, D.J. [Promotor]Boellaard, R. [Copromotor

In vitro studies of the role of mechanical cues in skeletal patterning and differentiation

Smit, T.H. [Promotor]Mooney, D.J. [Promotor

Beyond random and forbidden interactions in plant-pollinator networks : how optimizing energy gain results in morphological matching among subalpine Asteraceae and their flower-visitors

Plants and their pollinators form complex interaction networks. Within these networks, species differ widely in the number of species they interact with. These interaction patterns are important aspects in pollination ecology, since it influences species coexistence and community stability. An in-depth understanding of the mechanisms behind plant-pollinator interactions is thus important to predict the dependency of species on each other and responses of plant-pollinator communities to (global) changes, such as the introduction of invasive species and climate change. In this study, I investigated whether flower abundance, flower morphology (nectar tube depth and flower display area), nectar production and pollinator foraging efficiency can predict plant-pollinator interaction patterns and the stability of these interactions. This study shows that flower density might be less important for structuring plant-pollinator interactions. Pollinators do not forage randomly. Rather flower morphology, nectar production and pollinator foraging efficiency are important aspects that determine interaction patterns, including species generalization degree and matching between flower nectar tube depth and pollinator proboscis length (size-matching). Although plant species with deeper flowers are more specialized, they are visited by pollinator species which, locally, fluctuate less across years. Thus, specialized plants might be less vulnerable to yearly fluctuations in plant-pollinator communities than often assumed. Leids Universiteits Fonds; Stichting Fonds Doctor Catharine van Tussenbroek; Stichting Fonds Dr. Christine BuismanPlant science

Novel approaches in clinical development of cannabinoid drugs

The endocannabinoid system has only been discovered during the last few decades, and scientific progress in understanding the relevance of this system in health and disease has been limited and slow. CB1 antagonists were considered a __miracle drug__ for the treatment of obesity and smoking with __blockbuster__ potential. But due to central side effects (such as depression and suicidal behaviour) and a lack of systematic clinical pharmacologic research, market access of a CB1 antagonists failed. In this thesis, we explored some improvements in the early development of cannabinoids, and by systematically investigating, we found that the new cannabinoid antagonist TN38837 seems effective with a reduced propensity for central side effects, and that a new oral THC formulation enhances the pharmacological activities by its seemingly superior pharmacokinetics. Also, we experiment with new methodology to optimise effect measurement, including resting state-FMRI which we found suitable for early phase cannabinoid research, and including new concentration-effect models to improve the simulation and prediction of future studies. The research in this thesis shows that a revival of research on the cannabinoid system requires novel approaches to the administration of cannabinoids, to the measurements and the study designs, and to the analyses of the effects. This reflects the complexity of the highly integrated endocannabinoid system, but also sets the stage for other innovative drug development programsUBL - phd migration 201

The neurocomputational link between defensive cardiac states and approach-avoidance arbitration under threat

Avoidance, a hallmark of anxiety-related psychopathology, often comes at a cost; avoiding threat may forgo the possibility of a reward. Theories predict that optimal approach-avoidance arbitration depends on threat-induced psychophysiological states, like freezing-related bradycardia. Here we used model-based fMRI analyses to investigate whether and how bradycardia states are linked to the neurocomputational underpinnings of approach-avoidance arbitration under varying reward and threat magnitudes. We show that bradycardia states are associated with increased threat-induced avoidance and more pronounced reward-threat value comparison (i.e., a stronger tendency to approach vs. avoid when expected reward outweighs threat). An amygdala-striatal-prefrontal circuit supports approach-avoidance arbitration under threat, with specific involvement of the amygdala and dorsal anterior cingulate (dACC) in integrating reward-threat value and bradycardia states. These findings highlight the role of human freezing states in value-based decision making, relevant for optimal threat coping. They point to a specific role for amygdala/dACC in state-value integration under threat

Childhood abuse and deprivation are associated with distinct sex-dependent differences in brain morphology

Childhood adversity (CA) has been associated with long-term structural brain alterations and an increased risk for psychiatric disorders. Evidence is emerging that subtypes of CA, varying in the dimensions of threat and deprivation, lead to distinct neural and behavioral outcomes. However, these specific associations have yet to be established without potential confounders such as psychopathology. Moreover, differences in neural development and psychopathology necessitate the exploration of sexual dimorphism. Young healthy adult subjects were selected based on history of CA from a large database to assess gray matter (GM) differences associated with specific subtypes of adversity. We compared voxel-based morphometry data of subjects reporting specific childhood exposure to abuse (n = 127) or deprivation (n = 126) and a similar sized group of controls (n = 129) without reported CA. Subjects were matched on age, gender, and educational level. Differences between CA subtypes were found in the fusiform gyrus and middle occipital gyms, where subjects with a history of deprivation showed reduced GM compared with subjects with a history of abuse. An interaction between sex and CA subtype was found. Women showed less GM in the visual posterior precuneal region after both subtypes of CA than controls. Men had less GM in the postcentral gyms after childhood deprivation compared with abuse. Our results suggest that even in a healthy population, CA subtypes are related to specific alterations in brain structure, which are modulated by sex. These findings may help understand neurodevelopmental consequences related to C

The Effect of Growth-Mimicking Continuous Strain on the Early Stages of Skeletal Development in Micromass Culture

Embryonic skeletogenesis involves proliferation, condensation and subsequent chondrogenic differentiation of mesenchymal precursor cells, and the strains and stresses inherent to these processes have been hypothesized to influence skeletal development. The aim of this study was to determine the effect of growth-mimicking strain on the process of early skeletal development in vitro. To this end, we applied continuous uniaxial strain to embryonic skeletal precursor cells in micromass culture. Strain was applied at different times of culture to specifically address the effect of mechanical loading on the sequential stages of cellular proliferation, condensation and differentiation. We found that growth-mimicking strain at all three times did not affect proliferation or chondrogenic differentiation under the tested conditions. However, the timing of the applied strain did play a role in the density of mesenchymal condensations. This finding suggests that a mechanically dynamic environment, and specifically strain, can influence skeletal patterning. The growth-mimicking micromass model presented here may be a useful tool for further studies into the role of mechanical loading in early skeletal development