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Heavy maternal alcohol drinking during pregnancy has been associated with altered neurodevelopment in the child but the effects of low-dose alcohol drinking are less clear and any potential safe level of alcohol use during pregnancy is not known. We evaluated the effects of prenatal alcohol on reward-related behavior and substance use in young adulthood and the potential sex differences therein. Participants were members of the European Longitudinal Study of Pregnancy and Childhood (ELSPAC) prenatal birth cohort who participated in its neuroimaging follow-up in young adulthood. A total of 191 participants (28-30 years; 51% men) had complete data on prenatal exposure to alcohol, current substance use, and fMRI data from young adulthood. Maternal alcohol drinking was assessed during mid-pregnancy and pre-conception. Brain response to reward anticipation and reward feedback was measured using the Monetary Incentive Delay task and substance use in young adulthood was assessed using a self-report questionnaire. We showed that even a moderate exposure to alcohol in mid-pregnancy but not pre-conception was associated with robust effects on brain response to reward feedback (six frontal, one parietal, one temporal, and one occipital cluster) and with greater cannabis use in both men and women 30 years later. Moreover, mid-pregnancy but not pre-conception exposure to alcohol was associated with greater cannabis use in young adulthood and these effects were independent of maternal education and maternal depression during pregnancy. Further, the extent of cannabis use in the late 20 s was predicted by the brain response to reward feedback in three out of the nine prenatal alcohol-related clusters and these effects were independent of current alcohol use. Sex differences in the brain response to reward outcome emerged only during the no loss vs. loss contrast. Young adult men exposed to alcohol prenatally had significantly larger brain response to no loss vs. loss in the putamen and occipital region than women exposed to prenatal alcohol. Therefore, we conclude that even moderate exposure to alcohol prenatally has long-lasting effects on brain function during reward processing and risk of cannabis use in young adulthood., (© 2024. The Author(s).)

Clinical and preclinical studies report that chronic stress induces behavioral deficits as well as volumetric and synaptic alterations in corticolimbic brain regions including the anterior cingulate cortex (ACC), amygdala (AMY), nucleus accumbens (NAc) and hippocampus (HPC). Here, we aimed to investigate the volumetric changes associated with chronic restraint stress (CRS) and link these changes to the CRS-induced behavioral and synaptic deficits. We first confirmed that CRS increases behavioral emotionality, defined as collective scoring of anxiety- and anhedonia-like behaviors. We then demonstrated that CRS induced a reduction of total brain volume which negatively correlated with behavioral emotionality. Region-specific analysis identified that only the ACC showed significant decrease in volume following CRS (p < 0.05). Reduced ACC correlated with increased behavioral emotionality (r = -0.56; p = 0.0003). Although not significantly altered by CRS, AMY and NAc (but not the HPC) volumes were negatively correlated with behavioral emotionality. Finally, using structural covariance network analysis to assess shared volumetric variances between the corticolimbic brain regions and associated structures, we found a progressive decreased ACC degree and increased AMY degree following CRS. At the cellular level, reduced ACC volume correlated with decreased PSD95 (but not VGLUT1) puncta density (r = 0.35, p < 0.05), which also correlated with increased behavioral emotionality (r = -0.44, p < 0.01), suggesting that altered synaptic strength is an underlying substrate of CRS volumetric and behavioral effects. Our results demonstrate that CRS effects on ACC volume and synaptic density are linked to behavioral emotionality and highlight key ACC structural and morphological alterations relevant to stress-related illnesses including mood and anxiety disorders., (Copyright © 2021. Published by Elsevier Ltd.)

Maternal depression during pregnancy is associated with elevated risk of anxiety and depression in offspring, but the mechanisms are incompletely understood. Here we conducted a neuroimaging follow-up of a prenatal birth cohort from the European Longitudinal Study of Pregnancy and Childhood (n = 131; 53% women, age 23-24) to test whether deviations from age-normative structural brain development in young adulthood may partially underlie this link. Structural brain age was calculated based on previously published neuroanatomical age prediction models using cortical thickness maps from healthy controls aged 6-89. Brain age gap was computed as the difference between chronological and structural brain age. Participants also completed self-report measures of anxiety and mood dysregulation. Further, mothers of a subset of participants (n = 103, 54% women) answered a self-report questionnaire in 1990-1992 about depressive symptoms during pregnancy. Higher exposure to maternal depressive symptoms in utero showed a linear relationship with elevated brain age gap, which showed a quadratic relationship with anxiety and mood dysregulation in the young adult offspring. Our findings suggest that exposure to maternal depressive symptoms in utero may be associated with accelerated brain maturation and that deviations from age-normative structural brain development in either direction predict more anxiety and dysregulated mood in young adulthood., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Parallel clinical and preclinical research have begun to illuminate the biological basis of stress-related disorders, including major depression, but translational bridges informing discrete mechanistic targets for intervention are missing. To address this critical need, we used structural MRI in a mouse model and in a large human sample to examine stress effects on brain structure that may be conserved across species. Specifically, we focused on a previously unexplored approach, whole-brain structural covariance, as it reflects synchronized changes in neuroanatomy, potentially due to mutual trophic influences or shared plasticity across regions. Using the unpredictable chronic mild stress (UCMS) paradigm in mouse we first demonstrate that UCMS-induced elevated behavioral emotionality correlates with increased size of the amygdala and other corticolimbic regions. We further identify focal increases in the amygdala's 'hubness' (degree and strength) set against the background of a global stress-related loss of network clustering and modularity. These macroscopic changes are supported on the molecular level by increased postsynaptic density-95 protein in the amygdala, consistent with stress-induced plastic changes and synaptic strengthening. Finally, we provide clinical evidence that strikingly similar structural network reorganization patterns exist in young adults reporting high childhood trauma and increased mood symptoms. Collectively, we provide initial translational evidence for a conserved stress-related increase in amygdala-centered structural synchrony, as measured by enhanced structural covariance, which is paralleled by a decrease in global structural synchrony. This putative trade-off reflected in increased amygdala-centered plastic changes at the expense of global structural dedifferentiation may represent a mechanistic pathway for depression and related psychopathology.

Imaging genetics has identified many contributions of DNA sequence variation to individual differences in brain function, behavior, and risk for psychopathology. Recent studies have extended this work beyond the genome by mapping epigenetic differences, specifically gene methylation in peripherally assessed DNA, onto variability in behaviorally and clinically relevant brain function. These data have generated understandable enthusiasm for the potential of such research to illuminate biological mechanisms of risk. We use our research on the effects of genetic and epigenetic variation in the human serotonin transporter on brain function to generate a guardedly optimistic opinion that the available data encourage continued research in this direction, and suggest strategies to promote faster progress., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Major depressive disorder (MDD) is etiologically complex and has a heterogeneous presentation. This heterogeneity hinders the ability of molecular genetic research to reliably detect the small effects conferred by common genetic variation. As a result, significant research efforts have been directed at investigating more homogenous intermediate phenotypes believed to be more proximal to gene function and lie between genes and/or environmental effects and disease processes. In the current review we survey and integrate research on two promising intermediate phenotypes linked to depression: reward processing and stress sensitivity. A synthesis of this burgeoning literature indicates that a molecular genetic approach focused on intermediate phenotypes holds significant promise to fundamentally improve our understanding of the pathophysiology and etiology of depression, which will be required for improved diagnostic definitions and the development of novel and more efficacious treatment and prevention strategies. We conclude by highlighting challenges facing intermediate phenotype research and future development that will be required to propel this pivotal research into new directions., (Copyright © 2012 Elsevier Inc. All rights reserved.)