Behavioural outcomes and psychopathology during adolescence

Preterm birth is associated with a high risk of residual neurodevelopmental disability and cognitive impairment. These problems are closely associated with psychiatric disorders and thus it is unsurprising that preterm birth also confers high risk for poor long term mental health. The risk associated with preterm birth is not a general one, but appears to be specific to symptoms and disorders associated with anxiety, inattention and social and communication problems, and manifest in a significantly higher prevalence of emotional disorders, ADHD and Autism. Adolescence is a key period for mental health and studies have shown that problems evident in childhood persist over this time and are more stable amongst preterm individuals than term-born peers. There is also modest evidence for an increased prevalence of psychotic symptoms in preterm adolescents. The high prevalence of psychiatric disorders, present in around 25% of preterm adolescents, requires long term screening and intervention

Sex Differences in Myelin Deficits and Neuroinflammatory Responses to Adolescent Drinking in Rats

Alcohol binge drinking during adolescence is associated with higher risk of developing alcohol use disorders later in life. Alcohol can lead to decreased white matter volume, myelin damage, and neuroinflammation in animal models of adolescent binge alcohol exposure. These deficits in turn are associated with cognitive disfunctions that are long-lasting and could contribute to alcohol abuse and alcoholism later in life. Importantly, human males are more likely to develop alcohol use disorders than females, thus the mechanisms underlying this might be different between the sexes. Understanding how alcohol impacts the developing adolescent brain can help us identify molecular and cellular pathways to target for therapeutic intervention. Here we sought to determine whether males and females are affected differently by voluntary alcohol drinking using an operant self-administration paradigm, and whether this level of alcohol exposure is enough to elicit similar inflammatory responses as those seen in chronic models of binge alcohol exposure. We found that alcohol had a negative impact on myelin microstructure in both males and females, however, overall myelinated fiber density was significantly reduced only in males, suggesting impaired remyelination. Similarly, males appeared to have a more robust inflammatory response than females, as indicated by upregulation of the gene that encodes for Toll-like receptor 4 (Tlr4) after alcohol drinking. While females did have an inflammatory response to alcohol, there was no change in the levels of Tlr4, and this was not due to differing circulating levels of pubertal hormones, as ovariectomized females also exhibited a similar attenuated response to alcohol. Taken together, this suggests that males might be more vulnerable to the effects of alcohol pre-pubertally, partly due to a more robust inflammatory response to alcohol, possibly related to sex differences in innate and adaptive immunity

Open AccessArticle Sex Differences in the Effect of Alcohol Drinking on Myelinated Axons in the Anterior Cingulate Cortex of Adolescent Rats

Cognitive deficits associated with teenage drinking may be due to disrupted myelination of prefrontal circuits. To better understand how alcohol affects myelination, male and female Wistar rats (n = 7–9/sex/treatment) underwent two weeks of intermittent operant self-administration of sweetened alcohol or sweetened water early in adolescence (postnatal days 28–42) and we tested for macro- and microstructural changes to myelin. We previously reported data from the males of this study showing that alcohol drinking reduced myelinated fiber density in layers II–V of the anterior cingulate division of the medial prefrontal cortex (Cg1); herein, we show that myelinated fiber density was not significantly altered by alcohol in females. Alcohol drinking patterns were similar in both sexes, but males were in a pre-pubertal state for a larger proportion of the alcohol exposure period, which may have contributed to the differential effects on myelinated fiber density. To gain more insight into how alcohol impacts myelinated axons, brain sections from a subset of these animals (n = 6/sex/treatment) were used for microstructural analyses of the nodes of Ranvier. Confocal analysis of nodal domains, flanked by immunofluorescent-labeled contactin-associated protein (Caspr) clusters, indicated that alcohol drinking reduced nodal length-to-width ratios in layers II/III of the Cg1 in both sexes. Despite sex differences in the underlying cause (larger diameter axons after alcohol in males vs. shorter nodal lengths after alcohol in females), reduced nodal ratios could have important implications for the speed and integrity of neural transmission along these axons in both males and females. Alcohol-induced changes to myelinated axonal populations in the Cg1 may contribute to long-lasting changes in prefrontal function associated with early onset drinking

Morphological Differences in Adolescent Female to Male Transsexuals before Cross-Hormone Treatment

Early-onset gender identity disorder (EO-GID) describes a strong and persistent development of cross-gender identification. Using structural magnetic resonance imaging (sMRI) and blood samples, we studied 13 female to male patients with EO-GID and compared them to 11 biological female controls. We found that the EO-GID group in comparison to its control group showed several significant differences in regional brain volumes. These include an increase in cerebral gray matter and a decrease in volume of cerebellar white matter in the mid anterior and posterior part of the corpus callosum. Furthermore, we showed statistically significant relationships between hormone levels and regional brain volume. These include relationships between the free thyroid hormone thyroxine (T4) and volumes of the frontal lobe, the temporal lobe and cerebral white matter; between sex-hormone binding globulin (SHGB) and the frontal lobe; as well as between thyroid-stimulating hormone (TSH) and cerebral gray matter. The results of regression analyses indicate that brain volume (outcome variables) decreases with the lower thyroid hormone levels (predictor variables). We propose that abnormal hormonal development of thyroid hormones influences white matter volume in our EO-GID group. Such an abnormal development further might affect both structural and functional properties of the brain

The Effects of HPA Axis Genetic Variation and Early Life Stress on Cortisol Levels in Preschool Age Children and on Amygdala and Hippocampus Volumes, Reactivity, and Connectivity at School Age

Internalizing psychopathology has been linked to increased cortisol reactivity and alterations in limbic brain structure and function, yet the mechanisms underlying these alterations are unclear. One key hypothesis is that stress plays a major causal role in these mechanisms. Animal studies find that chronic stress or glucocorticoid administration lead to alterations in hippocampal and amygdala structure and function. Relatedly, life stress is a major risk factors for depression while candidate gene studies have related variation in hypothalamic-pituitary-adrenal (HPA) axis genes to increased prevalence and severity of depression. The present work tested the hypothesis that genetic profile scores combining variance across 10 single nucleotide polymorphisms from four HPA axis genes (CRHR1, NR3C2, NR3C1, FKBP5) and early life stress would predict increases in stress cortisol levels in preschool-age children as well as alterations in hippocampal and amygdala volumes, reactivity, and resting state functional connectivity in these same children at school age. The current results indicate that (1) childhood stress exposure and genetic profile scores both predict stress cortisol, (2) these factors interact to predict volumetric alterations, partially mediated by cortisol, (3) life stress predicts left amygdala reactivity while genetic profile scores interact with sex and pubertal status to predict amygdala and hippocampus reactivity to negative emotional stimuli, and (4) these factors and their interaction predict weakened amygdala functional connectivity with subcortical and prefrontal regions. Overall, these findings suggest a key role for stress exposure, genetic risk, and cortisol in contributing to individual differences in amygdala and hippocampus structure and function typically associated with internalizing pathology

The Neurobiology of Anorexia Nervosa

Anorexia nervosa is considered the most deadly psychological illness. Individuals with and recovered from anorexia nervosa experience numerous physical and mental health difficulties, and treatment outcomes remain unpromising. Anorexia nervosa is rare in the general population, but common among individuals with a first-degree relative with the disorder. In addition, the onset of anorexia nervosa is developmentally specific, which suggests a partly biological etiology. A better understanding of the biological and neurobiological etiology of anorexia nervosa is direly needed to inform new therapies and to identify individuals at risk for the disorder. This paper summarizes the research related to neurotransmitter abnormalities, aberrant brain activity, and genetic and epigenetic mechanisms that may contribute to the etiology of this deadly disorder

The immediate and persistent effects of binge ethanol exposure on myelin protein expression in DBA/2J mice

Binge drinking is the most lethal of drinking patterns, responsible for 77% of all U.S. alcohol misuse costs. Adolescents have increased sensitivity to ethanol’s rewarding properties and decreased sensitivity to ethanol’s aversive effects likely allowing for their increased binge drinking, as compared to adults. Ethanol consumption during adolescent neurodevelopment can lead to immediate and lasting neurobiological-consequences. We have previously shown that adolescent intermittent binge ethanol exposure decreases myelin-related gene expression in DBA/2J mice. Here, we hypothesize intermittent binge ethanol exposure in adolescent DBA/2J mice will decrease myelin protein expression in the prefrontal cortex (PFC) immediately following binge ethanol and this may persist into adulthood. Adolescent DBA/2J mice (PND 29-42) were intermittently dosed with 4g/kg ethanol or water through oral gavage. Markers of puberty onset and sexual maturation were tracked in males and females to assess if ethanol affects sexual development. To assess immediate and persistent effects of binge ethanol exposure, PFC was harvested in adolescence (PND 43) and adulthood (PND 66), cryosectioned and immunostained for myelin basic protein (MBP). Western blotting was conducted to provide a complementary semi-quantitative technique to further assess the effects of binge ethanol exposure on MBP and PLP protein expression. We found that binge ethanol did not significantly alter myelin protein expression, specifically for MBP and PLP. However, we noted that ethanol males displayed a slight trend towards decreased protein expression in adolescence. In addition, we found that adult control females had significantly more PLP protein expression as compared to control males in adulthood (PND 84). Thus, we added to our previous mRNA findings with a potential trend towards decreased MBP and PLP expression in ethanol males at the protein level and found sex differences. Further work to verify these trends is needed. Together, these findings help elucidate the potential effects of ethanol on white matter integrity in the PFC and bolster our earlier mRNA findings at the protein level, which may provide the framework for future studies to uncover a mechanism by which ethanol acts to disrupt white matter

Mothers’ Prenatal Distress Accelerates Adrenal Pubertal Development in Daughters

Human life history schedules vary, partly, because of adaptive, plastic responses to early-life conditions. Little is known about how prenatal conditions relate to puberty timing. We hypothesized that fetal exposure to adversity may induce an adaptive response in offspring maturational tempo. In a longitudinal study of 253 mother-child dyads followed for 15 years, we investigated if fetal exposure to maternal psychological distress related to children’s adrenarche and gonadarche schedules, assessed by maternal and child report and by dehydroepiandrosterone sulfate (DHEA-S), testosterone, and estradiol levels. We found fetal exposure to elevated maternal prenatal psychological distress predicted earlier adrenarche and higher DHEA-S levels in girls, especially first-born girls, and that associations remained after covarying indices of postnatal adversity. No associations were observed for boys or for gonadarche in girls. Adrenarche orchestrates the social-behavioral transition from juvenility to adulthood; therefore, significant findings for adrenarche, but not gonadarche, suggest that prenatal maternal distress instigates an adaptive strategy in which daughters have earlier social-behavioral maturation. The stronger effect in first-borns suggests that, in adverse conditions, it is in the mother’s adaptive interest for her daughter to hasten social maturation, but not necessarily sexual maturation, because it would prolong the duration of the daughter allomothering younger siblings. We postulate a novel evolutionary framework that human mothers may calibrate the timing of first-born daughters’ maturation in a way that optimizes their own reproductive success