<p>We are all born germ-free. Soon after birth, microbes colonize our body’s surfaces, with the intestine housing the highest density of microbes on earth. Most of us remain blissfully unaware of this co-existence because inflammatory responses to the indigenous microbes are normally not triggered. Nonetheless, intestinal microbes are true educators of our immune system, which is exemplified by the immature immune system observed in germ-free animals. Accumulating evidence suggests that microbial exposure and/or composition impacts on immune regulation. As an example, isotype switch to immunoglobulin E (IgE) is normally very tightly regulated such that in healthy individuals and mice, serum levels are maintained at very low levels. In contrast, total serum IgE levels are elevated in germ-free mice, indicating that in the absence of microbes the regulatory pathway that maintains IgE at basal levels is disrupted. We hypothesize that in the absence of stimuli from the resident intestinal bacteria the immune system does not receive adequate educational signals. We showed that in germ-free mice class switch recombination (CSR) to IgE occurred at intestinal mucosal lymphoid sites a few weeks after birth. IgE levels then remained at elevated levels throughout life, even when intestinal bacteria were introduced after weaning. In the first part of this thesis, the mechanisms involved in this hygiene-induced IgE were investigateted. In a second part, the immunoregulatory role of commensal bacteria was extended to a model of autoimmunity.</p> <p>Collectively these results demonstrate a new dimension of the impact of intestinal symbionts on the immune system: they dictate baseline immune system regulation. Elucidating the mechanisms whereby microbes induce immunoregulatory pathways may give insights into the increasing prevalence of allergic- and autoimmune diseases.</p> / Doctor of Philosophy (PhD)

Biological theory proposes that autonomic nervous system (ANS) hypo-reactivity may be more specific to proactive aggression, while ANS hyper-reactivity may be specific to affective aggression. However, the literature finds mixed support, which may be because no study to date has concurrently examined emotion dysregulation, a highly related variable, as a potential moderator. The present study examined these relationships in 76 undergraduate participants (29 men, mean age = 21.49) who identified as Caucasian (51%), African-American (23%), Asian (21%), or Other (5%). Participants completed questionnaires, a resting state task, and a provocation task. Results found that blunted overall ANS reactivity was associated with proactive aggression. Emotion dysregulation moderated the relationship between parasympathetic nervous system (PNS) and sympathetic nervous system (SNS) reactivity with both proactive (at a trending level for SNS reactivity) and affective aggression. Specifically, among those slightly above average and high on emotion dysregulation, PNS augmentation and blunted SNS reactivity were associated with proactive and affective aggression, respectively. In contrast, among those low on emotion dysregulation, PNS augmentation was associated with decreased affective aggression. Thus, among those elevated on emotion dysregulation, it may be beneficial to teach counter-regulatory strategies to reduce the impact of ANS hypo-reactivity on aggression (across function). / Psychology

Although there has been a recent surge in research examining comorbidity between externalizing and internalizing disorders in childhood, relatively less work has examined relations between specific externalizing conditions (i.e., oppositional defiant disorder (ODD) symptoms) and their co-occurrence with specific internalizing conditions (i.e., depressive symptoms). Furthermore, little empirical work has evaluated potential underlying processes, such as emotion dysregulation, which may explain relations between co-occurring ODD and depressive symptoms. There is also a paucity of research examining developmental patterns of co-occurring ODD and depressive symptoms. In the present study, I used latent class and latent transition analyses to (a) identify groups of children based on ODD and depressive symptom levels, (b) determine whether emotion dysregulation predicted co-occurring ODD and depressive symptoms, and (c) examine developmental patterns of change and continuity in groups across middle childhood within a community-based sample. Children were characterized by three latent classes based on ODD and depressive symptom severity: a group with very low levels of ODD or depressive symptoms, an ODD-only group with low levels of symptoms, and a co-occurring ODD and depressive symptom group with moderate levels of ODD and low levels of depressive symptoms. Furthermore, emotion dysregulation predicted to the class with moderate levels of ODD and low levels of depressive symptoms, although prediction from emotion dysregulation to class membership depended on the methodology used to index emotion dysregulation. Results of the LTA analyses suggested that symptom severity was relatively stable across middle childhood, with little evidence of changes in developmental patterns of ODD and depressive symptoms. Overall, the results of this study provide an important foundation for more sophisticated empirical inquiry regarding co-occurring ODD and depressive symptoms in childhood and potential processes that may explain their onset and development. / Psychology

Witnessing partner violence (WPV) in childhood and adolescence can have significant impact on psychological functioning throughout development. Studies have shown that parenting factors, perceived social support, coping strategies, age at exposure, and gender can influence the relationship between WPV and outcomes. Although WPV can have serious implications towards emotion regulation abilities, empirical research on the link between WPV and emotion regulation is inadequate. The current study examined the associations between the frequency and types of WPV in childhood and adolescence and emotion dysregulation in adulthood. The study further explored the roles of parental bonds, social support, coping strategies, age at exposure, and gender as moderators in the relationship between WPV and emotion dysregulation. Data were collected using an undergraduate sample at Virginia Tech (N = 1040). Results indicated that verbal violence exposure was a significant predictor of emotion dysregulation while physical violence and total WPV were not. Parental warmth moderated the relationship between all three types of WPV and emotion dysregulation, while parental control and age of onset were moderators for total and physical WPV. Social support moderated the relationship between verbal violence exposure and emotion dysregulation. Coping strategies and gender were not found to be significant moderators. Exploratory analyses were conducted to further explore these relationships. The findings and their implications are discussed. / Ph. D.

Le Trouble Déficit de l’Attention Hyperactivité (TDAH) est un trouble du neurodéveloppement associant des symptômes d’inattention, d’hyperactivité et/ou d’impulsivité. Fréquemment, le tableau clinique est marqué par une labilité émotionnelle pouvant se manifester sous différentes formes jusqu’à parfois s’agencer en un véritable syndrome : le Trouble Disruptif avec Dysrégulation Emotionnelle, récemment inclus dans le DSM-5. La labilité émotionnelle est-elle un symptôme du TDAH ou de troubles comorbides ? Est-elle caractéristique d’un tableau clinique du TDAH ? Ce travail de thèse propose d’étudier le profil psychopathologique associé à la labilité émotionnelle sous différentes approches, catégorielle et dimensionnelle, et à deux périodes clés du développement de l’enfant atteint de TDAH, l’âge préscolaire et l’âge scolaire. Quatre études composent ce travail de thèse : les trois premières en milieu clinique et la dernière en population générale. Les résultats ont indiqué que la labilité émotionnelle d’un point de vue dimensionnel mais également catégoriel au travers du diagnostic de Trouble Disruptif avec Dysrégulation Emotionnelle, était associée à des symptômes plus sévères et un retentissement fonctionnel plus important à l’âge préscolaire et scolaire. L’approche dimensionnelle s’est montrée plus pertinente pour identifier les enfants avec labilité émotionnelle ayant des besoins spéciaux de prises en charge au-delà de celle du TDAH. De plus, la labilité émotionnelle et l’irritabilité ont semblé être associées à des tableaux cliniques différents. Ces résultats suggèrent l’intérêt de l’évaluation de la labilité émotionnelle et des manifestations associées dans le diagnostic du TDAH chez l’enfant. Une approche clinique fine, à la fois quantitative et qualitative, semble prometteuse dans la prévention des formes prodromiques de TDAH et dans le pronostic de ce trouble afin de proposer des interventions adaptées afin d’infléchir de potentielles trajectoires développementales à risques. / Attention Deficit Hyperactivity disorder is a neurodevelopmental disorder characterized by inattentive, hyperactive and/or impulsive symptoms. Emotional lability is frequently associated with the disorder. It can cover several manifestations. These manifestations are sometimes that serious that there are parts of a disorder: the Disruptive Mood Dysregulation Disorder recently added to the DSM-5. Is emotional lability a core symptom of ADHD or one of a comorbid disorder? Is it featured with different symptoms and functional impairment in children with ADHD? This PhD work tried to provide elements to respond to these questions assessing the psychopathological profile associated with emotional lability as a categorical and dimensional feature at two crucial developmental periods: the preschool and the school aged. Four studies are part of this PhD work: three in clinical population and one in general population. Results emphasized that emotional lability is associated with more severe symptoms and functional impairment in both preschool a school aged children. Results were similar when emotional lability was assessed as a dimensional feature and as a categorical feature. Nevertheless, the dimensional approach of emotional lability seemed relevant identifying children with ADHD and emotional lability that were at special need for interventions, beyond the ADHD one. Moreover, emotional lability and irritability seemed associated with different clinical outcomes. These results suggested the value of the emotional lability assessment and of its others manifestations in the ADHD diagnosis in children. A qualitative and quantitative approach seems promising in preventing prodromal ADHD and in its prognostic. This might serve targeting adapted interventions in order to inflect potential harmful developmental trajectories.

La presente investigación tuvo como objetivo analizar las propiedades psicométricas de la Escala de Dificultades en la Regulación Emocional (DERS) de Gratz y Romer (2004). La muestra estuvo compuesta por 253 jóvenes (27.7% hombres y 72.3% mujeres) universitarios de carreras de ciencias de la salud con edades comprendidas entre los 18 y 25 años (M = 21.70, DE = 1.75). De dicha muestra, 120 jóvenes fueron encuestados de manera virtual y 133, fueron encuestados de forma presencial. En primer lugar, se analizó la validez basada en la estructura interna mediante el análisis factorial exploratorio (AFE) donde se obtuvo un KMO de .86 y una prueba de esfericidad de Bartlett que fue estadísticamente significativa (p < .001). Como resultado del AFE de la DERS se obtuvo 5 factores (Dificultades en la Regulación de Impulsos, Aceptación Emocional, Consciencia Emocional, Interferencia en Conductas y Claridad Emocional) de los 6 establecidos originalmente que explicaron el 44.96 % de la varianza. Respecto a las relaciones de convergencia con la Escala de Autorregulación Emocional, se encontró correlaciones no tan altas, aunque estadísticamente significativas entre las dimensiones. Respecto a la dimensión de reevaluación cognitiva se correlaciona negativa, baja e inversamente con dos dimensiones de la DERS (Dificultades en la regulación de impulsos y Falta de aceptación emocional). Asimismo, la dimensión de supresión emocional se correlaciona positiva, baja y directamente con una dimensión (Falta de conciencia emocional). En cuanta la confiabilidad los valores del alfa de Cronbach fueron aceptables (entre .72 y .86), así como los del coeficiente omega (entre .74 y .87). Finalmente, se concluye que la escala cuenta con adecuadas propiedades psicométricas para su uso en muestras similares. / The objective of this research was to analyze the psychometric properties of the Difficulties in Emotional Regulation Scale (DERS) by Gratz and Romer (2004). The sample consisted of 253 young people (27.7% men and 72.3% women) university health sciences aged between 18 and 25 years (M = 21.70, SD = 1.75). Of this sample, 120 young people were surveyed virtually and 133, were surveyed in person. First, the validity of the internal structure was analyzed by exploratory factor analysis (AFE), where a KMO of .86 was obtained and a Bartlett sphericity test was statistically significant (p <.001). As a result of the DIE of the DIE, we have obtained 5 factors (Difficulties in the Regulation of Impulses, Emotional Acceptance, Emotional Consciousness, Behavior Interference and Emotional Clarity) of the 6 elements that explain 44.96% of the variance. Regarding the relationships of convergence with the Emotional Self-Regulation Scale, there are correlations not so high, although statistically significant between the dimensions. Regarding the cognitive reassessment dimension, it correlates negatively, low and inversely with the dimensions of the DERS (Difficulties in the regulation of impulses and lack of emotional acceptance). Also, the dimension of emotional suppression correlates positively, lowly and directly with one dimension. In terms of reliability, the values of Cronbach's alpha were acceptable (between .72 and .86), as well as the omega coefficient (between .74 and .87). Finally, it is concluded that the scale has psychometric properties for its use in similar samples. / Tesis

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Changes in both sleep architecture and cognition are common with age. Typically these changes have a negative connotation: sleep fragmentation, insomnia, and deep sleep loss as well as forgetfulness, lack of focus, and even dementia and Alzheimer’s disease. Research has shown that psychosocial stressors, such as isolation from family and friends or loss of a loved one can also have significant negative effects on sleep architecture and cognitive capabilities. This leaves the elderly in a particularly vulnerable situation: suffering from cognitive decline and sleep dysregulation already, and more likely to respond negatively to psychosocial stressors. Taking all of these factors into account, it’s surprising that little research has been done to elucidate the mechanisms behind aged subjects’ enhanced vulnerability to new onset psychosocial stress. Our lab embarked on a series of studies to test the effects of age and psychosocial stress on sleep architecture and cognition. Our first study measured sleep stages in young adult and aged F344 rats during their resting and active periods. Animals were behaviorally characterized on the Morris water maze and gene expression profiles of their parietal cortices were taken. We confirmed previous studies that found impaired cognition and decreased resting deep sleep with age. However, it was increased active deep sleep that correlated best with poor cognitive performance. In the second study rats were subjected to immobilization (restraint stress) immediately preceding their final water maze task. Hippocampi were prepared for synaptic electrophysiology and trunk blood was taken for corticosterone measurement after post-stress sleep architecture data was collected. Young subjects responded to acute stress with decreased cognition, elevated CORT levels and altered sleep architecture. In contrast, stressed aged subjects were statistically indistinguishable from control aged subjects, suggesting that aged rats are less responsive to an acute psychosocial stress event. Together, these studies suggest that alleviating sleep dysregulation could therapeutically benefit cognition psychosocial stress resilience.

Title from first page of PDF document. Includes bibliographical references (p. 34-39).

Depression occurs in about one third of patients with stroke and cardiac arrest. Hyperactivity of the stress system is the most commonly observed neuroendocrine change in major depressive disorder (MDD), which involves elevated levels in the cerebrospinal fluid of corticotropin-releasing hormone (CRH), a key stress neurohormone. Substantial evidence suggests that normalization of the stress system may be a requirement for successful treatment of MDD through region-specific changes in the mesocorticolimbic circuitry. Thus, alteration in the stress system may underlie the emotional and functional impairments observed following brain ischemic events. In addition, recent findings suggest that ischemic brain injury triggers a restorative process, creating a cerebral environment similar to that of early brain development, a period characterized by rapid neuronal growth and neuroplasticity, critical to optimize functional recovery of individuals post stroke. In particular brain-derived neurotrophic factor (BDNF), has been shown to play an important role in the pathophysiology of major depression and cerebral ischemia. However, whether CRH can mediate the expression of BDNF in the reparative process triggered by ischemic injury remains to be characterized. Therefore, the purpose of the current thesis is to characterize the effect of pharmacological blockade of CRH signaling at the onset of a global ischemic stroke, on emotional and cognitive behaviors, alteration in the neuroendocrine stress system, and markers of neuroplasticity including BDNF. To do this, an animal model of global cerebral ischemia with subsequent behavioral testing and postmortem brain analysis was used to determine underlying biochemical and behavioral changes modulated by CRH signaling following brain ischemia. This doctoral work will help elucidate the relationship between CRH and BDNF in the context of cerebral ischemia, and may provide insights for therapies targeting the stress system. These studies address considerations such as: the interplay between stress, neuroplasticity and emotionality, and whether global ischemia can affect mood via changes in the HPA axis response.