Every day we are exposed to a large set of appetitive food cues, mostly of high caloric, high carbohydrate content. Environmental factors like food cue exposition can impact eating behavior, by triggering anticipatory endocrinal responses and reinforcing the reward value of food. Additionally, it has been shown that eating behavior is largely influence by neuroendocrine factors. Energy homeostasis is of great importance for survival in all animal species. It is challenged under the state of food deprivation which is considered to be a metabolic stressor. Interestingly, the systems regulating stress and food intake share neural circuits. Adrenal glucocorticoids, as cortisol, and the pancreatic hormone insulin have been shown to be crucial to maintain catabolic and anabolic balance. Cortisol and insulin can cross the blood-brain barrier and interact with receptors distributed throughout the brain, influencing appetite and eating behavior. At the same time, these hormones have an important impact on the stress response. The aim of the current work is to broaden the knowledge on reward related food cue processing. With that purpose, we studied how food cue processing is influenced by food deprivation in women (in different phases of the menstrual cycle) and men. Furthermore, we investigated the impact of the stress/metabolic hormones, insulin and cortisol, at neural sites important for energy metabolism and in the processing of visual food cues. The Chapter I of this thesis details the underlying mechanisms of the startle response and its application in the investigation of food cue processing. Moreover, it describes the effects of food deprivation and of the stress-metabolic hormones insulin and cortisol in reward related processing of food cues. It explains the rationale for the studies presented in Chapter II-IV and describes their main findings. A general discussion of the results and recommendations for future research is given. In the study described in Chapter II, startle methodology was used to study the impact of food deprivation in the processing of reward related food cues. Women in different phases of the menstrual cycle and men were studied, in order to address potential effects of sex and menstrual cycle. All participants were studied either satiated or food deprived. Food deprivation provoked enhanced acoustic startle (ASR) response during foreground presentation of visual food cues. Sex and menstrual cycle did not influence this effect. The startle pattern towards food cues during fasting can be explained by a frustrative nonreward effect (FNR), driven by the impossibility to consume the exposed food. In Chapter III, a study is described, which was carried out to explore the central effects of insulin and cortisol, using continuous arterial spin labeling to map cerebral blood flow patterns. Following standardized periods of fasting, male participants received either intranasal insulin, oral cortisol, both, or placebo. Intranasal insulin increased resting regional cerebral blood flow in the putamen and insular cortex, structures that are involved in the regulation of eating behavior. Neither cortisol nor interaction effects were found. These results demonstrate that insulin exerts an action in metabolic centers during resting state, which is not affected by glucocorticoids. The study described in Chapter IV uses a similar pharmacological manipulation as the one presented in Chapter III, while assessing processing of reward related food cues through the startle paradigm validated in Chapter II. A sample of men was studied during short-term food deprivation. Considering the importance of both cortisol and insulin in glucose metabolism, food pictures were divided by glycemic index. Cortisol administration enhanced ASR during foreground presentation of "high glycemic" food pictures. This result suggests that cortisol provokes an increase in reward value of high glycemic food cues, which is congruent with previous research on stress and food consumption. This thesis gives support to the FNR hypothesis towards food cues during states of deprivation. Furthermore, it highlights the potential effects of stress related hormones in metabolism-connected neuronal structures, and in the reward related mechanisms of food cue processing. In a society marked by increased food exposure and availability, alongside with increased stress, it is important to better understand the impact of food exposition and its interaction with relevant hormones. This thesis contributes to the knowledge in this field. More research in this direction is needed.

Cortisol exhibits typical ultradian and circadian rhythm and disturbances in its secretory pattern have been described in stress-related pathology. The aim of this thesis was to dissect the underlying structure of cortisol pulsatility and to develop tools to investigate the effects of this pulsatility on immune cell trafficking and the responsiveness of the neuroendocrine system and GR target genes to stress. Deconvolution modeling was set up as a tool for investigation of the pulsatile secretion underlying the ultradian cortisol rhythm. This further allowed us to investigate the role of the single cortisol pulses on the immune cell trafficking and the role of induced cortisol pulses on the kinetics of expression of GR target genes. The development of these three tools, would allow to induce and investigate in future the significance of single cortisol pulses for health and disease.

The stress hormone cortisol as the end-product of the hypothalamic-pituitary-adrenal (HPA) axis has been found to play a crucial role in the release of aggressive behavior (Kruk et al., 2004; Böhnke et al., 2010). In order to further explore potential mechanisms underlying the relationship between stress and aggression, such as changes in (social) information processing, we conducted two experimental studies that are presented in this thesis. In both studies, acute stress was induced by means of the Socially Evaluated Cold Pressor Test (SECP) designed by Schwabe et al. (2008). Stressed participants were classified as either cortisol responders or nonresponders depending on their rise in cortisol following the stressor. Moreover, basal HPA axis activity was measured prior to the experimental sessions and EEG was recorded throughout the experiments. The first study dealt with the influence of acute stress on cognitive control processes. 41 healthy male participants were assigned to either the stress condition or the non-stressful control procedure of the SECP. Before as well as after the stress induction, all participants performed a cued task-switching paradigm in order to measure cognitive control processes. Results revealed a significant influence of acute and basal cortisol levels, respectively, on the motor preparation of the upcoming behavioral response, that was reflected in changes in the magnitude of the terminal Contingent Negative Variation (CNV). In the second study, the effect of acute stress and subsequent social provocation on approach-avoidance motivation was examined. 72 healthy students (36 males, 36 females) took part in the study. They performed an approach-avoidance task, using emotional facial expressions as stimuli, before as well as after the experimental manipulation of acute stress (again via the SECP) and social provocation realized by means of the Taylor Aggression Paradigm (Taylor, 1967). Additionally to salivary cortisol, testosterone samples were collected at several points in time during the experimental session. Results indicated a positive relationship between acute testosterone levels and the motivation to approach social threat stimuli in highly provoked cortisol responders. Similar results were found when the testosterone-to-cortisol ratio at baseline was taken into account instead of acute testosterone levels. Moreover, brain activity during the approach-avoidance task was significantly influenced by acute stress and social provocation, as reflected in reductions of early (P2) as well as of later (P3) ERP components in highly provoked cortisol responders. This may indicate a less accurate, rapid processing of socially relevant stimuli due to an acute increase in cortisol and subsequent social provocation. In conclusion, the two studies presented in this thesis provide evidence for significant changes in information processing due to acute stress, basal cortisol levels and social provocation, suggesting an enhanced preparation for a rapid behavioral response in the sense of a fight-or-flight reaction. These results confirm the model of Kruk et al. (2004) proposing a mediating role of changed information processes in the stress-aggression-link.

There is a lot of evidence for the impact of acute glucocorticoid treatment on hippocampus-dependent explicit learning and memory (memory for facts and events). But there have been few studies, investigating the effect of glucocorticoids on implicit learning and memory. We conducted three studies with different methodology to investigate the effect of glucocorticoids on different forms of implicit learning. In Study 1, we investigated the effect of cortisol depletion on short-term habituation in 49 healthy subjects. 25 participants received oral metyrapone (1500 mg) to suppress endogenous cortisol production, while 24 controls received oral placebo. Eye blink electromyogram (EMG) responses to 105 dB acoustic startle stimuli were assessed. Effective endogenous cortisol suppression had no effect on short-term habituation of the startle reflex, but startle eye blink responses were significantly increased in the metyrapone group. The latter findings are in line with previous human studies, which have shown that excess cortisol, sufficient to fully occupy central nervous system (CNS) corticosteroid receptors, may reduce startle eye blink. This effect may be mediated by CNS mechanisms controlling cortisol feedback. In Study 2, we investigated delay or trace eyeblink conditioning in a patient group with a relative hypocortisolism (30 patients with fibromyaligia syndrome/FMS) compared to 20 healthy control subjects. Conditioned eyeblink response probability was assessed by EMG. Morning cortisol levels, ratings of depression, anxiety and psychosomatic complaints as well as general symptomatology and psychological distress were assessed. As compared to healthy controls FMS patients showed lower morning cortisol levels, and trace eyeblink conditioning was facilitated whereas delay eyeblink conditioning was reduced. Cortisol measures correlate significantly only with trace eyeblink conditioning. Our results are in line with studies of pharmacologically induced hyper- and hypocortisolism, which affected trace eyeblink conditioning. We suggest that endocrine mechanisms affecting hippocampus-mediated forms of associative learning may play a role in the generation of symptoms in these patients.rnIn Study 3, we investigated the effect of excess cortisol on implicit sequence learning in healthy subjects. Oral cortisol (30 mg) was given to 29 participants, whereas 31 control subjects received placebo. All volunteers performed a 5-choice serial reaction time task (SRTT). The reaction speed of every button-press was determined and difference-scores were calculated as a proof of learning. Compared to the control group, we found a delayed learning in the cortisol group at the very beginning of the task. This study is the first human investigation, indicating impaired implicit memory function after exogenous administration of the stress hormone cortisol. Our findings support a previous neuroimaging study, which suggested that the medial temporal lobe (including the hippocampus) is also active in implicit sequence learning, but our results may also depend on the engagement of other brain structures.

During pregnancy every eighth woman is treated with glucocorticoids. Glucocorticoids inhibit cell division but are assumed to accelerate the differentiation of cells. In this review animal models for the development of the human fetal and neonatal hypothalamic-pituitary-adrenal (HPA) axis are investigated. It is possible to show that during pregnancy in humans, as in most of the here-investigated animal models, a stress hyporesponsive period (SHRP) is present. In this period, the fetus is facing reduced glucocorticoid concentrations, by low or absent fetal glucocorticoid synthesis and by reduced exposure to maternal glucocorticoids. During that phase, sensitive maturational processes in the brain are assumed, which could be inhibited by high glucocorticoid concentrations. In the SHRP, species-specific maximal brain growth spurt and neurogenesis of the somatosensory cortex take place. The latter is critical for the development of social and communication skills and the secure attachment of mother and child. Glucocorticoid treatment during pregnancy needs to be further investigated especially during this vulnerable SHRP. The hypothalamus and the pituitary stimulate the adrenal glucocorticoid production. On the other hand, glucocorticoids can inhibit the synthesis of corticotropin-releasing hormone (CRH) in the hypothalamus and of adrenocorticotropic hormone (ACTH) in the pituitary. Alterations in this negative feedback are assumed among others in the development of fibromyalgia, diabetes and factors of the metabolic syndrome. In this work it is shown that the fetal cortisol surge at the end of gestation is at least partially due to reduced glucocorticoid negative feedback. It is also assumed that androgens are involved in the control of fetal glucocorticoid synthesis. Glucocorticoids seem to prevent masculinization of the female fetus by androgens during the sexual gonadal development. In this work a negative interaction of glucocorticoids and androgens is detectable.