During pregnancy, the basal activity is increased in both of our major stress response systems: the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis. At the same time, the reactivity towards stressors is reduced. These alterations sustain maternal and fetal homeostasis, and are involved in the regulation of gestational length. Although the feto-placental hormone synthesis produces the main endocrinological changes, also the central nervous system undergoes adaptation. Together, these profound adjustments have been suggested to make women’s mental health more vulnerable during pregnancy and postpartum period. The aim of this thesis was to examine factors connected to physiological stress responses during the late pregnancy in relation to pain, labour onset, emotional reactivity, and mental health. The first study examined the pain and sympathetic response during cold stress, in relation to time to delivery. Women with fewer days to spontaneous delivery had lower sympathetic reactivity, while no pain measure was associated with time to delivery. In the second study, acoustic startle response modulation was employed to study emotional reactivity during late gestation, and at four to six weeks postpartum. The startle response was measured by eye-blink electromyography, while the participants watched pleasant and unpleasant pictures, and positive and negative anticipation stimuli. A significant reduction in startle modulation by anticipation was found during the postpartum assessment. However, no startle modulation by pleasant, or unpleasant, pictures was detected at either time-point. The serum level of allopregnanolone, a neurosteroid implied in pregnancy-induced hyporeactivity, was analysed in relation to self-reported symptoms of anxiety and depression. Although the participants reported low levels of depression, the women with the highest depression scores had significantly lower levels of serum allopregnanolone. There was no correlation between allopregnanolone and anxiety scores. In the fourth study, the cortisol awakening response was compared between women with depression during pregnancy, women with depression prior to pregnancy, and women who had never suffered from depression. No group differences in cortisol awakening response during late pregnancy were found. The results are in line with the previously described pregnancy-induced hyporesponsiveness, and add to the knowledge on maternal stress hyporeactivity, gestational length, and maternal mental health.

L’axe hypothalamo-hypophyso-surrénalien joue un rôle essentiel dans l’adaptation et la réponse au stress. Toutefois, l’hyperactivation de cet axe ou des niveaux chroniquement élevés de glucocorticoïdes (GC) entraînent des conséquences pathologiques. Le système dopaminergique mésocortical, qui se projette dans le cortex préfrontal médian (CPFm), joue un rôle adaptatif en protégeant contre le stress. Jusqu’à présent, les interactions fonctionnelles entre les GC (ex : corticostérone) et le système dopaminergique mésocortical ne sont pas élucidées. Dans ce mémoire, nous avons évalué les effets des GC sur les fonctions dopaminergiques préfrontales en élevant chroniquement, à l’aide de minipompes osmotiques, les niveaux de corticostérone aux concentrations physiologiques maximales (1 mg/kg/h pendant 7 jours). Ce traitement n’a pas modifié significativement, chez les rats stressés ou non, les niveaux post mortem de dopamine et de son métabolite dans le tissu du CPFm. Toutefois, l’évaluation par voltamétrie in vivo des changements de dopamine extracellulaire dans le CPFmv a permis d’observer que la corticostérone augmente significativement la libération de dopamine en réponse à l’exposition à l’odeur de renard et au pincement de la queue. Nos études nous permettent de conclure que la corticostérone potentialise la fonction dopaminergique mésocorticale qui, à son tour, facilite la régulation négative en période de stress. / The hypothalamic-pituitary-adrenal axis plays an essential role in responding and adapting to stress, however overactivation of this axis or chronically high levels of glucocorticoids lead to pathological outcomes. The mesocortical dopamine (DA) system, terminating in the medial prefrontal cortex (mPFC), plays an adaptive role in protecting against stress, yet the functional interactions between glucocorticoids (eg. corticosterone) and the mesocortical DA system are not clear. In the present studies, we investigated the effects of glucocorticoids on prefrontal DA function using osmotic minipumps to chronically elevate corticosterone levels in the high physiological range (1 mg/kg/hr for 7 days). Chronic corticosterone treatment did not significantly affect post mortem levels of DA and its metabolites in PFC tissue in either unstressed or stressed rats. However, using in vivo voltammetry to monitor changes in extracellular DA release in PFC, corticosterone significantly increased DA release in response to both types of stress examined, exposure to predator odor and tail pinch stress. We conclude that corticosterone indeed potentiates mesocortical DA function, which in turn facilitates negative feedback regulation in times of stress.

Le diabète de type 2 et la dépression sont des problèmes majeurs de santé publique associés par un lien bidirectionnel. La dérégulation de l'axe hypothalamo-hypophyso-surrénalien (HPA), accompagnée par un taux élevé de glucocorticoïdes circulants, pourrait constituer un mécanisme commun à ces pathologies. L'axe HPA est régulé principalement au niveau de l'hypothalamus, siège de régulations nutritionnelles et émotionnelles. En ciblant les noyaux hypothalamiques, la néoglucogenèse intestinale (NGI) a des effets bénéfiques contre le développement du diabète de type 2 via la stimulation des nerfs vagal et spinal. Nous avons donc testé si la NGI, par sa communication avec l'hypothalamus, pourrait également réguler les comportements émotionnels et ainsi exercer des effets bénéfiques sur les maladies métaboliques et émotionnelles.L'absence de NGI provoque un dysfonctionnement de l'axe HPA et de son rétrocontrôle négatif (via des modifications moléculaires), caractérisés par une hypersécrétion de glucocorticoïdes et le développement d'une résistance aux glucocorticoïdes. Grâce à des études comportementales et moléculaires, nous montrons que les souris dépourvues de NGI développent des altérations phénotypiques et neurobiologiques caractéristiques d'un état anxio-dépressif. La restauration de la NGI par une perfusion de glucose portale rétablit les altérations neurobiologiques de l'axe HPA. L'induction de la NGI par un régime riche en protéines exerce des effets anxiolytiques et antidépresseurs. Ces données suggèrent que la NGI en ciblant l'hypothalamus, contrôle le métabolisme et, via l'axe HPA, les comportements émotionnels / Type 2 diabetes and major depressive disorder are major health concerns, which are highly comorbid. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction, associated with elevated circulating levels of glucocorticoids, was suggested to be a common mechanism for those pathologies. The hypothalamus, which mainly regulates the HPA axis, is a key integrative center, playing a role in both metabolic and emotional processes. By targeting hypothalamic nuclei, intestinal gluconeogenesis (IGN) exerts beneficial effects against the development of type 2 diabetes through the stimulation of the vagal and spinal nerves. We therefore evaluated whether IGN, via the hypothalamus, may represent a putative common regulator of metabolic and emotional disorders.In the absence of IGN, mice exhibited HPA axis dysregulation along with decreased glucocorticoid-mediated negative feedback (due to molecular modifications), highlighted by hypercortisolism and glucocorticoid resistance. Using behavioral and molecular studies, we demonstrated that mice lacking IGN displayed phenotypic and neurobiological hallmarks of anxiety/depression-like state. Rescuing IGN by portal glucose infusion reversed neurobiological alterations of the HPA axis. Induction of IGN by a protein-enriched diet had anxiolytic and antidepressant effects. Together, these data raise the possibility that IGN by targeting hypothalamus, controls metabolism and, via the HPA axis, emotional behavior

Indiana University-Purdue University Indianapolis (IUPUI) / Hypothalamic-pituitary-adrenal (HPA) axis dysfunction is found in heavy alcohol users. Negative urgency is a personality trait reflecting the tendency to act rashly in response to negative emotional states, and is associated with problematic alcohol consumption. The current study examined the relationship between negative urgency and HPA axis functioning following (1) negative mood induction and (2) intravenous alcohol administration among heavy social drinkers (proposed n = 40). I hypothesized the following: (1) Negative mood induction would result in an increase of cortisol release as compared to neutral mood induction; (1a) Negative urgency would be related to increased cortisol release in response to negative mood induction; (1b) Negative urgency would partially mediate the relationship between mood induction and cortisol release; (2) Acute IV alcohol administration would result in increased cortisol levels in the neutral mood condition, but decreased cortisol levels in the negative mood condition; and (2a) Negative urgency would be related to the suppression of cortisol release in the negative mood condition in response to acute IV alcohol administration. Repeated measures analyses of variance, the PROCESS macro, and paired samples t-tests were used to examine study hypotheses. Hypotheses were largely unsupported. Writing mood induction procedures reduced salivary cortisol levels in negative mood (t(35)= 2.49, p= 0.02) and there was a trend decrease in neutral mood (t(35)= 1.87, p= 0.07). Alcohol administration also reduced salivary cortisol levels in both negative mood (t(35)= 3.99, p< 0.01) and neutral mood (t(35)= 2.60, p= 0.01). However, salivary cortisol changes were no different than typical circadian patterns in response to mood induction (t(231)= 0.37, p=0.71) or in response to acute alcohol administration (t(231)= 0.44, p= 0.64). Negative urgency had a trend main effect on salivary cortisol level in response to acute IV alcohol administration, such that those higher in negative urgency were more similar to typical circadian patterns (F(19,28)= 1.59, p=0.13). This could serve as preliminary support for a psychological mechanism for the alcohol sensitivity hypothesis. Overall these findings suggest the current study failed to sufficiently manipulate salivary cortisol levels. Future studies should consider methodological techniques when exploring these relationships, including IV compared to oral alcohol administration, mood compared to stress manipulations, and cortisol compared to other HPA axis biomarkers.

Indiana University-Purdue University Indianapolis (IUPUI) / Prospective epidemiologic evidence indicates that both stressful life events (SLEs) and depression are associated with an increased risk of subclinical atherosclerosis and cardiovascular disease (CVD) events. Even though stressful life events (SLEs) and depression co-occur and may act together to influence cardiovascular disease (CVD) risk, these psychosocial factors have been mainly examined in isolation. For instance, depression may moderate the relationship between SLEs and CVD outcomes. I hypothesized that depressive symptoms would potentiate the deleterious effect of SLEs on subclinical atherosclerosis. This hypothesis is plausible, given that depressed adults exhibit exaggerated and prolonged sympathetic nervous system, hypothalamic-pituitary-adrenal (HPA) axis, and inflammatory responses to stress, which in turn could promote atherosclerosis. As compared to their nondepressed counterparts, depressed individuals may also be more likely to engage in maladaptive methods to cope with SLEs (e.g., increased tobacco use, alcohol use, and consumption of low-nutrient, energy dense foods), which could also promote atherosclerosis. I examined cross-sectional data from 274 to 279 (depending on the outcome measure) older, African American adults (mean age = 66 years, 67% female) with no evidence of clinical CVD or dementia who participated in the St. Louis African American Health-Heart study (2009–2011). Number of SLEs was assessed using the Life Events Calendar, a structured interview. From this interview, a continuous SLEs variable was computed (number of adult SLEs: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11+). Severity of depression symptoms was measured using the 17-item Hamilton Rating Scale for Depression (HAM-D). Two measures of subclinical atherosclerosis were obtained: carotid intima-media thickness (CIMT; assessed by ultrasonography) and coronary artery calcification (CAC; assessed by multi-detector computerized tomography). I conducted linear (CIMT) and logistic (CAC) regression models, first adjusted for demographics (age, sex, education) and then fully-adjusted (demographics; mean arterial pressure; low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C); hemoglobin A1c; BMI; tobacco use; diabetes diagnosis; and use of antihypertensitve, lipid lowering, antidiabetic, and antidepressant medications). No main effects of SLEs or HAM-D were found for CIMT or CAC. There were also no SLEs by HAM-D interactions for CIMT or CAC. Because the current results are largely inconsistent with prior literature and there is a paucity of studies utilizing African American samples, future research is needed to examine the independent and interactive associations of SLEs and depressive symptoms with measures of subclinical atherosclerosis. If the present results are replicated, it may suggest that SLEs, depressive symptoms, and their interactive effect are not cardiotoxic among African American adults.

Transdisciplinary research in general, and stress research in particular, requires an efficient integration of methodological knowledge of all involved academic disciplines, in order to obtain conclusions of incremental value about the investigated constructs. From a psychologist’s point of view, biochemistry and quantitative neuroendocrinology are of particular importance for the investigation of endocrine stress systems (i.e., the HPA axis, and the SNS). Despite of their fundamental role for the adequate assessment of endocrine activity, both topics are rarely covered by conventional psychological curriculae. Consequently, the transfer of the respective knowledge has to rely on other, less efficient channels of scientific exchange. The present thesis sets out to contribute to this exchange, by highlighting methodological issues that are repeatedly encountered in research on stress-related endocrine activity, and providing solutions to these issues. As outlined within this thesis, modern stress research tends to fall short of an adequate quantification of the kinetics and dynamics of bioactive cortisol. Cortisol has gained considerable popularity during the last decades, as its bioactive fraction is supposed to be reliably determinable from saliva and is therefore the most conveniently obtainable marker of HPA activity. However, a substantial fraction of salivary cortisol is metabolized to its inactivated form cortisone by the enzyme 11β-HSD2 in the parotid glands, which is likely to restrict its utility. Although the commonly used antibody-based quantification methods (i.e. immunoassays) might “involuntarily” qualify this issue to some degree (due to their inherent cross-reactivity with matrix components that are structurally-related to cortisol; e.g., cortisone), they also cause differential within-immunoassay measurement bias: Salivary cortisone has (as compared to salivary cortisol) a substantially longer half-life, which leads to an overestimation of cortisol levels the more time has passed since the onset of the prior HPA secretory episode, and thus tends to distort any inference on the kinetics of bioactive cortisol. Furthermore, absolute cortisol levels also depend on the between-immunoassay variation of antibodies. Consequently, raw signal comparisons between laboratories and studies, which are favorable as compared to effect comparisons, can hardly be performed. This finding also highlights the need for the long-sought standardization of biochemical measurement procedures. The presumably only way to circumvent both issues is to rely on quantification of ultrafiltrated blood cortisol by mass-spectrometric methods. Being partly related to biochemical considerations with research on HPA activity, a second topic arises concerning the operationalization of the construct itself: In contrast to the simple outcome measures like averaged reaction times, inclined stress researchers can only indirectly infer on the sub-processes being involved in HPA activity from longitudinally sampled hormone concentrations. HPA activity can be quantified either by (a) discrete-time, or by (b) continuous-time models. Although the former is the most popular and more convenient approach (as indicated by the overly frequent encounter of ANOVAs and trapezoidal AUC calculations in the field of psychobiological stress research), most discrete time models form rather data-driven, descriptive approaches to quantify HPA activity, that assume the existence of some endocrine resting-state (i.e., a baseline) at the first sampling point and disregard any mechanistic hormonal change occurring in between all following sampling points. Even if one ignores the fact, that such properties are unlikely to pertain to endocrine systems in general, many generic discrete time models fail to account for the specific structure of endocrine data that results from biochemical hormone measurement, as well as from the dynamics of the investigated system. More precisely speaking, cortisol time series violate homoscedasticity, residual normality, and sphericity, which need to be present in order to enable (mixed effects) GLM-based analyses. Neglecting these prerequisites may lead to inference bias unless counter-measures are taken. Such counter-measures usually involve alteration of the scale of hormone concentrations via transformation techniques. As such, a fourth-root transformation of salivary cortisol (being determined by a widely used, commercially available immunoassay) is shown to yield the optimal tradeoff for generating homoscedasticity and residual normality simultaneously. Although the violation of sphericity could be partly accounted for by several correction techniques, many modern software packages for structural equation modeling (e.g., Mplus, OpenMX, Lavaan) also offer the opportunity to easily specify more appropriate moment structures via path notation and therefore to relax the modeling assumptions of GLM approaches to the analysis of longitudinal hormone data. Proceeding from this reasoning, this thesis illustrates how one can additionally incorporate hypotheses about HPA functioning, and thus model all relevant sub-processes that give rise to HPA kinetics and dynamics. The ALT modeling framework being advocated within this thesis, is shown to serve well for this purpose: ALT modeling can recover HPA activity parameters, which are directly interpretable within a physiological framework, that is, distinct growth factors representing the amount of secreted cortisol and velocity of cortisol elimination can serve to interpret HPA reactivity and regulation in a more unambiguous way, as compared to GLM effect measures. For illustration of these advantages on a content level, cortisol elimination after stress induction was found to be elevated as compared to its known pharmacokinetics. While the mechanism behind this effect requires further investigation, its detection would obviously have been more difficult upon application of conventional GLM methods. Further extension of the ALT framework allowed to address a methodological question, which had previously been dealt with by a mere rule of thumb; what’s the optimal threshold criterion, that enables a convenient but comparably accurate classification of individuals whose HPA axis is or is not activated upon encountering a stressful situation? While a rather arbitrarily chosen baseline-to-peak threshold of 2.5 nmol/L was commonly used to identify episodes of secretory HPA activity in time series of salivary cortisol concentrations, a reanalysis of a TSST meta- dataset by means of ALT mixture modeling suggested that this 2.5 nmol/L criterion is overly conservative with modern biochemical measurement tools and should be lowered according to the precision of the utilized assay (i.e., 1.5 nmol/L). In sum, parametric ALT modeling of endocrine activity can provide a convenient alternative to the commonly utilized GLM-based approaches that enables the inference on and quantification of distinct HPA components on a theoretical foundation, and thus to bridge the gap between discrete- and continuous-time modeling frameworks. The implementation of the outlined modeling approaches by the respective statistical syntaxes and practical guidelines being derived from the comparison of cortisol assays mentioned above, are provided in the appendix of the present thesis, which will hopefully help stress researchers to directly quantify the construct they actually intend to assess.:1. Introduction 2. The hypothalamus-pituitary-adrenal (HPA) axis 3. Induction and quantification of HPA activity 4. The pitfalls of SCC measurement 5. Creating normality and homoscedasticity: GLM-based analyses 6. Relaxing sphericity: moment structure analyses 7. General conclusion

Les contrevenants de la conduite avec capacités affaiblies (CCA) n’entrent pas tous dans les registres de la sécurité routière avec le même risque de récidive. Pour pallier cette hétérogénéité, cette thèse propose de modéliser les interrelations entre les traits de personnalité et les comportements à risque associés à la récidive et de détecter un sous-groupe de contrevenants au risque de récidive élevé à l’aide de l’axe hypothalamo-hypophyso-surrénalien (HHS). Plus particulièrement, les trois articles de cette thèse s’intéressent au cortisol, l’hormone du stress. Le premier article élabore un modèle théorique réconciliant les connaissances sur l’axe HHS issues du domaine de la CCA et de domaines connexes. Lors de précédentes études, le nombre de condamnations antérieures pour CCA a été associé négativement à la réactivité du cortisol à la suite d’une situation stressante. Chez les récidivistes, cette faible réactivité s’explique partiellement par la recherche d’expériences, une dimension de la recherche de sensations. Au-delà ce trait de personnalité désinhibiteur, une faible activité de l’axe HHS a été associée à d’autres traits (c.-à-d. impulsivité et tendances antisociales) et d’autres comportements à risque (c.-à-d. infractions routières, arrestations criminelles et consommation problématique de substances psychoactives). Ce modèle intégrant la réactivité du cortisol permet une conceptualisation approfondie des diverses caractéristiques des contrevenants de la CCA et explique hypothétiquement la répétition des comportements à risque. Les deux articles suivants se penchent sur l’intérêt empirique d’utiliser l’axe HHS pour déterminer un sous-groupe de contrevenants à risque élevé de récidive. Plus précisément, le deuxième article émet l’hypothèse que les récidivistes (n = 30) ayant une faible activité de leur cortisol (c.-à-d. médiane de la surface sous la courbe relative au niveau de base et relative à la réactivité) ont davantage de traits de personnalité désinhibiteurs et de comportements à risque que les récidivistes ayant une forte activité. L’hypothèse n’a pas été confirmée. Au contraire, les récidivistes présentant une faible réactivité commettent moins d’infractions routières et d’arrestations criminelles que ceux ayant une forte réactivité. Quant à lui, le troisième article investigue une hypothèse similaire auprès des contrevenants primaires (n = 139). Les contrevenants manifestant une faible réactivité du cortisol (c.-à-d. différence entre prélèvements post-stress et pré-stress) ont davantage d’impulsivité attentionnelle, de non-planification, d’arrestations criminelles et de cigarettes fumées par jour que les contrevenants ayant une forte réactivité. Lors d’analyses exploratoires, la présence d’une variété de traits de personnalité désinhibiteurs et de comportements à risque chez les contrevenants primaires présentant une faible réactivité lorsque comparé au groupe contrôle (n = 31) suggère encore une fois leur risque élevé de récidive. L’intérêt d’ajouter un mécanisme neurobiologique pour modéliser les interrelations entre les traits de personnalité désinhibiteurs et les comportements à risque des contrevenants de la CCA a été exploré dans cette thèse. La détermination d’un sous-groupe de contrevenants présentant un risque élevé de récidive, à l’aide de l’axe HHS, semble davantage profitable auprès de l’hétérogène population des contrevenants primaires. En contrepartie, l’axe HHS ne permet pas de déterminer un sous-groupe ayant une problématique sévère auprès des récidivistes à l’extrême du continuum du risque. / Among driving while impaired (DWI) offenders, the risk of recidivism varies greatly. In order to overcome the heterogeneity among this population, the present thesis proposed a renewed conceptualization of DWI. More specifically, a model integrating disinhibitory personality traits and high-risk behaviours associated with DWI recidivism and the categorization of a high-risk subgroup of offenders based on hypothalamic-pituitary-adrenal (HPA) axis activity has been proposed. Three manuscripts aimed to answer these general objectives using salivary cortisol, that is, the stress hormone. In the first manuscript, the current HPA axis literature of DWI offenders and other high-risk populations have been merged into a comprehensive theoretical model. Previous studies have demonstrated an inverse correlation between DWI convictions frequency and cortisol reactivity to stress. Among recidivists, cortisol reactivity was partially explained by experience seeking, a sensation seeking dimension. Beyond this disinhibitory personality trait, low HPA axis activity has been linked to various traits (e.g., impulsivity and antisocial tendencies) and high-risk behaviours (e.g., traffic infractions, criminal arrests, and psychoactive drugs). By incorporating cortisol reactivity, this model stimulates a thorough conceptualization of several DWI offenders’ characteristics and as such, explains hypothetically repetition of high-risk behaviours. The following manuscripts are less theoretical and more empirical. The detection of a high-risk recidivism subgroup delineated with HPA axis activity has been investigated among two DWI offender populations. More specifically, the second manuscript hypothesized that among DWI recidivists (n = 30), low cortisol responders have more characteristics linked to recidivism such as disinhibitory personality traits and high-risk behaviours than high cortisol responders (as defined by the area under the curve sensitive to total hormonal release and to response to stimulation). This hypothesis was not supported. On the contrary, low cortisol DWI recidivists have less traffic infractions and criminal arrests than high cortisol recidivists. Finally, the third manuscript investigated a similar hypothesis but this time, among first-time DWI offenders (n = 139). Results demonstrated that low cortisol offenders have more attentional impulsiveness, non-planning impulsiveness, criminal arrests and cigarettes consumed per day than high cortisol offenders (as defined by post-stress minus pre-test episode). An exploratory analysis showed a more prevalent variety of disinhibitory personality trait and high-risk behaviours among low cortisol offenders compared to a non-DWI comparator group (n = 31). These results reinforce the potentially higher recidivism risk of this first-time DWI offenders subgroup. Neurobiological mechanism usefulness in modelling disinhibitory personality trait and high-risk behaviours of DWI offenders has been investigated in the present thesis. Additionally, detection of a high-risk recidivism subgroup seems more relevant among heterogeneous first-time DWI offenders. Instead, HPA axis activity is not as useful in detecting a problematic subgroup among the most severe offenders, namely recidivists.

No description available.

Les contrevenants de la conduite avec capacités affaiblies (CCA) n’entrent pas tous dans les registres de la sécurité routière avec le même risque de récidive. Pour pallier cette hétérogénéité, cette thèse propose de modéliser les interrelations entre les traits de personnalité et les comportements à risque associés à la récidive et de détecter un sous-groupe de contrevenants au risque de récidive élevé à l’aide de l’axe hypothalamo-hypophyso-surrénalien (HHS). Plus particulièrement, les trois articles de cette thèse s’intéressent au cortisol, l’hormone du stress. Le premier article élabore un modèle théorique réconciliant les connaissances sur l’axe HHS issues du domaine de la CCA et de domaines connexes. Lors de précédentes études, le nombre de condamnations antérieures pour CCA a été associé négativement à la réactivité du cortisol à la suite d’une situation stressante. Chez les récidivistes, cette faible réactivité s’explique partiellement par la recherche d’expériences, une dimension de la recherche de sensations. Au-delà ce trait de personnalité désinhibiteur, une faible activité de l’axe HHS a été associée à d’autres traits (c.-à-d. impulsivité et tendances antisociales) et d’autres comportements à risque (c.-à-d. infractions routières, arrestations criminelles et consommation problématique de substances psychoactives). Ce modèle intégrant la réactivité du cortisol permet une conceptualisation approfondie des diverses caractéristiques des contrevenants de la CCA et explique hypothétiquement la répétition des comportements à risque. Les deux articles suivants se penchent sur l’intérêt empirique d’utiliser l’axe HHS pour déterminer un sous-groupe de contrevenants à risque élevé de récidive. Plus précisément, le deuxième article émet l’hypothèse que les récidivistes (n = 30) ayant une faible activité de leur cortisol (c.-à-d. médiane de la surface sous la courbe relative au niveau de base et relative à la réactivité) ont davantage de traits de personnalité désinhibiteurs et de comportements à risque que les récidivistes ayant une forte activité. L’hypothèse n’a pas été confirmée. Au contraire, les récidivistes présentant une faible réactivité commettent moins d’infractions routières et d’arrestations criminelles que ceux ayant une forte réactivité. Quant à lui, le troisième article investigue une hypothèse similaire auprès des contrevenants primaires (n = 139). Les contrevenants manifestant une faible réactivité du cortisol (c.-à-d. différence entre prélèvements post-stress et pré-stress) ont davantage d’impulsivité attentionnelle, de non-planification, d’arrestations criminelles et de cigarettes fumées par jour que les contrevenants ayant une forte réactivité. Lors d’analyses exploratoires, la présence d’une variété de traits de personnalité désinhibiteurs et de comportements à risque chez les contrevenants primaires présentant une faible réactivité lorsque comparé au groupe contrôle (n = 31) suggère encore une fois leur risque élevé de récidive. L’intérêt d’ajouter un mécanisme neurobiologique pour modéliser les interrelations entre les traits de personnalité désinhibiteurs et les comportements à risque des contrevenants de la CCA a été exploré dans cette thèse. La détermination d’un sous-groupe de contrevenants présentant un risque élevé de récidive, à l’aide de l’axe HHS, semble davantage profitable auprès de l’hétérogène population des contrevenants primaires. En contrepartie, l’axe HHS ne permet pas de déterminer un sous-groupe ayant une problématique sévère auprès des récidivistes à l’extrême du continuum du risque. / Among driving while impaired (DWI) offenders, the risk of recidivism varies greatly. In order to overcome the heterogeneity among this population, the present thesis proposed a renewed conceptualization of DWI. More specifically, a model integrating disinhibitory personality traits and high-risk behaviours associated with DWI recidivism and the categorization of a high-risk subgroup of offenders based on hypothalamic-pituitary-adrenal (HPA) axis activity has been proposed. Three manuscripts aimed to answer these general objectives using salivary cortisol, that is, the stress hormone. In the first manuscript, the current HPA axis literature of DWI offenders and other high-risk populations have been merged into a comprehensive theoretical model. Previous studies have demonstrated an inverse correlation between DWI convictions frequency and cortisol reactivity to stress. Among recidivists, cortisol reactivity was partially explained by experience seeking, a sensation seeking dimension. Beyond this disinhibitory personality trait, low HPA axis activity has been linked to various traits (e.g., impulsivity and antisocial tendencies) and high-risk behaviours (e.g., traffic infractions, criminal arrests, and psychoactive drugs). By incorporating cortisol reactivity, this model stimulates a thorough conceptualization of several DWI offenders’ characteristics and as such, explains hypothetically repetition of high-risk behaviours. The following manuscripts are less theoretical and more empirical. The detection of a high-risk recidivism subgroup delineated with HPA axis activity has been investigated among two DWI offender populations. More specifically, the second manuscript hypothesized that among DWI recidivists (n = 30), low cortisol responders have more characteristics linked to recidivism such as disinhibitory personality traits and high-risk behaviours than high cortisol responders (as defined by the area under the curve sensitive to total hormonal release and to response to stimulation). This hypothesis was not supported. On the contrary, low cortisol DWI recidivists have less traffic infractions and criminal arrests than high cortisol recidivists. Finally, the third manuscript investigated a similar hypothesis but this time, among first-time DWI offenders (n = 139). Results demonstrated that low cortisol offenders have more attentional impulsiveness, non-planning impulsiveness, criminal arrests and cigarettes consumed per day than high cortisol offenders (as defined by post-stress minus pre-test episode). An exploratory analysis showed a more prevalent variety of disinhibitory personality trait and high-risk behaviours among low cortisol offenders compared to a non-DWI comparator group (n = 31). These results reinforce the potentially higher recidivism risk of this first-time DWI offenders subgroup. Neurobiological mechanism usefulness in modelling disinhibitory personality trait and high-risk behaviours of DWI offenders has been investigated in the present thesis. Additionally, detection of a high-risk recidivism subgroup seems more relevant among heterogeneous first-time DWI offenders. Instead, HPA axis activity is not as useful in detecting a problematic subgroup among the most severe offenders, namely recidivists.

Events around conception such as maternal undernutrition and twinning may have effects on offspring physiology and disease risk in adulthood. Periconceptional undernutrition alters offspring physiology and adult pathology without affecting birth size, while twinning affects birth size and physiology but with inconsistent effects on adult pathology. We investigated the effects of these two periconceptional events and their interaction on maternal cardiovascular adaptation to pregnancy and fetal growth, physiology and endocrinology in late gestation in sheep. Pre and/or postconception undernutrition resulted in increased uterine blood flow in late gestation, but no change in maternal blood volume. Preconception undernutrition alone resulted in a relatively large placenta with a small, slow-growing fetus in late gestation. In contrast, postconception undernutrition alone resulted in a fetus with rapid late-gestation growth that was maintained through a maternal fast. Fetuses of ewes undernourished throughout both periods were similar in growth rate and size to controls. Maternal fasting also demonstrated that plasma levels of C-type natriuretic peptide are acutely and independently regulated by nutrient supply in mother and fetus. Fetuses of ewes undernourished both pre- and postconception had increased glucose disposal following a glucose challenge. Hypothalamic-pituitary-adrenal axis tests in these fetuses showed decreased pituitary adrenocorticotropin hormone response to direct stimulation but increased adrenal response to decreased cortisol negative feedback. Twin fetuses grew more slowly in late gestation than singletons. Twins also had a smaller insulin response to arginine and a greater insulin response to glucose, but periconceptional undernutrition abolished this difference. Twins had suppressed baseline hypothalamic-pituitary-adrenal axis function and decreased adrenal sensitivity compared to singletons, but increased fetal pituitary adrenocorticotropin hormone response to direct stimulation and decreased cortisol negative feedback. These studies suggest that firstly, fetal size is a poor reflection of fetal growth trajectory, physiology and endocrinology. Secondly, pre- and postconception undernutrition affect late-gestation fetal growth in different ways, while undernutrition in both periods alters fetal endocrine status in late gestation. Thirdly, the biology of twin fetal development is fundamentally different from that of singletons, which may explain the inconsistency of the relationship between birth weight and adult disease risk in twins. / Auckland Medical Research Foundation, Health Research Council of New Zealand