Adolescent Offspring Research Articles

Maternal diet high in linoleic acid alters offspring fatty acids and cardiovascular function in a rat model.

Linoleic acid (LA), an essential n-6 fatty acid (FA), is critical for fetal development. We investigated the effects of maternal high LA (HLA) diet on offspring cardiac development and its relationship to circulating FA and cardiovascular function in adolescent offspring, and the ability of the postnatal diet to reverse any adverse effects. Female Wistar Kyoto rats were fed low LA (LLA; 1·44 % energy from LA) or high LA (HLA; 6·21 % energy from LA) diets for 10 weeks before pregnancy and during gestation/lactation. Offspring, weaned at postnatal day 25, were fed LLA or HLA diets and euthanised at postnatal day 40 (n 6-8). Maternal HLA diet decreased circulating total cholesterol and HDL-cholesterol in females and decreased total plasma n-3 FA in males, while maternal and postnatal HLA diets decreased total plasma n-3 FA in females. α-Linolenic acid (ALA) and EPA were decreased by postnatal but not maternal HLA diets in both sexes. Maternal and postnatal HLA diets increased total plasma n-6 and LA, and a maternal HLA diet increased circulating leptin, in both male and female offspring. Maternal HLA decreased slopes of systolic and diastolic pressure-volume relationship (PVR), and increased cardiac Col1a1, Col3a1, Atp2a1 and Notch1 in males. Maternal and postnatal HLA diets left-shifted the diastolic PVR in female offspring. Coronary reactivity was altered in females, with differential effects on flow repayment after occlusion. Thus, maternal HLA diets impact lipids, FA and cardiac function in offspring, with postnatal diet modifying FA and cardiac function in the female offspring.

Maternal high-sugar diet results in NMDA receptors abnormalities and cognitive impairment in rat offspring.

Cognitive impairment affects patients suffering from various neuropsychiatric diseases, which are often accompanied by changes in the glutamatergic system. Epidemiological studies indicate that predispositions to the development of neuropsychiatric diseases may be programmed prenatally. Mother's improper diet during pregnancy and lactation may cause fetal abnormalities and, consequently, predispose to diseases in childhood and even adulthood. Considering the prevalence of obesity in developed countries, it seems important to examine the effects of diet on the behavior and physiology of future generations. We hypothesized that exposure to sugar excess in a maternal diet during pregnancy and lactation would affect memory as the NMDA receptor-related processes. Through the manipulation of the sugar amount in the maternal diet in rats, we assessed its effect on offspring's memory. Then, we evaluated if memory alterations were paralleled by molecular changes in NMDA receptors and related modulatory pathways in the prefrontal cortex and the hippocampus of adolescent and young adult female and male offspring. Behavioral studies have shown sex-related changes like impaired recognition memory in adolescent males and spatial memory in females. Molecular results confirmed an NMDA receptor hypofunction along with subunit composition abnormalities in the medial prefrontal cortex of adolescent offspring. In young adults, GluN2A-containing receptors were dominant in the medial prefrontal cortex, while in the hippocampus the GluN2B subunit contribution was elevated. In conclusion, we demonstrated that a maternal high-sugar diet can affect the memory processes in the offspring by disrupting the NMDA receptor composition and regulation in the medial prefrontal cortex and the hippocampus.

Maternal stress and depressive symptoms and adolescents\u2019 body mass index: a prospective study

BackgroundGrowing evidence suggests that maternal mental health issues are associated with (young) children’s weight outcomes. However, most studies have been limited by cross-sectional designs and have been aimed at (younger) children. The current prospective study focuses on the link between maternal mental health (i.e., psychological stress and depressive symptoms) and adolescents’ zBMI development.MethodsThe participants in the present study were part of wave 1 and 2 of a longitudinal study on Dutch adolescents’ and their parents’ health behavior. Adolescents (aged 10–14) and their parents were recruited through six secondary schools in the South and the East of the Netherlands. For this study, we only included biological mothers and their adolescent children who participated in both waves, with data on the main measures in both waves, leaving a final sample of 336 biological mother-child dyads. Adolescents height and weight were measured, and both parents and adolescents filled in validated questionnaires on perceived stress and depressive symptoms and answered additional questions concerning domain-specific stress. Regression analyses were performed in R to examine longitudinal links between maternal stress and depressive symptoms at baseline (T1) and adolescents’ BMI standard deviation scores (zBMI) 6 months later (T2), corrected for baseline zBMI and covariates.ResultsMaternal general perceived stress (β = .20, p = .002) at T1 preceded higher adolescents’ zBMI at T2, after controlling for baseline zBMI and other covariates, whereas maternal depressive symptoms at T1 (β = −.05, p = .44) and other domain-specific stress did not (maternal financial stress, maternal stress at work, maternal stress at home). Additionally, lower educational level among adolescents (β = .16, p = .001) and adolescent depressive symptoms (β = .16, p = .001) was associated with a higher zBMI at T2.ConclusionsResults suggest that maternal general stress, but not depressive symptoms, may influence adolescents’ weight development. Our findings warrant future investigation on whether and how general stress among mothers may predict weight increases of their adolescent offspring.

Effects of prenatal synthetic cannabinoid exposure on the cerebellum of adolescent rat offspring

Cannabis is the most commonly used illicit drug worldwide. Recently, cannabis use among young pregnant women has greatly increased. However, prenatal cannabinoid exposure leads to long-lasting cognitive, motor, and behavioral deficits in the offspring and alterations in neural circuitry through various mechanisms. Although these effects have been studied in the hippocampus, the effects of prenatal cannabinoid exposure on the cerebellum are not well elucidated. The cerebellum plays an important role in balance and motor control, as well as cognitive functions such as attention, language, and procedural memories. The aim of this study was to investigate the effects of prenatal cannabinoid exposure on the cerebellum of adolescent offspring. Pregnant rats were treated with synthetic cannabinoid agonist WIN55,212-2, and the offspring were evaluated for various cerebellar markers of oxidative stress, mitochondrial function, and apoptosis. Additionally, signaling proteins associated with glutamate dependent synaptic plasticity were examined. Administration of WIN55,212-2 during pregnancy altered markers of oxidative stress by significantly reducing oxidative stress and nitrite content. Mitochondrial Complex I and Complex IV activities were also enhanced following prenatal cannabinoid exposure. With regard to apoptosis, pP38 levels were significantly increased, and proapoptotic factor caspase-3 activity, pERK, and pJNK levels were significantly decreased. CB1R and GluA1 levels remained unchanged; however, GluN2A was significantly reduced. There was a significant decrease in MAO activity although tyrosine hydroxylase activity was unaltered. Our study indicates that the effects of prenatal cannabinoid exposure on the cerebellum are unique compared to other brain regions by enhancing mitochondrial function and promoting neuronal survival. Further studies are required to evaluate the mechanisms by which prenatal cannabinoid exposure alters cerebellar processes and the impact of these alterations on behavior.

The risk of attention deficit hyperactivity disorder symptoms in the adolescent offspring of mothers with anxiety and depressive symptoms. Findings from the raine study

IntroductionWhile there exist some studies that explored the association between maternal anxiety and depressive symptoms and the risk of attention-deficit/hyperactivity disorder (ADHD) in early and late childhood, studies exploring the risk in late adolescence are however lacking.ObjectivesThis is the first study that aimed to investigate the association between maternal anxiety, depressive, as well as comorbid anxiety and depressive symptoms, and the risk of ADHD symptoms in late adolescence.MethodsWe used data from the Raine Study, a birth cohort in Western Australia. The Depression, Anxiety, and Stress Scale (DASS) was used to assess maternal depressive and anxiety symptoms when the child was aged 10. Whereas, the DSM-oriented scales of the child behavior checklist (CBCL) was used to assess ADHD symptoms offspring in adolescents aged 17. Log-binomial regression model was used to explore the associations.ResultsAfter adjusting for relevant covariates, we found an increased risk of ADHD symptoms in the adolescent children of mothers with anxiety [RR 2.84 (95%CI 1.18-6.83)] as well as comorbid anxiety and depressive symptoms [RR 5.60 (95%CI 3.02-10.37)]. No association was seen with maternal depressive symptoms.ConclusionsThis study suggested that adolescent offspring of mothers with anxiety as well as comorbid anxiety and depressive symptoms had an increased risk of ADHD symptoms. Early detection and management for ADHD symptoms in children of mothers with anxiety and comorbid anxiety and depressive symptoms are needed.DisclosureNo significant relationships.

Maternal Opioid Exposure Culminates in Perturbed Murine Neurodevelopment and Hyperactive Phenotype in Adolescence

Opioid use by women during pregnancy has risen dramatically since 2004, accompanied by a striking increase in the prevalence of neonatal opioid withdrawal syndrome (NOWS) and other long-term neurological deficits. However, the mechanisms underlying the impact of prenatal opioid exposure on fetal neurodevelopment are largely unknown. To translate from the clinical presentation, we developed a novel mouse model to study the neurodevelopmental consequences of maternal opioid use and management. Female mice were treated with oxycodone (OXY) before mating to mimic opioid use disorder (OUD) in humans. Following pregnancy confirmation, dams were switched to buprenorphine (BUP) via oral administration, simulating medication management of OUD (MOUD) in pregnant women. Here, we document critical changes in fetal brain development including reduced cortical thickness, altered corticogenesis, and ventriculomegaly in embryos from dams that were treated with opioids before and throughout pregnancy. Maternal care giving behavior was slightly altered without affecting gross growth of offspring. However, adolescent offspring exposed to maternal opioid use during pregnancy exhibited hyperactivity in late adolescence. Remarkably, we also show increased generation of dopaminergic neurons within the ventral tegmental area (VTA) of mice exposed to prenatal opioids. These data provide critical evidence of teratogenic effects of opioid use during pregnancy and suggest a causal relationship between maternal opioid use and neurodevelopmental/behavioral anomalies in adolescence.

Risk of conduct and oppositional defiant disorder symptoms in offspring of parents with mental health problems: Findings from the Raine Study

BackgroundEpidemiological data indicate that paternal and maternal mental health difficulties are predictors of conduct disorder (CD) and oppositional defiant disorder (ODD) in offspring. We tested the association between maternal anxiety and depressive symptoms and paternal emotional problems with CD and ODD symptoms in adolescent offspring aged 17. MethodsData was from the Raine Study, a birth cohort study based in Western Australia. Offspring CD and ODD symptoms at age 17 years were measured using the DSM-oriented scales of the Child Behavior Checklist (CBCL). Depression, Anxiety, and Stress Scale (DASS) was used to assess maternal depressive and anxiety symptoms, and a self-reported questionnaire measured paternal emotional problems when the offspring was 10 years. Negative binomial regression model was used to explore associations. ResultsAdjusting for potential confounding factors, we found an increased risk of CD symptoms in the offspring of mothers with anxiety [RR = 1.76 (95%CI; 1.08–2.86)], depressive [RR = 1.40 (95%CI; 1.01–1.95)], and comorbid anxiety and depressive symptoms [RR = 2.24 (95%CI 1.35–3.72)]. We also found an increased risk of ODD symptoms in offspring of mothers with depressive [RR = 1.24 (95%CI 1.02–1.52)], but not anxiety symptoms [RR = 1.23 (95%CI 0.92–1.67)]. No associations were seen with paternal emotional problems. ConclusionOur study showed that adolescents whose mothers reported anxiety, depressive, and comorbid anxiety and depressive symptoms had a higher risk of CD and ODD symptoms at age 17. The findings have implications for preventive strategies.

Interpersonal Problems in Parents and Adolescent Borderline Personality Disorder Features.

Research shows that parental personality pathology is associated with borderline personality disorder features and internalizing/externalizing symptoms in offspring. However, studies have been limited by DSM-IV-based assessments of parental personality pathology. The authors leveraged evidence that interpersonal problems described by the Interpersonal Circumplex align with Criterion A of the DSM-5 Alternative Model for Personality Disorders and therefore used a measure of interpersonal problems to capture parental personality pathology. The authors hypothesized that parental interpersonal problems would be associated with a latent variable of borderline features in adolescent offspring. They also examined whether this relation with offspring borderline features existed above and beyond relations with offspring internalizing/externalizing symptoms, age, and gender. The sample included 524 inpatient adolescents (Mage = 15.31, 62.4% female) and their parents (80.5% female). Parental interpersonal problems demonstrated unique relationships with adolescent borderline features and externalizing symptoms, but not internalizing symptoms. Implications of the results, limitations, and future directions are discussed.

Behavioral Alterations and Decreased Number of Parvalbumin-Positive Interneurons in Wistar Rats after Maternal Immune Activation by Lipopolysaccharide: Sex Matters.

Maternal immune activation (MIA) during pregnancy represents an important environmental factor in the etiology of schizophrenia and autism spectrum disorders (ASD). Our goal was to investigate the impacts of MIA on the brain and behavior of adolescent and adult offspring, as a rat model of these neurodevelopmental disorders. We injected bacterial lipopolysaccharide (LPS, 1 mg/kg) to pregnant Wistar dams from gestational day 7, every other day, up to delivery. Behavior of the offspring was examined in a comprehensive battery of tasks at postnatal days P45 and P90. Several brain parameters were analyzed at P28. The results showed that prenatal immune activation caused social and communication impairments in the adult offspring of both sexes; males were affected already in adolescence. MIA also caused prepulse inhibition deficit in females and increased the startle reaction in males. Anxiety and hypolocomotion were apparent in LPS-affected males and females. In the 28-day-old LPS offspring, we found enlargement of the brain and decreased numbers of parvalbumin-positive interneurons in the frontal cortex in both sexes. To conclude, our data indicate that sex of the offspring plays a crucial role in the development of the MIA-induced behavioral alterations, whereas changes in the brain apparent in young animals are sex-independent.

Alterations in Tau Protein Level and Phosphorylation State in the Brain of the Autistic-Like Rats Induced by Prenatal Exposure to Valproic Acid.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficient social interaction and communication besides repetitive, stereotyped behaviours. A characteristic feature of ASD is altered dendritic spine density and morphology associated with synaptic plasticity disturbances. Since microtubules (MTs) regulate dendritic spine morphology and play an important role in spine development and plasticity the aim of the present study was to investigate the alterations in the content of neuronal α/β-tubulin and Tau protein level as well as phosphorylation state in the valproic acid (VPA)-induced rat model of autism. Our results indicated that maternal exposure to VPA induces: (1) decrease the level of α/β-tubulin along with Tau accumulation in the hippocampus and cerebral cortex; (2) excessive Tau phosphorylation and activation of Tau-kinases: CDK5, ERK1/2, and p70S6K in the cerebral cortex; (3) up-regulation of mTOR kinase-dependent signalling in the hippocampus and cerebral cortex of adolescent rat offspring. Moreover, immunohistochemical staining showed histopathological changes in neurons (chromatolysis) in both analysed brain structures of rats prenatally exposed to VPA. The observed changes in Tau protein together with an excessive decrease in α/β-tubulin level may suggest destabilization and thus dysfunction of the MT cytoskeleton network, which in consequence may lead to the disturbance in synaptic plasticity and the development of autistic-like behaviours.

A Preliminary Examination of the Interaction between Maternal Generalized Anxiety Disorder and Offspring Negative Affect in Relation to Maternal Worry about Offspring and Perceptions of Psychological Control.

Both maternal symptoms and adolescent offspring characteristics are associated with maladaptive parenting among families at risk for anxiety. One disorder that may be particularly associated with maladaptive parenting behaviors is generalized anxiety disorder (GAD). Previous work suggests that offspring negative affect (NA) is associated with different levels of maladaptive parenting behaviors among mothers with GAD. No work to date, however, has examined the association between offspring reported NA, maternal GAD, and maternal worry about offspring or maternal perceptions of psychological control (PC) among mothers of adolescents. Sixty-five mothers who were elevated in anxious arousal and their adolescent offspring between the ages of 12 and 16 years old (n = 65, 55% male, Mage = 13.89) reported on parenting (mother report), NA (offspring report), and GAD symptoms (assessed via structured clinical interview), and maternal anxiety sensitivity (AS) symptoms. Study results indicated that maternal GAD status interacted with offspring NA in relation to maternal reported use of PC and worry about offspring. Specifically, offspring NA was positively related to PC for mothers without GAD, but not for mothers with GAD. Further, for mothers with GAD, offspring NA was negatively related to worry about offspring, but this relation did not persist for mothers without GAD. Maternal AS was related to overall higher levels of worry about offspring and PC. Mothers with GAD report using higher levels of maladaptive parenting when offspring report lower levels of NA, and lower levels when offspring report high NA. This pattern was specific to maternal GAD (c.f. anxiety sensitivity).

The offspring of alcohol-exposed sires exhibit heightened ethanol intake and behavioral alterations in the elevated plus maze.

Research suggests that addictive traits are indeed heritable, but very few preclinical studies have explored transgenerational effects of paternal alcohol exposure. The present study addressed this gap in knowledge. We explored whether offspring of ethanol-exposed sires would be more likely to accept ethanol than descendants of water-exposed and control sires. We also investigated whether the second generation of ethanol-exposed descendants would accept ethanol more than controls and were more or less likely to experience anxiety-like behavior in behavioral assessments. We exposed male rats to repeated binge doses of alcohol (4g/kg/day across 8 days), water, or left them untreated and mated them with untreated females. We then bred the offspring of these rats to test transgenerational effects of paternal alcohol exposure. We tested 14-day-old offspring from the first and second filial generation for their acceptance of ethanol and water, and measured anxiety-like behavior in 38-day-old, second-generation offspring using an elevated plus maze. The results indicate that offspring of ethanol-exposed sires increase ethanol acceptance in the first generation compared to untreated controls, whereas in the second-generation increased ethanol acceptance vs. these controls is seen in descendants of both ethanol- and vehicle-treated sires. At adolescence, the second generation of rats derived from alcohol-exposed sires exhibited significantly more time spent in the open arms and significantly more arm entries than any other group. The present study suggests that parental ethanol exposure is associated with lingering effects in the infant and adolescent offspring. The second filial generation was also found to be affected, albeit similarly by grandparental ethanol exposure or by the stress of the vehicle administration.

Emotional and cognitive conflict resolution and disruptive mood dysregulation disorder in adolescent offspring of parents diagnosed with major depressive disorder, bipolar disorder, and matched healthy controls

Aims Children of parents with mood disorders have an elevated risk for various psychopathologies. In this study rate of psychopathologies among adolescent offspring of parents with major depressive (MDDoff) and bipolar disorder (BDoff), including disruptive mood dysregulation disorder (DMDD) along with the offspring ability to resolve cognitive and emotional conflicts were evaluated. Method 12–16 years old children of parents with MDD (n = 31, children= 36), BP (n = 20, children = 26) and controls (n = 25, children = 28) were enrolled. Children and parents were evaluated by using the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) and the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID); respectively. The parents completed the Child Behavior Checklist (CBCL)-dysregulation profile. The Stroop test-TBAG form and emotional Stroop test were given out to evaluate conflict resolution ability. Results The most common diagnoses among the whole sample were attention deficit and hyperactivity, separation anxiety and oppositional defiant disorders. Five cases (5.5%) of lifetime DMDD were found (three from MDDoff, the rest from BDoff). Completion times for the Stroop test-TBAG form were ranked as: BDoff > MDDoff > Hoff. In the emotional Stroop test, the BDoff responded significantly later and had significantly reduced correct responses. Conclusion Rates of lifetime DMDD were similar in the MDDoff and BDoff groups. BDoff may experience greater difficulties in resolving cognitive and emotional conflicts.

Prenatal methadone exposure impairs adolescent cognition and GABAergic neurodevelopment in a novel rat model of maternal methadone treatment

Methadone maintenance treatment (MMT) is the most common treatment for opioid-dependent pregnant women worldwide. Despite its widespread use, MMT is associated with a variety of adverse neurodevelopmental outcomes in exposed offspring, particularly cognitive impairments. The neurobiological abnormalities underlying these cognitive impairments are, however, poorly understood. This is, in part, due to a lack of animal models that represents the standard of care that methadone is administered in the clinic, with inconsistencies in the timing, doses and durations of treatment. Here we describe the characterisation of a clinically relevant rat model of MMT in which the long-term behavioural and neurobiological effects of prenatal methadone exposure can be assessed in adolescent offspring. Female Sprague-Dawley rats were treated orally with an ascending methadone dosage schedule (5, 10, 15, 20, 25 and 30 mg/kg/day), self-administered in drinking water prior to conception, throughout gestation and lactation. Pregnancy success, maternal gestational weight gain, litter survival and size were not significantly altered in methadone-exposed animals. Methadone-exposed offspring body and brain weights were significantly lower at birth. Novel object recognition tests performed at adolescence revealed methadone-exposed offspring had impaired recognition memory. Furthermore, the rewarded T-maze alternation task demonstrated that methadone-exposed female, but not male, offspring also exhibit working memory and learning deficits. Immunoblots of the adolescent prefrontal cortex and hippocampus showed methadone-exposed offspring displayed reduced levels of mature BDNF, in addition to the GABAergic proteins, GAD67 and parvalbumin, in a sex- and brain region-specific fashion. This rat model closely emulates the clinical scenario in which methadone is administered to opioid-dependent pregnant woman and provides evidence MMT can cause cognitive impairments in adolescent offspring that may be underlined by perturbed neurodevelopment of the GABAergic system.

Maternal and paternal mental health problems and the risk of offspring depression in late adolescence: findings from the Raine study

Background There are limited studies on the risk of depressive symptoms in adolescent offspring exposed to parental mental health problems in middle childhood. Aim We investigated the association between parental mental health problems, particularly paternal emotional problems and maternal symptoms of anxiety and depression, and the risk of depressive symptoms in adolescent offspring aged 17. Methods The study included 995 parent-offspring pairs from the 1989–91 birth cohort (the Raine Study) in Western Australia. Log-binomial regression was used to assess the associations. Results An increased risk of depression symptoms was observed in the adolescent offspring of mothers with depressive [RR 1.45, 95% CI 1.13–1.86] as well as anxiety symptoms [RR 1.43, 95% CI 1.09–1.87].Compared to those non-exposed, offspring whose mothers reported comorbid anxiety and depressive symptoms were more likely to have developed depressive symptoms by late adolescence [RR 1.63, 95%CI 1.11–2.38]. An increased risk of depressive symptoms was also seen in the offspring of fathers with emotional problems [RR 1.29, 95%CI 1.01–1.53]. Conclusion Our findings suggest an increased risk of depressive symptoms in the adolescent offspring of parents with mental health problems, specifically paternal emotional problems (29%) and maternal anxiety (43%), depression (45%), as well as comorbid anxiety and depressive symptoms (63%).

Perinatal SSRI exposure affects brain functional activity associated with whisker stimulation in adolescent and adult rats

Selective serotonin reuptake inhibitors (SSRI), such as fluoxetine, are used as first-line antidepressant medication during pregnancy. Since SSRIs cross the placenta the unborn child is exposed to the maternal SSRI medication, resulting in, amongst others, increased risk for autism in offspring. This likely results from developmental changes in brain function. Studies employing rats lacking the serotonin transporter have shown that elevations in serotonin levels particularly affect the development of the whisker related part of the primary somatosensory (barrel) cortex. Therefore, we hypothesized that serotonin level disturbances during development alter brain activity related to whisker stimulation. We treated female dams with fluoxetine or vehicle from gestational day 11 onwards for 21 days. We investigated offspring’s brain activity during whisker stimulation using functional magnetic resonance imaging (fMRI) at adolescence and adulthood. Our results indicate that adolescent offspring displayed increased activity in hippocampal subareas and the mammillary body in the thalamus. Adult offspring exhibited increased functional activation of areas associated with (higher) sensory processing and memory such as the hippocampus, perirhinal and entorhinal cortex, retrospinal granular cortex, piriform cortex and secondary visual cortex. Our data imply that perinatal SSRI exposure leads to complex alterations in brain networks involved in sensory perception and processing.

The Synaptic Dysregulation in Adolescent Rats Exposed to Maternal Immune Activation.

Maternal immune activation (MIA) is a risk factor for neurodevelopmental disorders in offspring, but the pathomechanism is largely unknown. The aim of our study was to analyse the molecular mechanisms contributing to synaptic alterations in hippocampi of adolescent rats exposed prenatally to MIA. MIA was evoked in pregnant female rats by i.p. administration of lipopolysaccharide at gestation day 9.5. Hippocampi of offspring (52–53-days-old rats) were analysed using transmission electron microscopy (TEM), qPCR and Western blotting. Moreover, mitochondrial membrane potential, activity of respiratory complexes, and changes in glutathione system were measured. It was found that MIA induced changes in hippocampi morphology, especially in the ultrastructure of synapses, including synaptic mitochondria, which were accompanied by impairment of mitochondrial electron transport chain and decreased mitochondrial membrane potential. These phenomena were in agreement with increased generation of reactive oxygen species, which was evidenced by a decreased reduced/oxidised glutathione ratio and an increased level of dichlorofluorescein (DCF) oxidation. Activation of cyclin-dependent kinase 5, and phosphorylation of glycogen synthase kinase 3β on Ser9 occurred, leading to its inhibition and, accordingly, to hypophosphorylation of microtubule associated protein tau (MAPT). Abnormal phosphorylation and dysfunction of MAPT, the manager of the neuronal cytoskeleton, harmonised with changes in synaptic proteins. In conclusion, this is the first study demonstrating widespread synaptic changes in hippocampi of adolescent offspring prenatally exposed to MIA.

Assessment of Prescription Opioid Medical Use and Misuse Among Parents and Their Adolescent Offspring in the US

Limited information is available regarding the association between parental and adolescent medical prescription opioid use and misuse in the US. To examine the associations between parental and adolescent prescription opioid medical use and misuse. This cross-sectional, nationally representative study included 15 200 parent-adolescent dyads from the annual 2015-2017 National Survey on Drug Use and Health. Data were collected from January 6, 2015, to December 20, 2017, and analyzed from October 4, 2019, to October 15, 2020. Parental past 12-month exclusive medical prescription opioid use and any misuse (ie, using without a prescription or in any way not directed by a physician). Adolescent past 12-month medical prescription opioid use or misuse. Multivariable regressions estimated associations between parental and offspring medical prescription opioid use or misuse, controlling for sociodemographic and psychosocial variables. Respondents included 9400 mother-child and 5800 father-child dyads in the same household; children were aged 12 to 17 years (52.8% male; mean [SD] age, 14.5 [1.7] years). Controlling for other factors, parental medical prescription opioid use was associated with adolescent prescription opioid medical use (adjusted odds ratio [aOR], 1.28; 95% CI, 1.06-1.53) and misuse (aOR, 1.53; 95% CI, 1.07-2.25), whereas parental misuse was not. Parental medical prescription stimulant use was associated with adolescent medical prescription opioid use (aOR, 1.40; 95% CI, 1.02-1.91). Parental marijuana use (aOR, 1.84; 95% CI, 1.13-2.99), parent-adolescent conflict (aOR, 1.26; 95% CI, 1.05-1.52), and adolescent depression (aOR, 1.75; 95% CI, 1.26-2.44) were associated with adolescent prescription opioid misuse. Adolescent delinquency (aOR, 1.55; 95% CI, 1.38-1.74) and perceived schoolmates' drug use (aOR, 2.87; 95% CI, 1.95-4.23) were also associated with adolescent misuse and more weakly with medical use (aORs, 1.13 [95% CI, 1.05-1.22] and 1.61 [95% CI, 1.32-1.96], respectively). Youth use of prescription opioids is in part a structural/environmental issue. The findings of this study suggest that parental medical prescription opioid use is associated with offspring prescription opioid use, whereas parental misuse is not. Restricting physicians' opioid prescribing to parents is a crucial public health goal. In addition, parents could be educated on the risks of their prescription opioid use for offspring and on practices to mitigate risk, including safe medication storage and disposal. Screening for parental prescription opioid use could be part of pediatric practice. Addressing adolescent mental health could also reduce adolescent prescription opioid misuse.

Subtle alterations in neonatal neurodevelopment following early or late exposure to prenatal maternal immune activation in mice

Prenatal exposure to maternal immune activation (MIA) is a risk factor for a variety of neurodevelopmental and psychiatric disorders. The timing of MIA-exposure has been shown to affect adolescent and adult offspring neurodevelopment, however, less is known about these effects in the neonatal period. To better understand the impact of MIA-exposure on neonatal brain development in a mouse model, we assess neonate communicative abilities with the ultrasonic vocalization task, followed by high-resolution ex vivo magnetic resonance imaging (MRI) on the neonatal (postnatal day 8) mouse brain. Early exposed offspring displayed decreased communicative ability, while brain anatomy appeared largely unaffected, apart from some subtle alterations. By integrating MRI and behavioural assays to investigate the effects of MIA-exposure on neonatal neurodevelopment we show that offspring neuroanatomy and behaviour are only subtly affected by both early and late exposure. This suggests that the deficits often observed in later stages of life may be dormant, not yet developed in the neonatal period, or not as easily detectable using a cross-sectional approach.

The association between in utero exposure to maternal psychological stress and female reproductive function in adolescence: A prospective cohort study

BackgroundExperimental studies suggest that prenatal stress affects reproductive function in female offspring, but human evidence is sparse and inconsistent. In this present study, we aim to investigate whether maternal psychological stress, quantified as stressful life events during pregnancy, affect reproductive function in the female offspring. MethodIn a large population-based pregnancy cohort study (The Raine Study) continuously followed from prenatal life through to adolescence we examined the association between the number of maternal stressful life events in both early and late gestation and subsequent ovarian and uterine function in 228 female adolescent offspring. Mothers prospectively reported stressful life events during pregnancy at 18 and 34 weeks using a standardized 10-point questionnaire. Female offspring (n ​= ​228) age 14–16 years underwent gynecological examination including transabdominal abdominal ultrasound (TAUS) to measure uterine volume and ovarian AFC. Plasma samples on day 2–6 of the spontaneous menstrual cycle measured circulating AMH and inhibin B. Multivariate linear regression analysis was used to examine the associations between maternal stressful life events and reproductive function in female offspring. Adolescents taking hormonal contraception were excluded. ResultsMost adolescents (145/228, 64%) were exposed to at least one stressful life event in early gestation and around half (125/228, 55%) were exposed to at least one in later gestation. Exposure to one or more maternal stressful life events in late gestation was associated with a greater uterine volume (β ​= ​0.13, 95% CI 0.04; 0.23) and higher ovarian AFC (β ​= ​0.19, 95% CI 0.02; 0.35) at age 14–16 years. No associations between maternal stressful events in late gestation and reproductive function were identified. No associations between stressful life events in early or late gestation and circulating AMH or Inhibin B were observed. ConclusionMaternal psychological stress in late, but not early gestation was associated with a significantly greater uterine volume and ovarian antral follicle count (AFC) in adolescent offspring but did not affect ovarian production of antimullerian hormone (AMH) or Inhibin B. These findings suggest that female reproductive function is influenced by prenatal exposure to stress.