More than 45 years of research on the effects of glucocorticoids on brain function has yielded many insights, but also left a number of longstanding questions. One conundrum has been how activation... Show moreMore than 45 years of research on the effects of glucocorticoids on brain function has yielded many insights, but also left a number of longstanding questions. One conundrum has been how activation of the structurally comparable mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) can lead to very different, or even opposite effects. It also remained unclear how the consequence of activation of a single receptor, GR, can differ from cell to cell and from situation to situation. In this thesis we have investigated two aspects of transcriptional regulation in response to glucocorticoids: the cause of MR/GR specificity, and the role of crosstalk with other transcription factors. Within the hippocampus, we found NeuroD factors to drive the specificity in corticosteroid receptor DNA binding and subsequent gene regulation, i.e. by stimulating MR signaling. We identified Jun dimerization protein 2 (Jdp2) as a stress-responsive MR-specific target gene. In a stress hormone relevant memory task, GR was suggested to act context-dependently and several novel GR target genes were detected. Further elucidation of distinct MR/GR downstream pathways will enable us to better understand the stress physiology and more specifically target aspects of glucocorticoid signaling for treatment of stress-related disorders. 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
The human brain is able to flexibly adapt its information processing capacity to meet a variety of cognitive challenges. Recent evidence suggests that this flexibility is reflected in the dynamic... Show moreThe human brain is able to flexibly adapt its information processing capacity to meet a variety of cognitive challenges. Recent evidence suggests that this flexibility is reflected in the dynamic reorganization of the functional connectome. The ascending catecholaminergic arousal systems of the brain are a plausible candidate mechanism for driving alterations in network architecture, enabling efficient deployment of cognitive resources when the environment demands them. We tested this hypothesis by analyzing both resting-state and task-based fMRI data following the administration of atomoxetine, a noradrenaline reuptake inhibitor, compared with placebo, in two separate human fMRI studies. Our results demonstrate that the manipulation of central catecholamine levels leads to a reorganization of the functional connectome in a manner that is sensitive to ongoing cognitive demands. Show less
Brown, S.B.R.E.; Slagter, H.A.; Noorden, M.S. van; Giltay, E.J.; Wee, N.J.A. van der; Nieuwenhuis, S. 2016
This dissertation explores the involvement of the locus-coeruleus-noradrenaline (LC-NE) system in both temporal attention and uncertainty processing. To this end, a number of cognitive tasks are... Show moreThis dissertation explores the involvement of the locus-coeruleus-noradrenaline (LC-NE) system in both temporal attention and uncertainty processing. To this end, a number of cognitive tasks are used (Stroop, passive viewing, attentional blink, accessory stimulus, auditory oddball) and a number of techniques are utilized (electroencephalogram [EEG], pupillometry, phsychopharmacology). Show less
In this thesis, we report on our investigations regarding the involvement of several neurotransmitter and hormonal systems in generalized social anxiety disorder (gSAD), one of the most common... Show moreIn this thesis, we report on our investigations regarding the involvement of several neurotransmitter and hormonal systems in generalized social anxiety disorder (gSAD), one of the most common psychiatric disorders. We found evidence of the involvement of serotonin, dopamine, and noradrenaline/the autonomic nervous system, but not the hypothalamic-pituitary-adrenal-axis, in the neurobiology of gSAD. As a result of our studies, we hypothesize that serotonin and dopamine function is decreased in gSAD, that there is hyperfunctioning of the autonomic nervous system, and that the other part of the stress system, the hypothalamic-pituitary-adrenal-axis function is not concordant with autonomic nervous system activation, as we saw in basal conditions, and in stress conditions following manipulation of the serotonergic system. We also think that there are indications that the female gonadal hormones also have a modulatory role in gSAD in a subgroup of women. This exploration of the neurobiology of gSAD leads to the conclusion that a variety of brain systems are involved in gSAD in a complex way.involvement of several neurotransmitter and hormonal systems in gSAD. Show less
