The Role of Executive Function at 6 Years in the Association between Behavioral Inhibition at 5 Years and Anxiety at 7 Years.

EF skills play a central role in the etiology and maintenance of anxiety, but it is unclear whether they act as moderators or mediators in the relation between early behavioral inhibition (BI) and later anxiety. The current study tested two models by examining whether two executive functions (EF) skills (cognitive flexibility and working memory) assessed at age 6 acted as moderators or mediators in the relation between BI at 5 years and anxiety symptoms at 7 years. The sample consisted of 422 children from the Quebec Longitudinal Study of Child Development. We tested the moderation model, main and interaction effects using hierarchical multiple regression analyses and the mediation model with the product of coefficients test. Results showed that higher BI at 5 years predicted high anxiety at 7 years only at low levels of cognitive flexibility or working memory at 6 years. This suggests that high levels of cognitive flexibility or working memory at 6 years may act as protective factors. In contrast, neither cognitive flexibility nor working memory at age 6 acted as mediators in the association between BI at 5 years and anxiety at 7 years. Results support the hypothesis that goal-driven cognitive control processes act as moderators and promote adaptive functioning by dampening the effect of early BI on later anxiety.

Longitudinal Study of Early Adversity and Disturbing Dream Frequency: Moderating Role of Early Negative Emotionality.

Although disturbing dreams are prevalent in youth and are associated with psychopathology, little is known about their developmental course and risk factors. We aimed to examine the association between early social environment and subsequent disturbing dream frequency across adolescence as moderated by early negative emotionality. Measures of children's early social environment and negative emotionality were collected from the mothers of 410 children (5-42 months old) and measures of disturbing dream frequency directly from the children (13-18 years old). Preliminary steps identified subgroups of families with distinct profiles of social environment using latent variable mixture modeling, and captured changes in disturbing dream frequency using latent growth modeling. Regression and moderation analyses were conducted to test the study objectives. Results showed that the diverse family patterns were best captured by two profiles reflecting adverse and positive social environments and that overall disturbing dream frequency decreased during adolescence. Moderation analyses showed that when early negative emotionality was higher, DD frequency was not only more elevated in an adverse environment, but lower in a positive environment. These results indicate that the development of disturbing dreams is most strongly associated with a combination of individual and environment factors. Our study adds to the literature by refining our conception of individual traits and disturbing dream development and has implications for the prevention of bad dreams, nightmares, and associated psychopathologies.

Emotion Dysregulation Is Associated With Increased Problem Cannabis Use Among Emerging Adults During COVID-19.

OBJECTIVE: Emerging adulthood (18-25 years) is associated with peak prevalence of cannabis use. Although population-based longitudinal studies have found little change in cannabis use among emerging adults during COVID-19, research examining changes among vulnerable subgroups is lacking. The present study examined the association between emotion dysregulation at 23 years and change in cannabis use frequency and problem cannabis use among a large sample of emerging adults, from before to during the COVID-19 pandemic. METHOD: Longitudinal data were analyzed from 1,226 emerging adults (59% female; n = 738 reported cannabis use) who completed online surveys before the pandemic (2019; age 21) and 1 year into COVID-19 (2021; age 23) as part of the Québec Longitudinal Study of Child Development. RESULTS: There was no significant overall within-person change in cannabis use outcomes during COVID-19 among the emerging adult sample. However, emotional clarity (a dimension of emotion dysregulation) at 23 years significantly moderated change in problem cannabis use during COVID-19. Namely, low emotional clarity at 23 years was associated with increased problem cannabis use (B = 0.79, 95% CI [0.23, 1.34]), whereas high emotional clarity at 23 years was associated with decreased problem cannabis use (B = -0.68, 95% CI [-1.27, -0.09]) during COVID-19, among men only. CONCLUSIONS: Findings highlight the need to consider changes in cannabis use during COVID-19 among emerging adults with elevated emotion dysregulation (and particularly, low emotional clarity among men) and reiterate the need for supports and targeted interventions to reduce cannabis use and decrease associated harms as society emerges from COVID-19.

Redundant roles of AKT1 and AKT2 in fertility, estrous cyclicity and endometrial gland development.

In brief: The regulation of AKT in the endometrium during many cellular processes such as apoptosis and cell survival is crucial during the estrous cycle to ensure fertility. This research shows the specific function of AKT isoforms in the mouse endometrium for litter size, estrous cyclicity and endometrial gland development. Abstract: Apoptosis and cell survival regulation are crucial processes during the estrous cycle to prepare a receptive uterus during implantation for successful recognition of pregnancy. PI3K/AKT signaling has a crucial role during gestation, and AKT isoforms (1, 2 or 3) are regulated differently in the endometrium during the estrous cycle and embryo implantation. However, the specific roles of these isoforms are still unclear. We have previously shown that AKT isoforms expression during the rat estrous cycle and gestation is differently regulated. The present study aimed to establish the specific role of AKT isoforms in the mouse uterus. The hypothesis is that dysregulation of AKT isoforms expression could cause fertility-related issues in an isoform-specific manner. With four different mouse models and in-house crossbreeding, all isoforms KO combinations (single, double and triple) were obtained in progesterone receptor-expressing tissues. The results demonstrated that in absence of one or more AKT isoforms, female fertility was decreased. Mainly, we have observed smaller litter size, specifically in Akt1-2 KO mice. Additionally, we have found Akt1-2-3 KO mice to be fully infertile. Estrous cyclicity was also disrupted in Akt1-2 KO mice with longer diestrus stage. Moreover, the number of endometrial glands was decreased throughout the estrous cycle suggesting an important role in gland development for AKT1 and AKT2. Our results suggest not only specific roles between each isoform but also a partially redundant function of AKT1 and AKT2 in litter size, estrous cyclicity and endometrial gland development. This highlights the importance of AKT in the physiological regulation of mouse fertility.

A thorough investigation of the bifactor model of psychopathology in a representative birth cohort: Testing internal and predictive validity to inform models of comorbidity.

This study used symptom dimensions reflecting DSM-V internalizing, externalizing, eating disorders, and substance use (SU) and related problems to thoroughly investigate the structure of psychopathology in mid-adolescence (15 and 17 years, N = 1,515, 52% female). Compared to other hierarchical configurations (unidimensional, correlated factors, or higher-order model), a bifactor model of psychopathology wherein all first-order symptom dimensions loaded onto a second-order general psychopathology factor (P factor) and one of three, second-order specific internalizing, externalizing, or SU factors, best captured the structure of the psychopathology in mid-adolescence. This bifactor model was then used to predict several distinct mental health disorders and alcohol use disorder (AUD) at 20 years, via a structural equation model (SEM). The P factor (bifactor model) was associated with all but one outcome (suicidal ideation without an attempt), at 20 years. Controlling for the P factor, there were no additional, positive, temporal cross-associations (i.e., between mental health (mid-adolescence) and AUD at 20 years, or between SU (mid-adolescence) and mental health problems at 20 years). These results are bolstered by findings from a well-fitting correlated factors model. Namely, when mid-adolescent psychopathology was modeled using an adjusted correlated factors model, associations with outcomes at 20 years were largely masked, with no significant partial, temporal cross-associations. Thus, collectively, findings indicate that comorbidity between SU and mental health in youth may be largely attributable to an underlying liability to experience both problems (i.e., P factor). Ultimately, results support targeting the common liability to psychopathology in the prevention of later mental health problems and AUD. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Transactional associations between vocabulary and disruptive behaviors during the transition to formal schooling.

This study investigated the transactional relations between vocabulary and disruptive behaviors (DB; physical aggression and opposition/rule breaking/theft and vandalism), during the transition to formal schooling, using a community sample of 572 children. Cross-lagged panel model analyses were used to examine bidirectional relationships, comparing physical aggression to non-aggressive DB. Transactional associations between vocabulary and DB were observed, coinciding with school entry. Lower vocabulary in preschool (60mo.) was predictive of higher physical aggression scores in kindergarten. In turn, higher physical aggression in kindergarten was predictive of lower vocabulary in 1st grade. For non-aggressive DB, recurrent associations were found. Lower verbal skills in preschool (42mo.) and kindergarten predicted higher non-aggressive DB scores later in preschool and in 1st grade respectively. In turn, higher non-aggressive DB in kindergarten predicted lower vocabulary scores in 1st grade. In contrast to transactional paths from vocabulary to DB, transactional paths from DB to vocabulary observed after the transition to elementary school remained significant after controlling for comorbid hyperactivity, impulsivity and inattention behaviors, suggesting these links were specific to aggressive and non-aggressive DB. Practical implications for prevention are discussed.

Prenatal paternal anxiety symptoms predict child DHEA levels and internalizing symptoms during adrenarche.

Introduction: This study examined (1) whether measures of paternal anxious and depressive symptoms collected prenatally and during a follow-up assessment when the child was in middle childhood, predict child neuroendocrine outcomes, and (2) whether neuroendocrine outcomes are intermediate factors between paternal mental health and child cognitive/behavioral outcomes. Middle childhood coincides with increased autonomy as the child transitions into grade school, and with adrenarche, as the maturing adrenal gland increases secretion of dehydroepiandrosterone (DHEA) and its sulfated metabolite (DHEA-S), hormones that are implicated in corticolimbic development which regulate emotions and cognition. Methods: Participants were recruited from a subsample of a large prospective birth cohort study (3D study). We conducted a follow-up study when children were 6-8 years old (N = 61 families, 36 boys, 25 girls). Parental symptoms of anxiety, stress and depression were assessed via validated self-report questionnaires: prenatally using an in-house anxiety questionnaire, the Perceived Stress Scale (PSS) and the Center for Epidemiologic Studies Depression (CES-D), and at the follow up, using the Beck Anxiety and Beck Depression Inventories. Children provided salivary hormone samples, and their pituitary gland volume was measured from structural Magnetic Resonance Imaging (MRI) scans. Child behaviors were measured using the Strengths and Difficulties Questionnaire and cognitive outcomes using the WISC-V. Multiple regression analyses were used to test whether paternal mental health symptoms assessed prenatally and during childhood are associated with child neuroendocrine outcomes, adjusting for maternal mental health and child sex. Indirect-effect models assessed whether neuroendocrine factors are important intermediates that link paternal mental health and cognitive/behavioral outcomes. Results: (1) Fathers' prenatal anxiety symptoms predicted lower DHEA levels in the children, but not pituitary volume. (2) Higher prenatal paternal anxiety symptoms predicted higher child internalizing symptoms via an indirect pathway of lower child DHEA. No associations were detected between paternal anxiety symptoms measured in childhood, and neuroendocrine outcomes. No child sex differences were detected on any measure. Conclusion: These results highlight the often-overlooked role of paternal factors during pregnancy on child development, suggesting that paternal prenatal anxiety symptoms are associated with child neuroendocrine function and in turn internalizing symptoms that manifest at least up to middle childhood.

The moderating role of sex and self-, teacher-, and father-reported ADHD hyperactivity-impulsivity symptoms, on the association between early adolescent internalizing symptoms and substance use.

AIMS: Internalizing symptoms are theorized to lead to substance use (SU) via a tendency to use substances to cope with or self-medicate negative feelings and emotions; however, empirically, this association is mixed, pointing to the existence of moderating factors. The present study aimed to examine how self-, teacher-, and father-reported attention-deficit/hyperactivity disorder hyperactivity-impulsivity symptoms (ADHD-HI) and sex, moderated the association between self-reported internalizing symptoms and SU, in early adolescence. METHODS: Cross-sectional data obtained at 13 years of age, drawn from the Quebec Longitudinal Study of Child Development (N = 1,424; 53 % female). Alcohol, cigarette, and cannabis use, and internalizing and ADHD-HI symptoms were assessed. RESULTS: There was a significant three-way interaction between internalizing, ADHD-HI, and sex, for cigarette use, with Bayes factor (BF) indicating very strong evidence for an effect (BF = 48.40). While the three-way interaction for cannabis use did not reach statistical significance (self-report: p <.066; father-report: p <.053), BF indicated substantial evidence for an effect (self-report: BF = 3.54; father-report: BF = 9.08). Further analyses revealed internalizing was associated with cigarette and cannabis use only among females with high ADHD-HI symptoms (cigarette use: ß = 0.15, SE = 0.04, 95 %CI [0.07, 0.22]; cannabis use (self-reported ADHD-HI): ß = 0.14, SE = 0.06, 95 %CI [0.04, 0.25]; cannabis use (father-reported ADHD-HI): ß = 0.21, SE = 0.10, 95 %CI [0.01, 0.41]). CONCLUSIONS: Findings aid in clarifying the inconsistent relationship between internalizing symptoms and SU among adolescent females by underscoring the moderating role of ADHD-HI. Further, findings also support a growing body of literature which highlights the need for both self- and adult-informants (i.e., teacher and parent) in assessing ADHD-HI symptoms in females.

Longitudinal associations throughout adolescence: Suicidal ideation, disturbing dreams, and internalizing symptoms.

OBJECTIVE/BACKGROUND: Many studies have reported associations between disturbing dream occurrence and internalizing symptoms in adults, but the extent to which such associations also characterize adolescents remains unknown. The main goal of the present longitudinal study was to evaluate the strength and stability of the associations between disturbing dream frequency, suicidal ideation, and internalizing symptoms from ages 13 to 18. METHODS: Participants (N = 434) drawn from two longitudinal birth cohort studies on child development in the province of Quebec, Canada, completed annual self-reports of disturbing dream frequency, suicidal ideation, and levels of depression and anxiety. RESULTS: Two separate cross-lagged panel models for symptoms of depression and anxiety were conducted with both models showing similar results. In early adolescence, high levels of and higher change in disturbing dream frequency were associated with increased odds of reporting later suicidal ideation, whereas in mid to late adolescence, increased odds of reporting suicidal ideation at age 17 was associated with increased disturbing dream frequency at age 18. Across adolescence, increased levels of depression and anxiety were associated with increased odds of reporting later suicidal ideation and increased disturbing dream frequency. CONCLUSIONS: These findings support previous literature suggesting that disturbing dream frequency, depression, and anxiety, are risk factors for suicidal ideation throughout adolescence. The present longitudinal study allows for a refinement of our conceptualization of disturbing dream and their relation to suicide and internalizing symptoms throughout adolescence and suggests that the collection of information on disturbing dream and internalizing symptoms during early adolescence may help screen adolescents for suicide risk.

Transition from preschool to school: Children's pattern of change in morning cortisol concentrations.

Many studies show a general increase in stress hormones at the exposure to school entry, but inconsistencies among them due to small samples with varying methodologies and very few time-points, preclude robust conclusions. The current study aimed to describe the pattern of morning cortisol concentration in children across the transition from preschool to school by examining whether we could identify a response to the school entry, but also an anticipatory stress response (pre-entry) and a stress adaptation response (post-entry). We further tested the robustness of this pattern across several characteristics. Participants were 384 children recruited from two cohorts of the 3D pregnancy study, and followed across their transition from preschool to kindergarten. Children's morning salivary cortisol samples were collected over five time-points: twice before school entry, once at school entry and twice after school entry (one sample per time-point). Although no anticipatory stress response was observed two weeks before school entry, latent growth curve models showed that most children's morning cortisol concentrations increased during the first two weeks of school, and was not associated with any sociodemographic characteristics, supporting the hypothesis that school entry is a normative environmental stressor. In contrast, two months after school entry, some children showed stress adaptation whereas others showed a prolonged stress response to school entry. This between-children variance could not be explained by any specific sociodemographic characteristic. This study showed that the morning stress response rises at school entry and is sustained for at least two weeks in most children. However, the observed variability in the stress adaptation response remains to be elucidated and linked to functional correlates.

Changes in emerging adults' alcohol and cannabis use from before to during the COVID-19 pandemic: Evidence from a prospective birth cohort.

OBJECTIVE: Prospective research is needed to better-understand changes in substance use from before to during the coronavirus disease (COVID-19) pandemic, among emerging adults (18-25 years), a high-risk group for substance use. METHOD: N = 1,096 (weighted sample N = 1,080; 54% female) participants enrolled in the Québec Longitudinal Study of Child Development, who completed prepandemic (2019; 21 years) and COVID-19 (mid-March to mid-June 2020) surveys. COVID-19-related and preexisting factors were examined as moderators of change in substance use. RESULTS: Full sample analyses revealed decreased binge drinking (p < .001, Bayes factor [BF] = 22, Cohen's f² = 0.02), but no changes in alcohol and cannabis use. Stratified analyses revealed emerging adults who reported < monthly use prepandemic increased their alcohol use (p < .001, BF > 150, f² = 0.05) and binge drinking (p < .001, BF = 27, f² = 0.01), but not their cannabis use. Conversely, emerging adults who reported >monthly use prepandemic decreased their binge drinking (p < .001, BF > 150, f² = .12) and cannabis use (p < .001, BF > 150, f² = .06), but did not change their alcohol use frequency. Several factors moderated change in substance use, including employment loss (p = .005, BF > 39, f² = .03) and loneliness (p = .018, BF > 150, f² = .10) during COVID-19. CONCLUSIONS: Changes in alcohol and cannabis use frequency among emerging adults in the first 3 months of COVID-19 largely differed according to prepandemic substance use, COVID-19-related factors, and preexisting factors. While some youth with preexisting vulnerabilities (e.g., more frequent substance use prepandemic) remained stable or decreased their substance use during COVID-19, emerging adults who experienced employment loss, loneliness, and financial concerns during COVID-19 increased their substance use, highlighting the need for increased supports for vulnerable populations. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Transactional longitudinal relations between accuracy and reaction time on a measure of cognitive flexibility at 5, 6, and 7 years of age.

Whereas accuracy is used as an indicator of cognitive flexibility in preschool-age children, reaction time (RT), or a combination of accuracy and RT, provide better indices of performance as children transition to school. Theoretical models and cross-sectional studies suggest that a speed-accuracy tradeoff may be operating across this transition, but the lack of longitudinal studies makes this transition difficult to understand. The current study explored the longitudinal and bidirectional associations between accuracy and RT on the DCCS (mixed block) at 5, 6, and 7 years of age using cross-lagged panel analyses. The study also examined the roles of working memory and language, as potential longitudinal mediators between RT at Time X and accuracy at Time X + 1, and explored the role of inhibitory control. The sample consisted of 425 children from the Quebec Longitudinal Study of Child Development. Results show lagged associations from slower RT to greater improvements in accuracy between 5 and 6 years and between 6 and 7 years. Further, higher accuracy at 6 years predicted faster RT at 7 years. Only working memory acted as a partial mediator between RT at 5 years and accuracy at 6 years. These results provide needed longitudinal evidence to support theoretical claims that slower RT precedes improved accuracy in the development of cognitive flexibility, that working memory may be involved in the early stage of this process, and that accuracy and reaction time become more efficient in later stages of this process.

A three-factor model of common early onset psychiatric disorders: temperament, adversity, and dopamine.

Commonly comorbid early onset psychiatric disorders might reflect the varying expression of overlapping risk factors. The mediating processes remain poorly understood, but three factors show some promise: adolescent externalizing traits, early life adversity, and midbrain dopamine autoreceptors. To investigate whether these features acquire greater predictive power when combined, a longitudinal study was conducted in youth who have been followed since birth. Cohort members were invited to participate based on externalizing scores between 11 to 16 years of age. At age 18 (age 18.5 ± 0.6 y.o.), 52 entry criteria meeting volunteers had a 90-min positron emission tomography scan with [18F]fallypride, completed the Childhood Trauma Questionnaire, and were assessed with the Structured Clinical Interview for DSM-5. The three-factor model identified those with a lifetime history of DSM-5 disorders with an overall accuracy of 90.4% (p = 2.4 × 10-5) and explained 91.5% of the area under the receiver operating characteristic curve [95% CI: .824, 1.000]. Targeting externalizing disorders specifically did not yield a more powerful model than targeting all disorders (p = 0.54). The model remained significant when including data from participants who developed their first disorders during a three-year follow-up period (p = 3.5 × 10-5). Together, these results raise the possibility that a combination of temperamental traits, childhood adversity, and poorly regulated dopamine transmission increases risk for diverse, commonly comorbid, early onset psychiatric problems, predicting this susceptibility prospectively.

Longitudinal associations of cannabis, depression, and anxiety in heterosexual and LGB adolescents.

Cannabis use is linked to symptoms of depression and anxiety, particularly among sexual minorities. This study examines the relationships between cannabis, and depression and anxiety symptoms at 13, 15, and 17 years using cross-lagged models in a predominantly White (n = 1,430; 92%) subsample of 1,548 participants from the Quebec Longitudinal study of Child Development. Multigroup analyses were conducted to examine the models according to sexual orientation. Demographic covariates were included as control variables, as well as alcohol, cigarette, and other drug use to examine cannabis specificity. The full sample revealed small bidirectional associations, which remained significant once control variables were included in the model: cannabis at 13 and 15 years predicted anxiety symptoms at 15 and 17 years respectively, and depression symptoms at 15 years predicted cannabis at 17 years. The initial association between cannabis at 13 years and depression symptoms at 15 years was accounted for by other drug use at 13 years. Substantial differences were found between heterosexual participants and sexual minorities: LGB participants presented a substantially larger positive association between depression symptoms at 15 years and cannabis at 17 years, as well as a negative association between anxiety symptoms at 15 years and cannabis at 17 years. Both of these relationships remained significant when accounting for control variables. These results suggest that the relationships between cannabis, and depression and anxiety symptoms are bidirectional across adolescence, albeit small. Sexual minorities present particularly large associations that may represent self-medication efforts for depressive symptoms between 15 and 17 years. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The 3D-Transition Study: Objectives, Methods, and Implementation of an Innovative Planned Missing-Data Design.

The prevalence of mental health problems represents a significant burden on school and community health resources as early as preschool. Reducing this burden requires a better understanding of the developmental mechanisms linking children's early vulnerabilities with mental health after the transition to formal schooling. The 3D-Transition Study (2017-2021) follows 939 participants from a pregnancy cohort in the province of Québec, Canada, as they transition to kindergarten and first grade to examine these mechanisms. Biannual assessments include completed questionnaires from 2 parents as well as teachers, parent-child observations, anthropometric measurements, and age-sensitive cognitive assessments. Saliva is also collected on 11 days over a 16-month period in a subsample of 384 participants to examine possible changes in child salivary cortisol levels across the school transition and their role in difficulties observed during the transition. A combination of planned missing-data designs is being implemented to reduce participant burden, where incomplete data are collected without introducing bias after the use of multiple imputation. The 3D-Transition Study will contribute to an evidence-based developmental framework of child mental health from pregnancy to school age. In turn, this framework can help inform prevention programs delivered in health-care settings during pregnancy and in child-care centers, preschools, and schools.

Externalizing Risk Pathways for Adolescent Substance Use and Its Developmental Onset: A Canadian Birth Cohort Study: Trajectoires de comportements extériorisés et le risque pour l'initiation et l'usage de substances des adolescents : Une étude de cohorte de naissance canadienne.

OBJECTIVE: Only a minority of drug and alcohol users develops a substance use disorder. Previous studies suggest that this differential vulnerability commonly reflects a developmental trajectory characterized by diverse externalizing behaviors. In this study, we examined the relation between child and adolescent externalizing behaviors and adolescent substance use in a prospectively followed Canadian birth cohort, accounting for the temporal sequence of a wide variety of contributing factors. METHODS: Two hundred and forty-two adolescents followed since birth (date range: 1996 to 2012) were assessed on externalizing behavior (age 17 months to 16 years), alcohol and cannabis use at age 16, age of alcohol use onset, family history of substance use problems, family functioning (age 11 to 15), sensation seeking (age 16), prenatal substance exposure, socioeconomic status (age 1 to 9), and sex. RESULTS: Age of alcohol use onset was predicted by a family history of substance use problems, externalizing traits from ages 6 to 10 and 11 to 16, sensation seeking at age 16, prenatal alcohol and tobacco exposure and family functioning at ages 11 to 15. High frequencies of alcohol and cannabis use at age 16 were both predicted by externalizing traits from ages 11 to 16, a family history of substance use problems and sensation seeking after controlling for other individual, environmental and familial variables. The association between familial substance use problems and substance use during adolescence was partially mediated by externalizing traits from age 11 to 16. CONCLUSIONS: The present findings provide prospective evidence for a developmental risk pathway for adolescent substance use, potentially identifying those who could benefit from early interventions.

Pharmacologic inhibition of Akt in combination with chemotherapeutic agents effectively induces apoptosis in ovarian and endometrial cancer cell lines.

The PI3K/Akt signaling pathway, the most frequently altered signaling system in human cancer, is a crucial inducer of dysregulated proliferation and neoplastic processes; however, few therapeutic strategies using PI3K/Akt inhibitors singly have been shown to be effective. The purpose of this paper was to underline the potential benefit of pharmacological modulation of the PI3K/Akt pathway when combined with specific chemotherapeutic regimens. We have studied the ability of NVP-BEZ235 (PI3K/mTOR inhibitor) and AZD5363 (Akt inhibitor) in the sensitization of cancer cells to cisplatin and doxorubicin. Our results show that NVP-BEZ235 sensitizes cells preferentially to cisplatin while AZD5363 sensitizes cells to doxorubicin. At equal concentrations (5 µm), both inhibitors reduce ribosomal protein S6 phosphorylation, but AZD5363 is more effective in reducing GSK3ß phosphorylation as well as S6 phosphorylation. Additionally, AZD5363 is capable of inducing FOXO1 and p53 nuclear localization and reduces BAD phosphorylation, which is generally increased by cisplatin and doxorubicin. Finally, the combination of AZD5363 and doxorubicin induces apoptosis in cells and robustly reduces cell ability to clonally replicate, which underlines a potential cooperative effect of the studied compounds.

Disturbing Dreams and Psychosocial Maladjustment in Children: A Prospective Study of the Moderating Role of Early Negative Emotionality.

Although frequent disturbing dreams, including bad dreams and nightmares, have been repeatedly associated with poor psychological well-being in adults, considerably less information exists on their psychosocial correlates in children. Recent empirical and theoretical contributions suggest that the association between disturbing dream frequency and psychosocial adaptation in children may differ as a function of children's negative emotionality. The current study assessed the moderating effect of very early negative emotionality (17 months of age) in the relation between disturbing dream frequency and psychosocial maladjustment (i.e., externalizing + internalizing behaviors) in a sample of 173 11-year-old children. Mixed-model analyses revealed that disturbing dream frequency was associated with some internalizing behaviors but that the association between disturbing dream frequency and most externalizing behaviors was moderated by early negative emotionality. The latter result indicates that the relation between disturbing dream frequency and externalizing behaviors was significant in 11-year-old children showing moderate negative emotionality early in life, but particularly strong in those children with high early negative emotionality. Whereas, a moderating effect of early negative emotionality was not found between disturbing dream frequency and internalizing behaviors, the findings highlight the more specific role of early emotional negativity as a developmental moderator for the link between disturbing dreams and externalizing behaviors in children. The results are discussed in light of recent models of disturbed dreaming production.

mGlu5 receptor availability in youth at risk for addictions: effects of vulnerability traits and cannabis use.

The excitatory neurotransmitter glutamate has been implicated in experience-dependent neuroplasticity and drug-seeking behaviors. Type 5 metabotropic glutamate (mGlu5) receptors might be particularly important. They are critically involved in synaptic plasticity and their availability has been reported to be lower in people with alcohol, tobacco, and cocaine use disorders. Since these reductions could reflect effects of drug use or pre-existing traits, we used positron emission tomography to measure mGlu5 receptor availability in young adults at elevated risk for addictions. Fifty-nine participants (age 18.5 ± 0.6) were recruited from a longitudinal study that has followed them since birth. Based on externalizing traits that predict future substance use problems, half were at low risk, half were at high risk. Cannabis use histories varied markedly and participants were divided into three subgroups: zero, low, and high use. Compared to low risk volunteers, those at elevated risk had lower [11C]ABP688 binding potential (BPND) values in the striatum, amygdala, insula, and orbitofrontal cortex (OFC). Cannabis use by risk group interactions were observed in the striatum and OFC. In these regions, low [11C]ABP688 BPND values were only seen in the high risk group that used high quantities of cannabis. When these high risk, high cannabis use individuals were compared to all other participants, [11C]ABP688 BPND values were lower in the striatum, OFC, and insula. Together, these results provide evidence that mGlu5 receptor availability is low in youth at elevated risk for addictions, particularly those who frequently use cannabis.

Extra-striatal D2/3 receptor availability in youth at risk for addiction.

The neurobiological traits that confer risk for addictions remain poorly understood. However, dopaminergic function throughout the prefrontal cortex, limbic system, and upper brainstem has been implicated in behavioral features that influence addiction vulnerability, including poor impulse control, and altered sensitivity to rewards and punishments (i.e., externalizing features). To test these associations in humans, we measured type-2/3 dopamine receptor (DA2/3R) availability in youth at high vs. low risk for substance use disorders (SUDs). In this study, N = 58 youth (18.5 ± 0.6 years) were recruited from cohorts that have been followed since birth. Participants with either high (high EXT; N = 27; 16 F/11 M) or low pre-existing externalizing traits (low EXT; N = 31; 20 F/11 M) underwent a 90-min positron emission tomography [18F]fallypride scan, and completed the Barratt Impulsiveness Scale (BIS-11), Substance Use Risk Profile scale (SURPS), and Sensitivity to Punishment (SP) and Sensitivity to Reward (SR) questionnaire. We found that high vs. low EXT trait participants reported elevated substance use, BIS-11, SR, and SURPS impulsivity scores, had a greater prevalence of psychiatric disorders, and exhibited higher [18F]fallypride binding potential (BPND) values in prefrontal, limbic and paralimbic regions, even when controlling for substance use. Group differences were not evident in midbrain dopamine cell body regions, but, across all participants, low midbrain BPND values were associated with low SP scores. Together, the results suggest that altered DA2/3R availability in terminal extra-striatal and dopamine cell body regions might constitute biological vulnerability traits, generating an EXT trajectory for addictions with and without co-occurring alterations in punishment sensitivity (i.e., an internalizing feature).