The structural and functional decline of the ageing human brain varies by brain region, cognitive function and individual. The underlying biological mechanisms are poorly understood. One potentially important mechanism is exposure to glucocorticoids (GCs; cortisol in humans); GC production is increasingly varied with age in humans, and chronic exposure to high levels is hypothesised to result in cognitive decline via cerebral remodelling. However, studies of GC exposure in humans are scarce and methodological differences confound cross-study comparison. Furthermore, there has been little focus on the effects of GCs on the frontal lobes and key white matter tracts in the ageing brain. This thesis therefore examines relationships among cortisol levels, structural brain measures and cognitive performance in 90 healthy, elderly community-dwelling males from the Lothian Birth Cohort 1936. Salivary cortisol samples characterised diurnal (morning and evening) and reactive profiles (before and after a cognitive test battery). Structural variables comprised Diffusion Tensor Imaging measures of major brain tracts and a novel manual parcellation method for the frontal lobes. The latter was based on a systematic review of current manual methods in the context of putative function and cytoarchitecture. Manual frontal lobe brain parcellation conferred greater spatial and volumetric accuracy when compared to both single- and multi-atlas parcellation at the lobar level. Cognitive ability was assessed via tests of general cognitive ability, and neuropsychological tests thought to show differential sensitivity to the integrity of frontal lobe sub-regions. The majority of, but not all frontal lobe test scores shared considerable overlap with general cognitive ability, and cognitive scores correlated most consistently with the volumes of the anterior cingulate. This is discussed in light of the diverse connective profile of the cingulate and a need to integrate information over more diffuse cognitive networks according to proposed de-differentiation or compensation in ageing. Individuals with higher morning, evening or pre-test cortisol levels showed consistently negative relationships with specific regional volumes and tract integrity. Participants whose cortisol levels increased between the start and end of cognitive testing showed selectively larger regional volumes and lower tract diffusivity (correlation magnitudes <.44). The significant relationships between cortisol levels and cognition indicated that flatter diurnal slopes or higher pre-test levels related to poorer test performance. In contrast, higher levels in the morning generally correlated with better scores (correlation magnitudes <.25). Interpretation of all findings was moderated by sensitivity to type I error, given the large number of comparisons conducted. Though there were limited candidates for mediation analysis, cortisol-function relationships were partially mediated by tract integrity (but not sub-regional frontal volumes) for memory and post-error slowing. This thesis offers a novel perspective on the complex interplay among glucocorticoids, cognition and the structure of the ageing brain. The findings suggest some role for cortisol exposure in determining age-related decline in complex cognition, mediated via brain structure.

Research conducted over the past two decades has contributed a wealth of new knowledge to the field's understanding of stress effects on memory. It has been widely demonstrated that stress can either facilitate or impair memory, depending on 1) the phase of memory processing influenced by stress hormones and 2) the valence or arousing nature of the encoded information. It has also been reported that, when stress levels are significantly elevated at encoding, emotional memory is preserved (or enhanced) while memory for non-emotional information is impaired. These effects have been discussed at the neurobiological level with respect to the stress hormone, cortisol, and the impairing and facilitating modulatory effects it has on regions of the brain involved in emotional learning and memory. Whether diurnal shifts in basal levels of cortisol modulate these effects remains unknown. Additionally, it remains unknown whether enhancing and impairing effects of stress on memory result in memory traces that are more or less open to alteration by subsequent experiences, such as observed in the so-called "misinformation" effect.The current dissertation aimed to investigate the effects of stress on encoding of thematically negatively arousing and non-emotional events, composed of negatively arousing and neutral stimuli. Our goal in using more complex materials, in lieu of stimuli (e.g. word lists, images) traditionally used in studies of emotion and memory, was to examine the effects of stress on encoding of information more representative of a real-world event. Within this framework we examined 1) the effects of basal cortisol levels on stress modulation of memory encoding, and 2) the integration of subsequent misinformation on memory for negatively arousing versus non-arousing events encoded under stress. The research included in this dissertation aims to further the field's current understanding of the effects of stress on memory processes. Findings are relevant to the literature on traumatic memory, eyewitness testimony, and the effects of moderate to severe emotion on long-term episodic memory.

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Kynurenine (KYN) is the first stable metabolite of the kynurenine pathway, which accounts for over 95% of tryptophan metabolism. Two previous studies by this research group reported elevated plasma KYN in Tourette syndrome (TS) patients when compared with age and sex matched controls and another study showed that KYN potentiated 5-HT2A-mediated head-shakes (HS) in rodents. These movements have been suggested to model tics in TS. This raised the questions how KYN acts in eliciting this response and whether it is an action of its own or of a further metabolite along the kynurenine pathway. In the liver, where most of the kynurenine pathway metabolism takes place under physiological conditions, the first and the rate limiting enzyme is tryptophan-dioxygenase (TDO) which can be induced by cortisol. In extrahepatic tissues the same step of the pathway is catalyzed by indoleamine-dioxygenase (IDO), which is induced by cytokines, predominantly interferon-y (INF-y). Plasma neopterin, which shows parallel increase with KYN following immune stimulation, was also found elevated in one of these studies positively correlating with KYN. In the present work animal studies suggested that KYN potentiates and quinolinic acid (QUINA) dose dependently inhibits the 5-HT2A-mediated HS response in mice. The potentiating effect seen with KYN was suggested to be an effect of KYN itself. Radioligand binding and phosphoinositide (PI) hydrolysis studies were done to explore the mechanisms by which kynurenine pathway metabolites could alter a 5-HT2A-receptor mediated response. None of the kynurenine pathway metabolites tested showed direct binding to 5-HT2A-receptors. PI hydrolysis studies with KYN and QUINA showed that KYN did not have any effect while QUINA inhibited 5-HT2A-mediated PI hydrolysis. Plasma cortisol determination in TS patients with elevated plasma KYN did not show elevated plasma cortisol levels, suggesting that the increase of plasma KYN in these TS patients is unlikely to be due to an increased TDO activity induced by increased cortisol. Attention deficit hyperactivity disorder (ADHD) is commonly associated with TS. Salivary cortisol detected in a group of children primarily affected with ADHD showed significantly lower salivary cortisol levels when compared with age and sex matched controls. Plasma tryptophan, KYN, neopterin, INF-y and KYN/tryptophan ratio and night-time urinary 6-sulphatoxymelatonin (aMT6s) excretion measured in a group of TS patients did not show any difference in their levels when compared with age and sex matched controls, but TS patients failed to show the expected positive correlation seen between plasma INF-y, neopterin and KYN and the negative correlation seen between plasma KYN and night-time urinary aMT6s excretion seen in healthy controls. The relevance of the kynurenine pathway, melatonin secretion and cortisol to Tourette Syndrome and associated conditions and the mechanism by which KYN and QUINA alter the 5-HT2A-receptor mediated HS response are discussed.

Abstract EXAMINATION OF BASAL NEUROENDOCRINE LEVELS IN OIF/OEF/OND VETERANS By Sage E. Hawn, B.S. A thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. Virginia Commonwealth University, 2015. Major Director: Ananda B. Amstadter, PhD. Associate Professor Departments of Psychiatry, Psychology, & Human and Molecular Genetics High rates of combat exposure exist among veterans of the recent conflicts, and are associated with debilitating mental health conditions, including posttraumatic stress disorder (PTSD). Numerous psychosocial and biologic factors are associated with PTSD, including the HPA-axis. The present study aimed to compare baseline neuroendocrine levels by trauma group (PTSD, trauma exposed [TE], and non-trauma controls [NTC]) among a sample of young veterans. An exploratory aim was to examine potential moderators of the relation between PTSD and basal cortisol/ACTH. Group differences in cortisol were nominally significant, with the NTC group having significantly higher cortisol than the PTSD group. Sleep disturbance was the only moderator of this relationship in cortisol, although lifetime trauma load significantly predicted basal cortisol across all models. No significant effects were demonstrated for ACTH. Examining effects of trauma on basal physiology provides a critical stepping ground for future investigations that may inform targeted prevention and intervention efforts.

Contemporary understanding of the brain indicates that a reciprocal relationship exists between mind and body. Biological functioning adjusts to the consequences of our behavior and our behavior is influenced by our biology. This is the case with the stress responsivity system. The stress hormone cortisol follows a biologically-predetermined daily cycle of secretion (controlled by circadian rhythm) that correlates with expected activity throughout the day, however this cycle can accommodate to different environmental changes that can occur. It has been noticed that individuals who report stress problems also report sleep problems. I hypothesized that sleep quality can predict maladjustments in cortisol’s rhythm. All participants provided saliva samples and had to take the Pittsburgh Sleep Quality Index (PSQI). Salivivay cortisol was measured via was enzyme-immuno-assayed for cortisol. I analyzed the data for three independent studies: (1)12 samples were taken for basal and lab days in 65 individuals. People who scored worse in total PSQI showed decreased stress reactivity (γ 21=-.02, t(63)=-2.27, p=0.026) and faster recovery (γ31=-0.102, t(608)=-2.044, p=0.041). (2)6-8 samples per day across 5 days in 120 maltreated or control adolescents. I used a 3-level hierarchical linear model to examine rhythms within each day and within each individual. The cortisol rhythm was flattened on days when adolescents had poor sleep latency (β;=.013, p=.025 for time-since-waking, β=-.0008, p=.039 for quadratic time-since-waking). (3) 10 samples were taken in 44 skydivers for jumping and basal days. Those who scored worse in sleep latency had slower reactivity (γ31=-0.16, t(284)=-3.701, p<.001) and slower recovery (γ31=0.22, t(284)=3.311, p<0.001). Stress and sleep problems are related to cognitive and physiological issues; finding an appropriate connection between them can be elemental in preventing problems.

Stress often precedes the onset of physical and mental health disorders, leading to costly and extended disability and even increased risk for death. I investigate psychosocial and endocrine precursors to stress responses, specifically examining the causal effects of status-relevant factors that modulate endocrine, affective, and behavioral responses to social-evaluative stressors. For example, while high social status reduces stress responses in numerous species, this stress-buffering effect of status may dissipate or even reverse during times of hierarchical instability. Similarly, some research links testosterone to reduced stress system activity, but correlational research indicates that higher testosterone is related to increased stress responses in threatening social situations. In each case, the causal influence of these psychosocial (status and hierarchy stability) and endocrine (testosterone) antecedents to stress responses was unclear. Results from this work (Chapter 2) reveal that high status in a stable hierarchy buffered stress responses and improved behavioral responses to the stressor, but high status in an unstable hierarchy boosted stress responses and did not lead to better performance. This general pattern of effects was observed across endocrine (cortisol and testosterone), psychological (feeling in control), and behavioral (competence, dominance, and warmth) responses to the stressor. Further (Chapters 4 & 6), exogenous testosterone treatment caused increased motivated persistence – which can help persevere through stressful encounters – but, once exposed to a stressor, testosterone caused increased cortisol reactivity, increased negative affect, and decreased motivation in response to social-evaluative stress, especially for individuals high in trait dominance. This work provides evidence of the causal effects of psychosocial and endocrine factors on stress responses and demonstrates the importance of considering these status-relevant precursors when investigating stress within social contexts.

Cortisol is one of the stress hormones produced as a result of stimulus to the hypothalamus triggering the hypothalamic-pituitary-adrenal axis (HPA).The result of cortisol production after this trigger is to return the body and its relevant systems back to homeostasis. This is a desired state of physiologic equilibrium in the body. A number of physiological and environmental conditions trigger the HPA pathway. This includes hypoglycemia (low blood sugar), dehydration (low blood volume), exercise, which are considered stress triggers, and changes to the circadian cycle. It is no wonder then that extreme diet and exercise can impact the HPA axis due to the stress caused by such activities or lifestyle choices. Fortunately, the production of cortisol in response to exercise has been extensively studied. Generally, studies have shown that the level of plasma cortisol levels increase proportionally during high intensity exercise, while a general decrease has been observed during moderate or low intensity exercise (Davis & Few, 1973). In addition, several scientific texts provide substantial information on the correlation between hypoglycemia and cortisol synthesis. This information in addition to other sources has proven useful for assessing the effect of extreme dieting on cortisol production. The aim of this thesis is to expand on the changes in cortisol caused by extreme exercise and diet as well as elaborate on the physiological effects that these cortisol levels in turn may have.

Orientador: Simon Biagio Chiacchio / Banca: Roberto Calderon Gonçalves / Banca: Rogério Martins Amorim / Banca: José Giometti / Banca: Laurenil Gaste / Resumo: O objetivo do experimento foi avaliar o efeito de diferentes suplementações com selênio (Se) sobre a resposta imune humoral anti-rábica, na concentração sérica de selênio e cortisol em bovinos. Utilizou-se sessenta bovinos machos não castrados da raça Nelore, com 10 a 12 meses de idade, alimentados com pastagem de Brachiaria decumbens. Os animais foram divididos em 4 grupos (N=15) sendo que o primeiro deles não receberam suplementação (Gc) e os outros três suplementados diariamente e individualmente com concentrações de Se de 3,6 mg (G3,6), 5,4 mg (G5,4) ou 6,4 mg (G6,4). Os animais foram imunizados no dia zero com uma dose de vacina anti-rábica comercial, líquida e inativada. Nos dias zero, 15, 30, 60, 90 e 120 durante os quais submetidos ao estresse de manejo no curral e colheita de sangue. As amostras de sangue foram colhidas depois da vacinação e depois de serem submetidos ao estresse para determinação da concentração sérica de selênio, títulos de anticorpos anti-rábicos e cortisol sérico. A concentração de selênio também foi determinada nas amostras das forrageiras colhidas dos piquetes utilizados pelos bovinos. A concentração de Se na B. decumbens foi de 0,04 mg de Se/Kg de matéria seca. A concentração sérica de Se obtida no dia zero no grupo Gc era mais elevada que nos grupos G5,4 e G6,4 (P= 0,005). A concentração sérica de Se diminuiu ao longo do experimento no Gc (P<0,004), aumentou no G3,6 (P<0,000) e no grupo G5,4 (P<0,000), entretanto, no grupo G6,4 aumentou no dia 60 (P<0,002). Os títulos de anticorpos anti-rábicos não diferiram entre os grupos tratados ou não com selênio. Entretanto, 120 dias após a vacinação os títulos de anticorpos no grupo G3,6 permaneceram acima do mínimo considerado protetor (=0,5 UI/mL) (P<0,000), enquanto que nos outros grupos permaneceram baixos (P<0,05). A concentração sérica de cortisol dos bovinos... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: This study evaluated the effect of different concentrations of selenium (Se) supplementation on cattle antirabies humoral immune response, serum Se concentrations and cortisol levels. Sixty uncastrated male Nelore calves from 10 to 12 months grazing on Brachiaria decumbens forage were studied. The animals were assigned to one of four groups (N=15 each), which received nonsupplemented diets (Gc) or supplemented with daily and individual Se concentrations of 3.6 mg (G3.6), 5.4 mg (G5.4) or 6.4 mg (G6.4). The animals were immunized on day 0 with one dose of commercial liquid inactivated rabies vaccination. On days 15, 30, 60, 90 and 120, the cattle underwent the same stressing procedures used for vaccination in the corral. Cattle blood samples were collected after vaccination and stressing procedures to determine serum Se levels, rabies antibody titers and serum cortisol. Se levels were also determined in forage samples collected from the paddocks in which the cattle were held. Se concentration in B. decumbens was 0.04 mg of Se/Kg dry matter. Baseline Se levels obtained on day 0 were higher in Gc than in G5.4 and G6.4 (P= 0.005). Serum Se levels decreased in Gc throughout the experiment (P<0.004), increased in G3.6 (P<0.000) and G5.4 (P<0.000) and were kept high from day 60 on in group G6.4 (P<0.002). Rabies antibody titers did not differ between control and supplemented groups. However, 120 post-vaccination rabies antibody titers were kept above the protecti ve levels (=0.5 UI/mL) only in group G3.6 (P<0.00002), whereas they dropped in the other groups (P<0.05). Serum cortisol levels did not differ among the experimental groups (P=0.79), reached peak levels on day 90 and returned close to baseline levels on day 120. Se and cortisol levels were not markedly correlated. Serum cortisol and rabies antibody titers were correlated only in group G6.4, on day 60 (R=0.513; P=0.05)... (Complete abstract click electronic access below) / Doutor

Fishers (Pekania pennanti) are a species of concern in the Sierra Nevada Mountains of California. Cortisol is a glucocorticoid hormone released to mobilize energy in response to stress and has been used as an indication of an individual’s physiological response to its environment. By collecting samples of fisher hair and measuring an individual’s cortisol, we examined the physiological stress response of the animals to human disturbances (housing density, road density, habitat type, and silvicultural treatements) and drought (tree mortality) in their home ranges. Using AICc model selection, we found that levels of tree mortality within a fisher’s home range significantly influenced cortisol levels. Various human disturbances had a smaller effect on cortisol levels. Furthermore, we examined the relationship between cortisol and fitness through the metrics of body condition, female kit counts, and survival. We found that females with low cortisol had significantly higher survival rates than females with medium and high cortisol. With the recent drought, bark beetle infestation and subsequent tree mortality being >80% in some areas of our study, cortisol levels could continue to increase, potentially leading to further decreased fitness within this fisher population. We also examined the difference in habitat selection between the core and entirety of the home ranges and found that fishers prefer late-successional forest in the core of their home ranges.