Modulation of orbitofrontal-striatal reward activity by dopaminergic functional polymorphisms contributes to a predisposition to alcohol misuse in early adolescence.

BACKGROUND: Abnormalities in reward circuit function are considered a core feature of addiction. Yet, it is still largely unknown whether these abnormalities stem from chronic drug use, a genetic predisposition, or both. METHODS: In the present study, we investigated this issue using a large sample of adolescent children by applying structural equation modeling to examine the effects of several dopaminergic polymorphisms of the D1 and D2 receptor type on the reward function of the ventral striatum (VS) and orbital frontal cortex (OFC), and whether this relationship predicted the propensity to engage in early alcohol misuse behaviors at 14 years of age and again at 16 years of age. RESULTS: The results demonstrated a regional specificity with which the functional polymorphism rs686 of the D1 dopamine receptor (DRD1) gene and Taq1A of the ANKK1 gene influenced medial and lateral OFC activation during reward anticipation, respectively. Importantly, our path model revealed a significant indirect relationship between the rs686 of the DRD1 gene and early onset of alcohol misuse through a medial OFC × VS interaction. CONCLUSIONS: These findings highlight the role of D1 and D2 in adjusting reward-related activations within the mesocorticolimbic circuitry, as well as in the susceptibility to early onset of alcohol misuse.

The role of the cannabinoid receptor in adolescents' processing of facial expressions.

The processing of emotional faces is an important prerequisite for adequate social interactions in daily life, and might thus specifically be altered in adolescence, a period marked by significant changes in social emotional processing. Previous research has shown that the cannabinoid receptor CB1R is associated with longer gaze duration and increased brain responses in the striatum to happy faces in adults, yet, for adolescents, it is not clear whether an association between CBR1 and face processing exists. In the present study we investigated genetic effects of the two CB1R polymorphisms, rs1049353 and rs806377, on the processing of emotional faces in healthy adolescents. They participated in functional magnetic resonance imaging during a Faces Task, watching blocks of video clips with angry and neutral facial expressions, and completed a Morphed Faces Task in the laboratory where they looked at different facial expressions that switched from anger to fear or sadness or from happiness to fear or sadness, and labelled them according to these four emotional expressions. A-allele versus GG-carriers in rs1049353 displayed earlier recognition of facial expressions changing from anger to sadness or fear, but not for expressions changing from happiness to sadness or fear, and higher brain responses to angry, but not neutral, faces in the amygdala and insula. For rs806377 no significant effects emerged. This suggests that rs1049353 is involved in the processing of negative facial expressions with relation to anger in adolescence. These findings add to our understanding of social emotion-related mechanisms in this life period.

New evidence of factor structure and measurement invariance of the SDQ across five European nations.

The main purpose of the present study was to analyse the internal structure and to test the measurement invariance of the Strengths and Difficulties Questionnaire (SDQ), self-reported version, in five European countries. The sample consisted of 3012 adolescents aged between 12 and 17 years (M = 14.20; SD = 0.83). The five-factor model (with correlated errors added), and the five-factor model (with correlated errors added) with the reverse-worded items allowed to cross-load on the Prosocial subscale, displayed adequate goodness of-fit indices. Multi-group confirmatory factor analysis showed that the five-factor model (with correlated errors added) had partial strong measurement invariance by countries. A total of 11 of the 25 items were non-invariant across samples. The level of internal consistency of the Total difficulties score was 0.84, ranging between 0.69 and 0.78 for the SDQ subscales. The findings indicate that the SDQ's subscales need to be modified in various ways for screening emotional and behavioural problems in the five European countries that were analysed.

Functional Outcomes Among Young People With Trajectories of Persistent Childhood Psychopathology.

Importance: Understanding which children in the general population are at greatest risk of poor functional outcomes could improve early screening and intervention strategies. Objective: To investigate the odds of poor outcomes in emerging adulthood (ages 17 to 20 years) for children with different mental health trajectories at ages 9 to 13 years. Design, Setting, and Participants: Growing Up in Ireland is a longitudinal, nationally representative population-based cohort study. Data collection began in August 2007 and was repeated most recently in September 2018. All results were weighted to account for sampling bias and attrition and were adjusted for socioeconomic factors. Data analysis took place from October 2022 to April 2023. Exposure: Four latent classes captured variation in mental health in children aged 9 and 13 years, based on the parent-completed Strengths and Difficulties Questionnaire. Classes included no psychopathology, internalizing, externalizing, and high (comorbid) psychopathology. Those who remained in the same class from ages 9 to 13 years were included. Main Outcomes and Measures: Poor functional outcomes in emerging adulthood were measured at approximate ages 17 years (range, 16 to 18 years) and 20 years (range, 19 to 21 years). Outcomes included poor mental health, poor physical health, social isolation, heavy substance use, frequent health service use, poor subjective well-being, and adverse educational/economic outcomes. Results: Of 5141 included participants, 2618 (50.9%) were male. A total of 3726 (72.5%) were classed as having no childhood psychopathology, 1025 (19.9%) as having persistent externalizing psychopathology, 243 (4.7%) as having persistent internalizing psychopathology, and 147 (2.9%) as having persistent high psychopathology. Having any childhood psychopathology was associated with poorer functional outcomes in emerging adulthood. The internalizing group had elevated odds of most outcomes except for heavy substance use (range of odds ratios [ORs]: 1.38 [95% CI, 1.05-1.81] for frequent health service use to 3.08 [95% CI, 2.33-4.08] for poor mental health). The externalizing group had significantly elevated odds of all outcomes, albeit with relatively small effect sizes (range of ORs: 1.38 [95% CI, 1.19-1.60] for frequent health service use to 1.98 [95% CI, 1.67-2.35] for adverse educational/economic outcomes). The high psychopathology group had elevated odds of all outcomes (nonsignificantly for frequent health service use), though with wide confidence intervals (range of ORs: 1.53 [95% CI, 1.06-2.21] for poor physical health to 2.91 [95% CI, 2.05-4.12] for poor mental health). Female participants with any psychopathology had significantly higher odds of poor physical health and frequent health service use compared with male participants with any psychopathology. Conclusions and Relevance: In this longitudinal cohort study, childhood psychopathology was associated with a widespread pattern of functional impairment in emerging adulthood. Findings point to the need for a wider range of preventive interventions in child and adolescent mental health services.

Investigating the contributions of circadian pathway and insomnia risk genes to autism and sleep disturbances.

Sleep disturbance is prevalent in youth with Autism Spectrum Disorder (ASD). Researchers have posited that circadian dysfunction may contribute to sleep problems or exacerbate ASD symptomatology. However, there is limited genetic evidence of this. It is also unclear how insomnia risk genes identified through GWAS in general populations are related to ASD and common sleep problems like insomnia traits in ASD. We investigated the contribution of copy number variants (CNVs) encompassing circadian pathway genes and insomnia risk genes to ASD risk as well as sleep disturbances in children with ASD. We studied 5860 ASD probands and 2092 unaffected siblings from the Simons Simplex Collection (SSC) and MSSNG database, as well as 7509 individuals from two unselected populations (IMAGEN and Generation Scotland). Sleep duration and insomnia symptoms were parent reported for SSC probands. We identified 335 and 616 rare CNVs encompassing circadian and insomnia risk genes respectively. Deletions and duplications with circadian genes were overrepresented in ASD probands compared to siblings and unselected controls. For insomnia-risk genes, deletions (not duplications) were associated with ASD in both cohorts. Results remained significant after adjusting for cognitive ability. CNVs containing circadian pathway and insomnia risk genes showed a stronger association with ASD, compared to CNVs containing other genes. Circadian genes did not influence sleep duration or insomnia traits in ASD. Insomnia risk genes intolerant to haploinsufficiency increased risk for insomnia when duplicated. CNVs encompassing circadian and insomnia risk genes increase ASD liability with little to no observable impacts on sleep disturbances.

The accumulation of genetic diversity within a canopy-stored seed bank.

Many plants regenerate after fire from a canopy-stored seed bank, in which seed are housed in fire resistant confructescences (cones) that remain on maternal plants. This strategy would be favoured if plants accumulate a sufficiently large and genetically diverse seed bank during interfire intervals. We use a 16-year demographic study and surveys of microsatellite variation to quantify and explain the rate of accumulation of genetic diversity within the canopy seed bank of the shrub Banksia spinulosa. Flowering and fruit set were highly variable. An initial sample in 1991 of 354 reproductively mature plants generated 426 cones over 16 years, of which only 55 cones from 40 maternal plants persisted until 2005. By genotyping seed from these 55 cones we demonstrated that genetic diversity accumulated rapidly within the seed bank. Resampling revealed that diversity was determined by the number, not the age, of cones. Cones were widely distributed among plants, outcrossing rates were high (mean t(m) = 1.00 +/- 0.04) and biparental inbreeding low. Adults displayed little evidence of isolation by distance and the genotypic diversity of seed cohorts was independent of the density of neighbouring potential sires. We therefore estimate that within at least 13 individual years the number of cones produced per year (14-63) would have contained 100% of the adult genetic diversity. We conclude that a highly outcrossed mating system and relatively widespread pollen dispersal ensure the rapid development of a genetically diverse and spatially and temporally homogeneous seed bank.

Does post-fire plant regeneration mode affect the germination response to fire-related cues?

Vegetative resprouting, soil or canopy-stored seed banks, post-fire seed dispersal and germination are the major strategies by which plants regenerate after fires. Post-fire regeneration modes of plants are commonly based on the presence or absence of post-fire recruitment as well as the presence or absence of post-fire resprouting. High temperatures, smoke and ash are characteristics of fire and the post-fire environment. We hypothesized that heat, smoke, ash and pH will have differential effects on seed germination depending on species' post-fire regeneration strategies: serotinous vs. nonserotinous (which may have soil seed banks) and resprouters vs. nonresprouters (which may be obligate seeders). Here we examined the effects of these factors on the germination of 27 common east Australian species. Most serotinous species supported our hypothesis by showing no effect or reduced germination in response to heat. However, contrary to our prediction, all nonserotinous nonresprouting species also showed no effect or reduced germination in response to heat. Smoke, contrary to our hypothesis, had a negative or no effect on all serotinous and nonresprouting species, but no clear directional effect on serotinous and resprouting species. Supporting our hypotheses, ash and high pH showed positive or nonsignificant effects on the germination of all serotinous resprouting species, and a negative or no effect on nonserotinous resprouting species. However, contrary to our prediction, it had a negative or no effect on the serotinous nonresprouting species and no clear effect on nonserotinous nonresprouting species. We also discovered large differences in germination responses between conspecific populations that varied in their degree of resprouting. Although our data confirmed several of our predictions, the overall conclusion is that the responses of seeds to heat, smoke, ash and pH are not tightly associated with post-fire regeneration functional types.

COMT Val158Met Polymorphism and Social Impairment Interactively Affect Attention-Deficit Hyperactivity Symptoms in Healthy Adolescents.

The dopaminergic system has been shown to have substantial effects on the etiology of attention-deficit hyperactivity disorder (ADHD). However, while some studies found a significant direct effect, others did not. In this context, social behavior might play an important role as a factor that is related both to the dopaminergic system and ADHD. In a large epidemiological sample of adolescents (N = 462; 16-17 years), we assessed the level of ADHD symptoms using the Strengths and Difficulties Questionnaire, social behavior using the Social Responsiveness Scale, and the allelic distribution of the dopaminergic catechol-O-methyltransferase (COMT) Val158Met polymorphism. We found a significant association between COMT and social impairment, insofar as Met-allele carriers showed increased levels of social impairment. Moreover, social impairment significantly determined an association between COMT and ADHD (explained variance: 19.09%). This effect did not significantly differ between males and females. COMT and social impairment might interactively affect ADHD symptomatology, and could thus represent significant gene-phenotypic risk factors for ADHD symptomatology. This might have interesting implications for prevention and intervention strategies with a focus on social behavior in genetically at-risk individuals.

Brain substrates of reward processing and the µ-opioid receptor: a pathway into pain?

The processing of reward and reinforcement learning seems to be important determinants of pain chronicity. However, reward processing is already altered early in life and if this is related to the development of pain symptoms later on is not known. The aim of this study was first to examine whether behavioural and brain-related indicators of reward processing at the age of 14 to 15 years are significant predictors of pain complaints 2 years later, at 16 to 17 years. Second, we investigated the contribution of genetic variations in the opioidergic system, which is linked to the processing of both, reward and pain, to this prediction. We used the monetary incentive delay task to assess reward processing, the Children's Somatization Inventory as measure of pain complaints and tested the effects of 2 single nucleotide polymorphisms (rs1799971/rs563649) of the human µ-opioid receptor gene. We found a significant prediction of pain complaints by responses in the dorsal striatum during reward feedback, independent of genetic predisposition. The relationship of pain complaints and activation in the periaqueductal gray and ventral striatum depended on the T-allele of rs563649. Carriers of this allele also showed more pain complaints than CC-allele carriers. Therefore, brain responses to reward outcomes and higher sensitivity to pain might be related already early in life and may thus set the course for pain complaints later in life, partly depending on a specific opioidergic genetic predisposition.

The Brain's Response to Reward Anticipation and Depression in Adolescence: Dimensionality, Specificity, and Longitudinal Predictions in a Community-Based Sample.

OBJECTIVE: The authors examined whether alterations in the brain's reward network operate as a mechanism across the spectrum of risk for depression. They then tested whether these alterations are specific to anhedonia as compared with low mood and whether they are predictive of depressive outcomes. METHOD: Functional MRI was used to collect blood-oxygen-level-dependent (BOLD) responses to anticipation of reward in the monetary incentive task in 1,576 adolescents in a community-based sample. Adolescents with current subthreshold depression and clinical depression were compared with matched healthy subjects. In addition, BOLD responses were compared across adolescents with anhedonia, low mood, or both symptoms, cross-sectionally and longitudinally. RESULTS: Activity in the ventral striatum was reduced in participants with subthreshold and clinical depression relative to healthy comparison subjects. Low ventral striatum activation predicted transition to subthreshold or clinical depression in previously healthy adolescents at 2-year follow-up. Brain responses during reward anticipation decreased in a graded manner between healthy adolescents, adolescents with current or future subthreshold depression, and adolescents with current or future clinical depression. Low ventral striatum activity was associated with anhedonia but not low mood; however, the combined presence of both symptoms showed the strongest reductions in the ventral striatum in all analyses. CONCLUSIONS: The findings suggest that reduced striatal activation operates as a mechanism across the risk spectrum for depression. It is associated with anhedonia in healthy adolescents and is a behavioral indicator of positive valence systems, consistent with predictions based on the Research Domain Criteria.