This paper describes two experiments, each of which investigated the impact of stress on human episodic memory. All participants watched narrated slide shows containing emotional and neutral information. Experiment 1 demonstrated that pre-learning exposure to a psychological stressor (the Trier Social Stress Test or "TSST"; Kirschbaum, Pirke & Hellhammer, 1993) preserved or enhanced memory for emotional aspects of the slide show, but impaired memory for neutral aspects of the slide show. Moreover, stress exposure disrupted memory for information that was visually and thematically central to the slide show. Memory for peripheral information, on the other hand, was unaffected by stress. Experiment 2 replicated these results and extended them to a similar paradigm, where participants viewed separate emotional and neutral slide shows, and saliva was tested for the stress hormones cortisol and norepinephrine. Similar to the results of Experiment 1, stress disrupted memory for the neutral slide show, but enhanced memory for the emotional slide show. Salivary cortisol levels at retrieval were negatively correlated with memory for the neutral slide show. These results are consistent with theories invoking differential effects of stress on brain systems responsible for encoding and retrieving emotional memories (the amygdala) and non-emotional memories (e.g. the hippocampal formation, frontal cortex), and inconsistent with the view that memories formed under high levels of stress are qualitatively the same as those formed under ordinary emotional circumstances. These data, which are also consistent with results obtained in a number of studies using animals and humans, have implications for the traumatic memory debate and theories regarding human memory.

ABSTRACT With aging, changes in the immune system, makes cognitive performance, and the prevalence of stressors can lead to poorer overall functioning. Within the immune system, a balance should exist between cytokines regulating Th1 and Th2 immune responses; however, age-related declines in the endocrine and immune systems can disrupt this equilibrium. Several studies report higher levels of Th1 associated cytokines in inflammatory conditions of the brain, whereas fewer studies remark on Th2 associated cytokines and cognitive functioning. Declining cognitive abilities are a common concern that accompanies advancing age and some research has suggested the prevalence and impact of stressors lead to poorer performance. Participants included 92 older adults (M = 74.05 years) who completed tests of cognitive performance and stress measures, and 41 persons who had valid data on Th1 and Th2 cytokines. The results indicated that increasing age is significantly associated with several cognitive domains including executive functioning, speed of processing, and episodic memory. As hypothesized, moderation analysis revealed the relationship between Th1 and Th2 cytokinic profiles, as denoted by the IFN-γ/IL-4 ratio, is a significant moderator between stress and cognitive performance. Specifically, immune profiles skewed towards Th1 predict a significant amount of variation between high stress scores and low cognitive performance, whereas this was not found for immune profiles skewed towards Th2. Overall, the current study suggests that a pro-inflammatory state permits stress to exert a negative influence on cognitive performance.

Alexithymia represents a deficit in identifying and expressing emotions, paucity of fantasies, and an externally oriented cognitive style. Currently, numerous studies document that alexithymia and several mental and somatic disorders are significantly related. Several findings also indicate that this association might be caused by alexithymia related dysregulation of neuroendocrine and immune functions. Together these findings indicate that stressors related to alexithymia could underlie the process of neuroendocrine and immune dysregulation that likely may present a significant risk, sustaining and mediating pathogenesis of several disorders and particulary psychosomatic illnesses. In this context, it is also known that several proinflammatory cytokines may play a role in pain generation and that alexithymia is significantly associated with pain symptoms in several pain disorders. Following these findings this study includes several new data developing current state of the art and showing some alexithymia specific changes in patients with neurological disorders. Main finding of this study shows that alexithymia and anxiety in their specific interactions are linked to increased levels of interleukine-8 (IL-8) in cerebrospinal fluid (CSF) in the group of patients with non-inflammatory neurological...

Há evidencias de interação bidirecional dos eixos HPA e HPG envolvendo diferentes estruturas, entretanto, os mecanismos envolvidos são pouco compreendidos. Situações de estresse podem alterar a função reprodutiva, e hormônios gonadais podem modificar a resposta de estresse. O objetivo deste trabalho foi verificar se estrógeno (E 2) e progesterona (P4) modificam a atividade basal do eixo hipotálamo-hipófise-adrenal (HPA), analisada pelas secreções de corticosterona (CORT) e de P4 e pelas expressões de receptores para corticosteróides (mineralocorticóides, MR e glicocorticóides, GR) em sítios cerebrais de retroalimentação do eixo HPA. Ratas Wistar adultas foram mantidas em ciclo claro-escuro de 12h e acesso livre à ração e água. O ciclo estral foi monitorado por esfregaço vaginal e a determinação da secreção de hormônio luteinizante (LH) foi realizada para confirmação do proestro. Seis amostras de sangue foram coletadas através de cateter na jugular, durante a tarde (13-18h), dos seguintes grupos de ratas: ovariectomizadas (OVX); controles em proestro; tratadas com antagonista de E 2 (tamoxifen) ou de P4 (RU486), ou ambos; tratadas com os respectivos veículos dos antagonistas. O plasma foi separado e estocado para dosagens hormonais por radioimunoensaio. Após a última coleta de sangue, os animais foram anestesiados e perfundidos para remoção dos cérebros, que foram manipulados para verificação por imunofluorescência, da expressão de MR e de GR na região CA1 e no subículo do hipocampo ventral, e de GR no núcleo paraventricular (PVN). Os resultados mostram que: a secreção de LH confirmou a fase de proestro; a secreção basal de CORT não foi alterada pelas manipulações de injeções nem pela remoção dos ovários; ocorreu pico de secreção de CORT e de P 4 às 14h em todos os grupos experimentais; os antagonistas de E 2 e de P 4 não alteraram a secreção total de CORT, porém o RU486 aumentou (às 13 e 15h) e o tamoxifen reduziu (às 15h) a concentração de CORT; um segundo pico de secreção de P 4 no final da tarde (17-18h) foi bloqueado pela ovariectomia e por Tamoxifen , e amplificado por RU486; o segundo pico de P 4 também não ocorreu em ratas tratadas com Tamoxifen e RU486 ; não houve alteração do número de neurônios com expressão de GR e MR na região CA 1 e no subículo do hipocampo ventral nem de GR no PVN. Em conclusão, nossos resultados indicam que: E2 e P 4 podem exercer efeitos antagônicos sobre a secreção basal de CORT, respectivamente estimulatório e inibitório; os picos de secreção de P 4 têm origens diferentes, o primeiro (14h) da adrenal e o segundo (17-18h) do ovário; E 2 estimula a secreção ovariana de P 4 na tarde de proestro; E2 e P 4 não alteram o número de neurônios que expressam GR e MR em sítios de retroalimentação do eixo HPA, mas não se pode descartar que alterem a atividade desses neurônios. / There is evidence for a bidirectional communication between HPA and HPG axis involving different structures, however the involved mechanisms are poorly known. Stress situations may alter the reproductive function, and gonadal steroids may modify the stress response. The aim of this study was verify if estrogen (E 2) and progesterone (P 4 ) can alter the basal activity of hypothalamic-pituitary-adrenal axis, analyzed by corticosterone (CORT) and P 4 secretions and by mineralocorticoid and glicocorticoid receptors (MR and GR, respectively) expression at HPA axis central feedback sites. Adult female Wistar rats were kept in 12h light-dark cycle and had free access to food and water. The estrous cycle was monitored by vaginal smears and the luteinizing hormone dosage was done to confirm proestrus. Six samples of blood were collected by jugular cannula, during the afternoon (13-18h), of the following groups: ovariectomized (OVX), proestrus controls, treated with E 2 or P 4 antagonists (tamoxifen or RU486, respectively), or with both, and treated with antagonists vehicle. The plasm was stored for hormonal dosages by radioimmunoassay. After the last blood sample, animals were anesthetized, perfused, and the brains were removed and processed for immunofluorescence to analyze MR and GR expression at ventral hippocampus CA 1 and subiculum, and GR expression at paraventricular nucleus (PVN). The results showed that: LH secretion confirmed the proestrus; CORT basal secretion was not altered by injections neither by ovariectomy; there was a CORT and a P4 secretion peak at 14h in all experimental groups, E 2 and P 4 antagonists did not modify the CORT total secretion, however RU486 increased (at 13 and 15h) and tamoxifen reduced (at 15h) CORT levels, another P4 secretion peak in the late afternoon (17-18h) was blocked by ovariectomy and tamoxifen, but enhanced by RU486, the P 4 second peak did not occur in rats treated with both tamoxifen and RU486, there were no changes in the number of neurons expressing GR and MR at ventral hippocampus CA 1 and subiculum neither of GR expressing neurons at PVN. In conclusion, our results indicate that: E2 and P 4 can have antagonistic effects over basal CORT secretion; stimulatory and inhibitory, respectively; the P 4 secretion peaks have different origins, the first (14h) is adrenals and the second (17-18h) is ovarian: E2 stimulates ovarian P 4 secretion in the proestrus afternoon; E 2 and P 4 do not alter the number of neurons that express MR and GR at HPA axis feedback sites, but one can not exclude the possibility that they alter the activity of these neurons.

The mesocorticolimbic system is involved in fundamental processes that drive motivational behaviors essential for survival (feeding, reproduction and sexual behavior, etc.), as well as neurochemical activity involved in mood regulation. Stressful life events are an important cause of dysregulated psychological functioning, which in some leads to a pathophysiology of mood disorders. A source of such disorder could be, among other underlying factors, an impairment of synaptic plasticity induced by alterations in the levels of neurotrophins and/or aberrant glucocorticoid responses. The role of the brain derived neurotrophic factor (BDNF) and its high affinity receptor tyrosine-related kinase B (TrkB) in the mesocorticolimbic reward circuitry has been largely studied in adulthood, yet a possible role of this system in mediating memory and emotional responses induced by stress during the juvenile, adolescence period has not been elucidated. The proposed set of thesis studies are designed to investigate the roles of BDNF and TrkB signaling, via the selective and non-competitive TrkB antagonist, ANA-12 (N-[2-[[(Hexahydro-2-oxo-1H-azepin-3-yl)amino]carbonyl]phenyl] benzo[b]thiophene-2-carboxamide), in the expression of stress-induced changes in the brain stress circuitry (including the medial prefrontal cortex (mPFC), hypothalamic-pituitary-adrenal (HPA) axis, and hippocampus) and reward signaling systems of the brain (including the nucleus accumbens (NAc) and ventral tegmental area (VTA)). In addition, experiments aim to determine behavioral changes following stress exposure in male and female Wistar rats. Finally, the possible interplay between BDNF, dopamine, glutamate and orexins in response to repeated stress is examined. Articles 1 and 2, aimed to assess the biochemical and behavioral effects of direct ANA-12 infusion (0.25 µg/ 0.5µl) into the nucleus accumbens shell during exposure to a 10-day heterotypic stress paradigm in male rats. Specifically, Article 1 demonstrated a key role for BDNF/TrkB signaling to regulate stress-induced effects. Notably, the impact of ANA-12 to attenuate anxiety-like behavior in repeatedly stressed rats while increasing anxiety behavior in non-stress rats suggest an interesting behavioral and neurochemical state-dependent process induced by TrkB receptor signaling. Article 2 supports the key role for BDNF secretion in basal and stress-induced behaviors in rats suggesting an influence of TrkB in sociability, motivation and passive avoidance. Furthermore, this role of TrkB extended to increased expression of orexin A in the Perifornical area (PfA) and a decrease in the ventral CA1 of the hippocampus, and in stress-induced elevations in orexinergic projections to the VTA, of which reductions were observed in non-stress groups treated with ANA-12. Article 3 demonstrated gender-specific behavioral and biochemical responses in different developmental periods and the impact of TrkB activation, dependent on stress exposure, to affect the regulation of TrkB receptor isoforms (full length and truncated TrkB, TrkB.FL and TrkB.T1, respectively) in adulthood. Results revealed increased CORT responses in adolescent females relative to males and attenuated CORT secretions in both genders by TrkB inhibition. Elevated activity levels in young adult females and increased passive coping behavior in the forced swim in stress-naïve females were also noted, in addition to novel observations on brain region and sex differences in TrkB receptor isoforms. Taken together, thesis findings derived from applications of ANA-12, shall foster knowledge on the contribution of BDNF in regulation of mood upon stress exposure at times when the brain is undergoing important maturation and remodelling, as well as on the relationship of stress exposure during adolescence and lasting brain and behavioral disorders in adulthood.

Une grande diversité dans la réponse adaptative au stress est observée entre les individus favorisant une sensibilité variable face aux stresseurs et pouvant conduire à une vulnérabilité à développer divers troubles et pathologies. Cette diversité est sous tendue par les caractéristiques propres de chaque individu, déterminées par le patrimoine génétique en interaction avec les facteurs environnementaux. Des études génétiques menées au laboratoire ont permis de placer le gène de la Cbg comme un candidat important influençant les réponses de stress. L’équipe a alors développé un modèle de souris déficiente pour le gène Cbg (k.o. total). La CBG est une glycoprotéine plasmatique responsable de la biodisponibilité et du transport jusqu’à leur cible des glucocorticoïdes, produits finaux de l’axe corticotrope. A l’aide de ce modèle original, l’objectif de mon travail de thèse a été d’étudier les conséquences fonctionnelles de la déficience en CBG sur les réponses de stress. Nous avons ainsi analysé l’activité et la réactivité de l’axe corticotrope ainsi que les comportements émotionnels des mâles et des femelles k.o. Cbg dans des conditions de repos, de stress aigu et dans un contexte mimant l’effet d’un style de vie occidentale (modélisé par une alimentation enrichie en gras, associée à un stress chronique). Nous présentons ainsi un modèle murin unique d’hypo-réponse des glucocorticoïdes au stress associé à une réponse comportementale adaptative ralentie au niveau émotionnel et cognitif. L’ensemble de ces travaux contribue à placer la CBG et son gène comme acteur majeur de la variabilité individuelle des réponses de stress. / A great diversity in the adaptive response to stress is observed between individuals favoring a variable sensitivity to face stressors and leading to a vulnerability to develop various disorders and diseases. This diversity is due to the characteristics of each individual, as determined by the genetic background in interaction with environmental factors. Genetic studies conducted in the laboratory demonstrated that the Cbg gene is an important candidate influencing stress responses. The team then developed a mouse model deficient for the gene Cbg (total k.o.). CBG is a plasma glycoprotein responsible for the bioavailability and the transport of glucocorticoids, the final products of the HPA axis, to their target.Using this original model, the objective of my thesis was to study the functional consequences of CBG deficiency on responses to stress exposure. We have analyzed the activity and reactivity of the HPA axis and the emotional behaviors of males and females k.o. Cbg in resting conditions, acute stress and in a context that mimics the effect of a Western life style (modeled by a high fat diet, associated with chronic stress). We present an unique mouse model of glucocorticoid hyposignaling in response to stress associated with behavioral responses slowed down at the emotional and cognitive levels. Overall, this work contributes to place CBG and its gene as major actor of individual variability to stress.

Chronic stress exposure is hypothesized to increase the risk for developing a mental or physical disease, which can be summarized as an overall increased vulnerability to adverse health conditions. This thesis shows one potential pathway of stress exposure entering the body via activation of the hypothalamus pituitary adrenal (HPA) axis and the interaction between HPA axis and immune activation. Chronic stress caused by work overload or the experience of stressful life events was associated with altered levels of cortisol, the main effector hormone of the HPA axis. Further, chronic stress was shown to effect the distribution of neutrophils, a leukocyte subtype known for its defence properties as well as for its side effects of tissue damage. Additional analyses support a theory that HPA axis and immune cells work in synergy to adapt the organism to chronic stress exposure and therefore represent one pathway how stress can cause altered immune defence toward an increased vulnerability to disease.

Purpose: Moderate-intensity aerobic exercise (MAE) has been shown to elicit improvements in cognition and subsequent academic performance among preadolescents. Aerobic exercise has also shown to increase cortisol release in response to increasing exercise intensity. However, it is unknown if increased cortisol levels following exercise are related to acute improvements in executive function following a bout of MAE in preadolescents. The purpose of this study was to examine the potential effects of increased cortisol release after acute MAE on attention and working memory among preadolescents. Methods: Eleven preadolescents [6 males, 5 females] volunteered to participate in this study (age=9.45±1.03). Participants were randomized in a counterbalanced fashion to 30 minutes of rest or 30 minutes of treadmill MAE (60-70% HR max). Immediately pre-post each condition, participants completed a cognitive battery consisting of tests of attention (Flanker Test) and working memory (List Sorting Working Memory Test), as well as salivary samples for the analysis of cortisol. Linear Regression models were used to assess significance of covariates. Generalized linear models were used to assess significance of changes in each dependent variable against time, condition, time*condition and change in cortisol. Tukey’s HSD post-hoc tests for multiple comparisons were used to assess the effect of condition on working memory, attention, and salivary cortisol. Results: There was a significant effect of condition on working memory (F=3.16, p =0.04), with no change from pre-post rest (p=0.93) and improving from pre-post exercise (p=0.04). There was no effect of condition on attention or salivary cortisol, most likely due to a small sample size. Multiple linear regression models showed a significant effect of age (p=0.03) and change in cortisol (p=0.007) on working memory. Conclusion: Exercise had a positive effect on working memory, however, we were unable to relate this improvement to changes in salivary cortisol due to a lack of statistical power. This study could provide insight into the physiological effects of increased cortisol release on cognition, specifically in regard to working memory. However, more data are needed to achieve sufficient statistical power to detect these relationships.

Animal personality is a fairly new branch of biology and has been defined as a difference in behaviour between individuals that is relatively consistent across time and/or context. What researchers now are interested in is to find out what it is that creates and maintains this relatively consistent difference between individuals. One possibility is the stress hormone, corticosterone. I have in this report summed up some of the available studies regarding animal personality and its possible correlation to corticosterone. The personality traits that have been reviewed in this report are boldness, exploration, activity, aggressiveness and sociability. The result of these studies show that boldness have both a negative and a positive correlation; exploration showed different correlations between studies; aggressiveness showed different correlation between different animal types and sociability showed both a negative and none correlations. The only one that I could not determent the correlation for was activity. The research regarding animal personality and corticosterone can be of use when looking at animal welfare and how stress affects different individuals. This can give us a direction in our work to reduce stress for animals in research facilities and food production.

Exercise is widely recognized for its role in the health management and prevention of several chronic diseases. Exercise is considered as a stimulus in the form of physical stress to which a group of anatomical structures in the human body responds by generating a stress response that enables certain physiological modifications essential for restoring systemic homeostasis. A major component of the response is produced through the complex hypothalamic-pituitary-adrenal (HPA) axis mechanism that results in the release of cortisol which then intercedes with the effects of the stimulus. To investigate how cortisol helps the body adapt to this physical stress it is necessary to gain deep insight into the cortisol response mechanism. However, this is a complex mechanism, so to better understand the mechanics and to be able to analyze complex data, mathematical models are used. Various mathematical models have already been developed that describe different metabolic responses to exercise but to date, to my knowledge, none of these existing models has illustrated the HPA axis response mechanism, particularly cortisol response to physical exercise. Therefore, I have developed a mathematical model that describes cortisol variations on a normal day in the absence of any form of stress and on the day of exercise. The developed cortisol response model could fit simulation to experimental data and also passed the χ2- statistical test. Additionally, the model has been validated on different cortisol experimental data with satisfying results. At last, considering the positive outcome of this mathematical model, it could be used as a groundwork for developing a comprehensive model which can describe other metabolic processes response to exercise such as glucose metabolism together with the cortisol response mechanism in the future.