Clinical and preclinical research both indicate that early life adversities alter sensitivity to stress well into adulthood. Although clinical research identifies infancy, childhood, and adolescence as periods of heightened vulnerability, the majority of preclinical research experiments have examined the enduring impact of stressors delivered either prenatally or prior to weaning. It was recently shown that exposing rats to intermittent stressors across the childhood/ adolescent period (PD 21-51) increased their behavioural and endocrine sensitivity to stress in adulthood. The purpose of the current project was to determine whether specific developmental periods are differentially sensitive to the lasting effects of intermittent stress. Male and female Long-Evans rats were exposed to three stressors (foot shock, elevated platform exposure, and cold water emersion) two times each, randomly over a twelve day period (childhood: PD 22-33 vs. adolescence: PD 35-46). Age-matched controls were briefly handled on each of the stressor application days. After completion of the stress exposure period, rats were left undisturbed for 27 days and behavioural testing commenced in adulthood. Intermittent physical stress exposure during the childhood period increased anxiety-like behaviours in adulthood, as indexed by the Elevated-Plus Maze (EPM) and Shock Probe Burying Test (SPBT). This also increased depression-like behaviour in adult male rats and decreased depression-like behaviour in adult female rats, as indexed by the Forced Swim Test (FST). Intermittent physical stress exposure in the adolescent period increased open-arm activity, increased burying behaviour and increased immobility in the forced swim test, in both male and female rats. Stress during either developmental period, failed to alter corticosterone (CORT) reactivity to restraint stress in adulthood. Thus, it appears that the long lasting behavioural impact of early-life adversity can vary, according to the developmental period the stressors are experienced in, but this is further modified by sex and the type of test used to evaluate adult behaviour. / Thesis (Master, Psychology) -- Queen's University, 2010-08-25 18:53:24.136

Background Suicidal behavior is an important global health problem affecting also significant others. Both genetic and environmental influences play an important role in the development of suicidal behavior. There is a need of interventions for family and friends after a suicide attempt. The aim of this thesis was to assess the impact of family history of suicide (FHS) and early life adversity (ELA) on severity of suicidal behavior and on level of interpersonal problems in suicide attempters. Furthermore it aimed to evaluate a DBT-based skills training program, Family Connections (FC), for relatives and friends of suicide attempters. Methods Studies I and II included 181 suicide attempters. FHS was assessed with the Karolinska Self-Harm History Interview or in patient records. ELA was assessed with the Karolinska Interpersonal Violence Scale (KIVS) measuring exposure to interpersonal violence in childhood. Suicide intent was measured with the Freeman scale. Interpersonal problems were assessed with the Inventory of Interpersonal Problems (IIP). Study III, a pilot study evaluating the effect of FC for family members of suicide attempters, included 13 participants who completed the program with pre- and post-questionnaires. The experience of burden was assessed with the Burden Assessment Scale (BAS), general wellbeing with Brief Symptom Inventory (BSI) and level of depression was assessed with Beck Depression Inventory (BDI). The Swedish scale Questions About Family Members (QAFM) was used to explore the quality of the participants’ relationship with the patient and the Quality of Life Inventory (QOLI) was used to measure satisfaction with life situation. Study IV included 132 family members, and investigated the feasibility and preliminary efficacy of FC in psychiatric care. Participants were assessed pre- and post-intervention with the following self-report questionnaires: BAS, QAFM and Five Facet Mindfulness Questionnaire. Results Male suicide attempters with FHS made more serious and well planned suicide attempts and had higher suicide risk. FHS and exposure to interpersonal violence as a child were independent predictors of suicide in male suicide attempters. Regarding interpersonal problems, suicide attempters with FHS had significantly more often an intrusive personal style, indicating that they might have an impaired ability to create stable, long-lasting relationships. In the pilot study the participants reported a significant reduction in burden, an improved psychic health and an improvement in the relationship with the patient after completing FC. In the fourth study, FC showed to be feasible and effectively implemented in a psychiatric outpatient services clinic. Regarding burden, results were in line with the pilot study, with a significant reduction in all subscales in BAS. Conclusions High-risk patients call for a consideration of both ELA and FHS in clinical suicide risk assessment. In suicide attempters at biological risk, suicide might be prevented with the early recognition of environmental risks. Further, the interpersonal problems associated with FHS may cause difficulties for suicide attempters to accept or benefit from treatment, and caregivers should take into account the characteristics of the suicide attempter´s interpersonal functioning. The results from the pilot study provide support for the need and importance of an educational program addressed specifically to family members of suicide attempters. Preliminary results support the feasibility and potential value of an implementation of FC in psychiatric open care clinics.

Ovarian cancer is a malignancy characterized by poor prognosis, high levels of distress, and impaired quality of life (QOL). Investigation into the contributors to QOL is of psychological and prognostic significance in cancer. Contemporary stress theories and empirical accounts identify early life adversity and recent life stress as those sources which exert significant impact on physical and psychological health. To date, life stress research in cancer has yielded few designs which operationalize both indices of early life and recent life stress exposures. Moreover, despite the high-resolution stress data provided by the Life Events and Difficulties Schedule (LEDS) system, no studies to date comprehensively operationalize the early life adversity data obtained during each interview. Therefore, the proposed study is the first of its kind to comprehensively obtain ratings and examine effects of early life adversity data collected as part of the LEDS interview. It is also the first to examine independent influences of differentially timed life stress indices on psychological variables important to psychosocial functioning in ovarian cancer. Early life adversity was experienced by 43.1% of the sample. Adversity varied in content, number of occurrences, and severity. Ongoing difficulties, but not recent life events or early life adversity, were significantly associated with pre-surgical depression and QOL. Ongoing difficulties were also associated with lower depression, sleep, and QOL scores at all time-points. Early life adversity was associated with a poorer trajectory of sleep and QOL over the first year post-diagnosis. Findings are discussed with attention to behavioral and biological mechanisms. Applications to generative and cumulative theories of life stress are proposed. These findings lend support to the potential benefit of interventions aimed toward practical support and stress management in patients with ovarian cancer, as well as provide guidelines for use of early life adversity data obtained through the LEDS interview.

Les maladies psychiatriques présentent de fortes comorbidités avec des désordres gastrointestinaux, ce qui suggère l’existence de bases physiopathologiques communes. Une littérature abondante démontre que l’adversité précoce (infection, stress) augmente la vulnérabilité aux désordres psychiatriques à l’âge adulte. Chez le rongeur, le modèle de séparation maternelle induit chez la descendance adulte des comportements hyperanxieux associés à une hypersensibilité au stress, ainsi que des dysfonctionnements de la sphère gastrointestinale. De plus, des études récentes rapportent une hyperperméabilité de la barrière intestinale chez les ratons soumis au stress de séparation, un effet conduisant potentiellement à une dysbiose et une perturbation de la communication intestin-cerveau. Le but de ma thèse était donc d’étudier le rôle de l’axe intestin-cerveau dans la mise en place des effets à long terme du stress précoce. Nos travaux récents ont montré que certains effets à long-terme de la séparation maternelle peuvent être atténués par l’exposition des mères à un régime hyperlipidique. Dans un premier temps, nous avons testé les effets du régime hyperlipidique maternel sur le cerveau et l’intestin de ratons soumis à la séparation maternelle. Nos résultats montrent que le régime maternel hyperlipidique protège de l’augmentation de la permeabilité intestinale induite par le stress. Nous avons ensuite testé le rôle causal de la perméabilité intestinale sur les comportements émotionnels à travers une approche pharmacologique et une approche génétique. Nous rapportons 1) que la restauration de la fonction barrière de l’intestin atténue certains effets de la séparation maternelle et 2) qu’une hyperperméabilité intestinale chez des souris transgéniques non soumises à un stress produit des effets similaires à ceux de la séparation maternelle. Enfin, nous avons examiné les effets d’une adversité précoce multifactorielle sur le cerveau et l’intestin (perméabilité et microbiote) chez la descendance adulte mâle et femelle dans un modèle combinant infection prénatale et séparation maternelle. Nos résultats mettent en évidence un effet sexe très marqué sur les phénotypes comportements et intestinaux. D’autres études sont nécessaires pour identifier les mécanismes sous-tendant les effets de la perméabilité et la dysbiose intestinale sur la vulnérabilité émotionnelle associée au stress précoce. / Early-life adversity is a main risk factor for psychiatric disorders at adulthood; however the mechanisms underlying the programming effect of stress during development are still unknown. In rodents, chronic maternal separation has long lasting effects in adult offspring, including hyper-anxiety and hyper-responsiveness to a novel stress, along with gastrointestinal dysfunctions. Moreover, recent studies report gut barrier hyper-permeability in rat pups submitted to maternal separation, an effect that could potentially lead to dysbiosis and altered gut-brain communication. Therefore, the aim of my PhD was to unravel the role of the gut-brain axis in the neurobehavioral effects of early-life stress. We recently reported that some neural, behavioral and endocrine alterations associated with maternal separation in rats could be prevented by maternal exposure to a high-fat diet. We first addressed the effects of maternal high-fat diet on brain and gut during development in the maternal separation model. We show that maternal high-fat diet prevents the stress-induced decrease in spine density and altered dendritic morphology in the medial prefrontal cortex. Moreover, maternal high-fat diet also attenuates the exacerbated intestinal permeability associated with maternal separation. To explore a potential causal impact of gut leakiness on brain functions, we then examined the impact of pharmacological and genetic manipulations of intestinal permeability on brain and behavior. We report 1) that restoration of gut barrier function attenuates some of the behavioral alterations associated with maternal separation and 2) that chronic gut leakiness in naive adult transgenic mice recapitulates the effects of maternal separation. Finally, we examined the effects of multifactorial early-life adversity on behavior, gut function and microbiota composition in males and females using a combination of prenatal inflammation and maternal separation in mice. At adulthood, offspring exposed to early adversity displayed sex-specific behavioral (social behavior deficits in males and increased anxiety in females) and intestinal phenotypes. In conclusion, our work demonstrates an impact of gut dysfunctions, in particular gut leakiness, on the emergence of emotional alterations. Further studies are needed to unravel the role of the gut dysbiosis in the expression of the behavioral phenotypes associated with early-life adversity.

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