abstract: The development of self-regulation is believed to play a crucial role in predicting later psychopathology and is believed to begin in early childhood. The early postpartum period is particularly important in laying the groundwork for later self-regulation as infants' dispositional traits interact with caregivers' co-regulatory behaviors to produce the earliest forms of self-regulation. Moreover, although emerging literature suggests that infants' exposure to maternal stress even before birth may be integral in determining children's self-regulatory capacities, the complex pathways that characterize these developmental processes remain unclear. The current study considers the complex, transactional processes in a high-risk, Mexican American sample. Data were collected from 305 Mexican American infants and their mothers during prenatal, 6- and 12-week home interviews. Mother self-reports of stress were obtained prenatally between 34-37 weeks gestation. Mother reports of infant temperamental negativity and surgency were obtained at 6-weeks as were observed global ratings of maternal sensitivity during a structured peek-a-boo task. Microcoded ratings of infants' engagement orienting and self-comforting behaviors were obtained during the 12-week peek-a-boo task. Study findings suggest that self-comforting and orienting behaviors help to modulate infants' experiences of distress, and also that prenatal stress influences infants' engagement in each of those regulatory behaviors, both directly by influence tendencies to engage in orienting behaviors and indirectly by programming higher levels of infant negativity and surgency, both of which may confer risk for later regulatory disadvantage. Advancing our understandings about the nature of these developmental pathways could have significant implications for targets of early intervention in this high-risk population. / Dissertation/Thesis / M.A. Psychology 2013

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Prenatal stress exposure (PNS) has detrimental effects on the offspring’s brain and behaviour and has been identified as an etiological factor in inducing cognitive function deficits in rodents and humans. The neural mechanisms are unclear, however reprogramming of the neuroendocrine stress axis, the hypothalamo-pituitary- adrenal (HPA) axis is hypothesised. A psychosocial stressor (residentintruder paradigm) was used to generate PNS rat offspring, making these studies clinically compatible. The hippocampus and the medial prefrontal cortex (mPFC) are critical in regulating cognitive function and also contribute to the negative feedback control of the HPA axis via corticosteroid receptors, including the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). Here the Barnes maze was used to assess spatial learning and memory in male and female PNS offspring during adulthood under different scenarios, including basal and acute and chronic stress conditions. Under basal conditions, PNS was associated with reduced GR and MR mRNA expression in the medial prefrontal cortex (mPFC) and the hippocampus, respectively; suggesting inhibitory feedback control of the HPA axis may be compromised in PNS rats. Moreover, impaired spatial learning was observed in male PNS rats following acute restraint stress. Bilateral lesions of the prelimbic cortex and central administration of an MR antagonist in control rats suggested acute stress-induced learning deficits in PNS males were a result of impaired hippocampus-mediated inhibitory feedback control of the HPA axis. Conversely, a one-week variable stress regimen facilitated spatial learning in PNS rats and this was associated with elevated MR mRNA expression in the dentate gyrus. Moreover, facilitated learning in the PNS rats exposed to chronic stress could be blocked by central administration of an MR antagonist, indicating a facilitatory role of hippocampal MR in spatial learning. In summary, opposite effects of PNS on spatial learning were observed under acute and chronic stress conditions, in which hippocampal MR played a key role in regulating behavioural performance. The effect of age was also examined in PNS rats, and the findings from middle-aged (10-11 months old) rats indicated PNS may accelerate cognitive decline. Sex differences were also studied, with control females’ out-performing males under basal conditions in terms of spatial learning and behavioural flexibility; however following prenatal or chronic stress these sex differences were no longer detected. Furthermore, acute stress impaired spatial learning to a greater extent in females, and this might be attributed to greater HPA axis responses to stress in females compared with males. In conclusion, prenatal stress alters later cognitive performance, in a sex- and stress context-dependent manner. Hippocampal MR plays a critical role in mediating spatial learning, particularly during stress conditions.

abstract: Clinically meaningful emotional and behavioral problems are thought to be present beginning in infancy, and may be reliably assessed in children as young as 12 months old. However, few studies have investigated early correlates of emotional and behavioral problems assessed in infancy. The current study investigates the direct and interactive contributions of early infant and caregiver characteristics thought to play an important role in the ontogeny of behavior problems. Specifically, the study examines: (1) the links between temperamental reactivity across the first year of life and behavior problems at 18 months, (2) whether children high in temperamental reactivity are differentially susceptible to variations in maternal sensitivity, (3) the extent to which child temperamental risk or susceptibility may further be explained by mothers’ experiences of stressful life events (SLEs) during and before pregnancy. Data were collected from 322 Mexican American families during prenatal, 6-, 12-, 18-, and 24-week home interviews, as well as during 12- and 18-month lab interviews. Mother reports of SLEs were obtained between 23-40 weeks gestation; temperamental negativity and surgency at 6 weeks and 12 months; and internalizing and externalizing behaviors at 18 months. Maternal sensitivity during structured mother-infant interaction tasks at the 6-, 12-, 18-, and 24-week visits was assessed by objective observer ratings. Study findings indicated that maternal SLEs before birth were associated with more infant negativity across the first year of life, and that negativity in turn was associated with more internalizing problems at 18 months. Ecological stressors thought to be associated with sociodemographic risk factors such as low-income and ethnic minority status may begin to exert cascades of influence on children’s developmental outcomes even before birth. / Dissertation/Thesis / Doctoral Dissertation Psychology 2016

Introduction: major depressive disorder is a common psychiatric disorder associated with high economic cost, severe human suffering, and low remission rates. Imbalanced neurotransmission of the monoaminergic serotonin (5-HT), dopamine (DA) and norepinephrine (NE) systems is implicated in this disorder. However, the etiology underlying this presumed imbalance and the mechanism by which antidepressant strategies restore this imbalance requires further exploration. Accordingly, the present work assessed the effects of depressogenic and antidepressant-like conditions on these systems. Methodology: Electrophysiological extracellular single unit recordings from 5-HT, DA, NE, and hippocampal pyramidal neurons were obtained in adult male chloral hydrate anaesthetized Sprague-Dawley rats. Effects on relevant receptors were characterized using established electrophysiological and/or pharmacological strategies. Prenatal stress was used to model depressogenic-like conditions. The effects on monoamine systems of asenapine and brexpiprazole, two atypical antipsychotics with antidepressant potential, were characterized after acute (brexpiprazole) and sustained administration. These sustained regimens resulted in clinically relevant blood plasma levels. Results: Prenatal stress exposure altered monoamine system activities but did not produce detrimental effects on behavior. Asenapine and brexpiprazole had unique effects on the activities of monoamine systems. Unlike other antipsychotics, both agents did not produce a cessation of the firing of dopamine neurons in the ventral tegmental area, thereby providing novel insights in the role of this system in the treatment of mood disorders. Furthermore, both agents enhanced the tonic activation of postsynaptic 5-HT1A receptors, similarly to the effects of all antidepressant strategies. Conclusion: Prenatal stress altered the activities of 5-HT, NE and DA neurons. Since these central changes were obtained in animals displaying normal behavior, they presumably reflect adaptations to depressogenic-like conditions. The characterization of asenapine and brexpiprazole contributed to a further understanding of their mechanisms of action. Together, these studies provide insight in neural substrates presumably relevant to the antidepressant response.

Several factors can modulate the link between fetal disruptions and later-life illnesses. The main objective of this thesis was to determine, in a mouse model, the impact of prenatal stressor timing and offspring sex on prepubertal metabolic and mental health outcomes. C57BL/6 dams in the first or second trimester of pregnancy experienced a restraint stressor or were left undisturbed. Pups were weighed daily until postnatal day (PND) 21, at which time fat distribution was measured. Anxiety- and depressive-like behaviors were tested on PND19-20 in open field, elevated plus maze, splash and tail suspension tests. Second trimester stressed males gained more weight and had increased fat deposits surrounding the kidneys. Although anxiety- and depressive-like behaviors were not apparent in prenatally stressed offspring of either sex, females stressed in utero exhibited a hyperactive phenotype. This work is the first to show sex- and trimester-specific consequences of early pregnancy stressors in prepubertal offspring.

Ette thèse est centrée sur les capacités sensorielles, cognitives et sur les effets du stress chez deux espèces de seiche : Sepia officinalis et Sepia pharaonis. Nous avons d’abord démontré que les embryons répondent à différents stimuli environnementaux (lumière, proies, prédateurs, encre de seiche) mettant en évidence que l'information sensorielle passe à travers la capsule de l'œuf, ce qui permet une continuité sensorielle transnatale. De telles réponses sont possibles puisque leur système chimiosensoriel et visuel sont fonctionnels avant l'éclosion. Nous avons également montré que les embryons des deux espèces sont capables d'apprentissage simple (empreinte alimentaire) et associatif (conditionnement classique) et que ces capacités précoces pourraient augmenter leurs chances de survie avant et après l'éclosion en permettant la reconnaissance des proies et des prédateurs. Enfin, nous avons montré que le stress embryonnaire naturel (odeur de prédateur) et artificiel (lumière) ont des effets modérés voire nuls sur les capacités d’apprentissage périnatal. Ces résultats comportementaux ont été observés sans grande différence entre les deux espèces qui vivent pourtant dans des environnements très éloignés. Pris ensemble, ces résultats démontrent que les embryons de seiche ne sont pas isolés de leur environnement mais détectent et traitent les informations environnementales qui modulent leur comportement après l’éclosion. / The focus of this thesis centres on the sensory, cognitive abilities and stress effect of two cuttlefish species: Sepia officinalis and Sepia pharaonis. First, we demonstrated that embryos respond to different environmental stimuli (i.e. light, prey, predators, ink) showing that sensory information passes through the egg capsule which allows a sensory transnatal continuity. Such responses to external stimuli are likely facilitated through their visual and chemosensory systems that are functional prior to hatching. We also demonstrated that the embryos of these two species are capable of simple learning (food imprinting) and associative learning (classical conditioning). These early abilities might increase their survival chance before and after hatching because they allow prey and predator recognition event before hatching. Finally, we showed that both natural embryonic stress (predatory odour) and artificial stress (light) have moderate or no effects on perinatal learning abilities. The same behavior was observed on the two species whereas they live in different continent. Taken together, these results demonstrate that cuttlefish embryos are not isolated from their environment, but rather detect and process external information which shapes their behaviors after hatching.

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<p>Prenatal life events have been long observed to be able to influence disease into adulthood in both epidemiological and animal studies. Prenatal stress (maternal stress during gestation) is one of such factors that has been shown to impact cognition and behaviour of the offspring. However, the effects of prenatal stress on the immune system are not understood. This study has evaluated the effects of prenatal stress on a murine model. Prenatal stress increased allergic airway inflammation in male, but not female offspring following sensitization and challenge with cockroach extract. This corresponded with stress-induced changes in the immune environment of non-sensitized animals. These changes included a decrease in regulatory T cells at baseline in males compared to non-stressed controls and increased splenic dendritic cell percentage and cytokine, particularly IFN-γ, secretion compared to prenatally stressed females. In females, prenatal stress decreased allergic inflammation, which corresponded to a decreased percentage of dendritic cells in the lung and mesenteric lymph node. Prenatal stress did not affect dendritic cell antigen presentation in ether male or female offspring. There was no evidence to suggest a prenatal stress induced change in glucocorticoid sensitivity of dendritic cells. In order to explore the possibility of prenatal stress induced decrease of parasympathetic output, a vagotomy model was used as a proof of concept in naïve animals not exposed to prenatal stress. Vagal modulation of dendritic cell phenotype and function was assessed. While there was some evidence that vagotomy may indirectly modulate dendritic cell function, its effects on the immune system were different then the changes caused by prenatal stress and thus it is a role of reduced parasympathetic output was not supported. Overall this data indicates a role of prenatal stress on the immune system with clear sex differences, but the mechanism for how this occurs is currently unknown. Further research is needed to investigate the role of TLRs and IFN-γ in this model, as well as other possible mediators of prenatal stress such as the changes to the parasympathetic nervous system that may in turn mediate alterations to the immune system. Differences in when the effects of prenatal stress are expressed during postnatal life are discussed.</p> / Master of Science (MSc)