Gabriela Alarcón

Expression of specific hepatocyte and cholangiocyte transcription factors in human liver disease and embryonic development

Transcription factors are major determinants of cell-specific gene expression in all cell types. Studies in rodent liver have shown that alterations in transcription factor expression determine lineage specification during fetal liver development and signify transdifferentiation of cells of the biliary compartment into ‘oval’ cells and eventually hepatocytes in adult liver. We examined the cellular localization of hepatocyte- or BEC-associated transcription factors in human fetal and adult liver and in diseases in which transdifferentiation between hepatocytes and biliary cells may play a role. In the normal adult human liver, hepatocyte nuclear factor (HNF)4α and HNF6 appeared exclusively in hepatocytes; HNF1β, HNF3α, and HNF3β were observed only in BEC. During fetal development both BEC and hepatocytes expressed HNF3α, HNF3β, and HNF6. HNF1α was expressed only in fetal hepatocytes. We further examined expression of transcription factors in massive hepatic necrosis and in specific types of chronic liver disease. Hepatocyte-associated transcription factors HNF4α and HNF6 also appeared in BEC in massive hepatic necrosis and chronic hepatitis C virus infection. Similarly, HNF3β that is expressed only in BEC in normal adult liver was also observed in hepatocytes in primary biliary cirrhosis and chronic biliary obstruction. These data mimic previous findings in rodents in which hepatocyte-associated transcription factors appear in biliary cells prior to emergence of oval cells, which function as progenitor cells for hepatocytes when the regenerative capacity of the latter is compromised.

Developmental sex differences in resting state functional connectivity of amygdala sub-regions

During adolescence, considerable social and biological changes occur that interact with functional brain maturation, some of which are sex-specific. The amygdala is one brain area that has displayed sexual dimorphism, specifically in socio-affective (superficial amygdala [SFA]), stress (centromedial amygdala [CMA]), and learning and memory (basolateral amygdala [BLA]) processing. The amygdala has also been implicated in mood and anxiety disorders which display sex-specific features, most prominently observed during adolescence. Using functional magnetic resonance imaging (fMRI), the present study examined the interaction of age and sex on resting state functional connectivity (RSFC) of amygdala sub-regions, BLA and SFA, in a sample of healthy adolescents between the ages 10 and 16 years (n = 122, 71 boys). Whole-brain, voxel-wise partial correlation analyses were conducted to determine RSFC of bilateral BLA and SFA seed regions, created using the Eickhoff-Zilles maximum probability maps based on cytoarchitectonic mapping and FMRIBs Integrated Registration and Segmentation Tool (FIRST). Monte Carlo simulation was implemented to correct for multiple comparisons (threshold of 53 contiguous voxels with a z-value ≥ 2.25). Results indicated that with increasing age, there was a corresponding decrease in RSFC between both amygdala sub-regions and parieto-occipital cortices, with a concurrent increase in RSFC with medial prefrontal cortex (mPFC). Specifically, boys and girls demonstrated increased coupling of mPFC and left and right SFA with age, respectively; however, neither sex showed increased connectivity between mPFC and BLA, which could indicate relative immaturity of fronto-limbic networks that is similar across sex. A dissociation in connectivity between BLA- and SFA-parieto-occipital RSFC emerged, in which girls had weaker negative RSFC between SFA and parieto-occipital regions and boys had weaker negative RSFC of BLA and parieto-occipital regions with increased age, both standing in contrast to adult patterns of amygdala sub-regional RSFC. The present findings suggest relative immaturity of amygdala sub-regional RSFC with parieto-occipital cortices during adolescence, with unique patterns in both sexes that may support memory and socio-affective processing in boys and girls, respectively. Understanding the underlying normative functional architecture of brain networks associated with the amygdala during adolescence may better inform future research of the neural features associated with increased risk for internalizing psychopathology.

Adolescent neural response to reward is related to participant sex and task motivation

HighlightsBoys show more robust activation of nucleus accumbens during reward processing.Task motivation partially mediates sex differences in nucleus accumbens activity.Boys make a higher percentage of risky selections on a risky decision‐making task.Boys report higher motivation to earn money; girls report higher state anxiety. Abstract Risky decision making is prominent during adolescence, perhaps contributed to by heightened sensation seeking and ongoing maturation of reward and dopamine systems in the brain, which are, in part, modulated by sex hormones. In this study, we examined sex differences in the neural substrates of reward sensitivity during a risky decision‐making task and hypothesized that compared with girls, boys would show heightened brain activation in reward‐relevant regions, particularly the nucleus accumbens, during reward receipt. Further, we hypothesized that testosterone and estradiol levels would mediate this sex difference. Moreover, we predicted boys would make more risky choices on the task. While boys showed increased nucleus accumbens blood oxygen level‐dependent (BOLD) response relative to girls, sex hormones did not mediate this effect. As predicted, boys made a higher percentage of risky decisions during the task. Interestingly, boys also self‐reported more motivation to perform well and earn money on the task, while girls self‐reported higher state anxiety prior to the scan session. Motivation to earn money partially mediated the effect of sex on nucleus accumbens activity during reward. Previous research shows that increased motivation and salience of reinforcers is linked with more robust striatal BOLD response, therefore psychosocial factors, in addition to sex, may play an important role in reward sensitivity. Elucidating neurobiological mechanisms that support adolescent sex differences in risky decision making has important implications for understanding individual differences that lead to advantageous and adverse behaviors that affect health outcomes.

Lower Working Memory Performance in Overweight and Obese Adolescents Is Mediated by White Matter Microstructure

OBJECTIVES Elevated body mass index (BMI) is associated with deficits in working memory, reduced gray matter volume in frontal and parietal lobes, as well as changes in white matter (WM) microstructure. The current study examined whether BMI was related to working memory performance and blood oxygen level dependent (BOLD) activity, as well as WM microstructure during adolescence. METHODS Linear regressions with BMI and (1) verbal working memory BOLD signal, (2) spatial working memory BOLD signal, and (3) fractional anisotropy (FA), a measure of WM microstructure, were conducted in a sample of 152 healthy adolescents ranging in BMI. RESULTS BMI was inversely related to IQ and verbal and spatial working memory accuracy; however, there was no significant relationship between BMI and BOLD response for either verbal or spatial working memory. Furthermore, BMI was negatively correlated with FA in the left superior longitudinal fasciculus (SLF) and left inferior longitudinal fasciculus (ILF). ILF FA and IQ significantly mediated the relationship between BMI and verbal working memory performance, whereas SLF FA, but not IQ, significantly mediated the relationship between BMI and accuracy of both verbal and spatial working memory. CONCLUSIONS These findings indicate that higher BMI is associated with decreased FA in WM fibers connecting brain regions that support working memory, and that WM microstructural deficits may underlie inferior working memory performance in youth with higher BMI. Of interest, BMI did not show the same relationship with working memory BOLD activity, which may indicate that changes in brain structure precede changes in function.

Variation in Parasympathetic Dysregulation Moderates Short-term Memory Problems in Childhood Attention-Deficit/Hyperactivity Disorder

Although attention deficit/hyperactivity disorder (ADHD) is associated with impairment in working memory and short-term memory, up to half of individual children with ADHD perform within a normative range. Heterogeneity in other ADHD-related mechanisms, which may compensate for or combine with cognitive weaknesses, is a likely explanation. One candidate is the robustness of parasympathetic regulation (as indexed by respiratory sinus arrhythmia; RSA). Theory and data suggest that a common neural network is likely tied to both heart-rate regulation and certain cognitive functions (including aspects of working and short-term memory). Cardiac-derived indices of parasympathetic reactivity were collected during short-term memory (STM) storage and rehearsal tasks from 243 children (116 ADHD, 127 controls). ADHD was associated with lower STM performance, replicating previous work. In addition, RSA reactivity moderated the association between STM and ADHD – both as a category and a dimension – independent of comorbidity. Specifically, conditional effects revealed that high levels of withdrawal interacted with weakened STM but high levels of augmentation moderated a positive association predicting ADHD. Thus, variations in parasympathetic reactivity may help explain neuropsychological heterogeneity in ADHD.

Sex differences in the neural substrates of spatial working memory during adolescence are not mediated by endogenous testosterone

Adolescence is a developmental period characterized by notable changes in behavior, physical attributes, and an increase in endogenous sex steroid hormones, which may impact cognitive functioning. Moreover, sex differences in brain structure are present, leading to differences in neural function and cognition. Here, we examine sex differences in performance and blood oxygen level-dependent (BOLD) activation in a sample of adolescents during a spatial working memory (SWM) task. We also examine whether endogenous testosterone levels mediate differential brain activity between the sexes. Adolescents between ages 10 and 16 years completed a SWM functional magnetic resonance imaging (fMRI) task, and serum hormone levels were assessed within seven days of scanning. While there were no sex differences in task performance (accuracy and reaction time), differences in BOLD response between girls and boys emerged, with girls deactivating brain regions in the default mode network and boys showing increased response in SWM-related brain regions of the frontal cortex. These results suggest that adolescent boys and girls adopted distinct neural strategies, while maintaining spatial cognitive strategies that facilitated comparable cognitive performance of a SWM task. A nonparametric bootstrapping procedure revealed that testosterone did not mediate sex-specific brain activity, suggesting that sex differences in BOLD activation during SWM may be better explained by other factors, such as early organizational effects of sex steroids or environmental influences. Elucidating sex differences in neural function and the influence of gonadal hormones can serve as a basis of comparison for understanding sexually dimorphic neurodevelopment and inform sex-specific psychopathology that emerges in adolescence.

Adolescent Gender Differences in Cognitive Control Performance and Functional Connectivity Between Default Mode and Fronto-Parietal Networks Within a Self-Referential Context

Ineffective reduction of functional connectivity between the default mode network (DMN) and frontoparietal network (FPN) during cognitive control can interfere with performance in healthy individuals—a phenomenon present in psychiatric disorders, such as depression. Here, this mechanism is studied in healthy adolescents by examining gender differences in task-regressed functional connectivity using functional magnetic resonance imaging (MRI) and a novel task designed to place the DMN—supporting self-referential processing (SRP)—and FPN—supporting cognitive control—into conflict. Compared to boys, girls showed stronger functional connectivity between DMN and FPN during cognitive control in an SRP context (n = 40; boys = 20), a context that also elicited more errors of omission in girls. The gender difference in errors of omission was mediated by higher self-reported co-rumination—the extensive and repetitive discussion of problems and focus on negative feelings with a same-gender peer—by girls, compared to boys. These findings indicate that placing internal and external attentional demands in conflict lead to persistent functional connectivity between FPN and DMN in girls, but not boys; however, deficits in performance during this context were explained by co-rumination, such that youth with higher co-rumination displayed the largest performance deficits. Previous research shows that co-rumination predicts depressive symptoms during adolescence; thus, gender differences in the mechanisms involved with transitioning from internal to external processing may be relevant for understanding heightened vulnerability for depression in adolescent girls.

Prosocial Behavior and Depression: a Case for Developmental Gender Differences

Purpose of ReviewProsocial behavior and depression are related constructs that both increase during adolescence and display gender-specific effects. The current review surveys literature examining the association between depressive symptoms and prosociality, measured with behavioral economic paradigms, across development and proposes a theoretical model explaining a mechanism through which adolescent girls have higher risk for depression than boys.Recent FindingsRelative to healthy controls, prosocial behavior is reduced in adults with major depressive disorder (MDD) but may be increased in adolescents with MDD. The relationship between non-clinical levels of depressive symptoms and prosocial behavior remains to be studied experimentally; however, self-reported prosocial behavior is negatively associated with depressive symptoms in non-clinical adolescents, which may suggest a shift in the relation of prosocial behavior and depressive symptoms across the non-clinical (i.e., negative) to clinical range (i.e., positive).SummaryThe effect of gender on these developmental and clinical status shifts has not been studied but could have important implications for understanding the emergence of higher rates of depression in girls than boys during adolescence. We propose that girls are at heightened risk for depression due to higher social-evaluative concern and other-oriented prosocial motivation that emphasize the needs of others over the self, leading to more altruistic prosocial behavior (despite personal cost) and a higher burden that enables depressive symptoms.