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Background: Prenatal stress influences brain development and mood disorder vulnerability. Brain structural covariance network (SCN) properties based on inter-regional volumetric correlations may reflect developmentally-mediated shared plasticity among regions. Childhood trauma is associated with amygdala-centric SCN reorganization patterns, however, the impact of prenatal stress on SCN properties remains unknown., Methods: The study included participants from the European Longitudinal Study of Pregnancy and Childhood (ELSPAC) with archival prenatal stress data and structural MRI acquired in young adulthood (age 23-24). SCNs were constructed based on Freesurfer-extracted volumes of 7 subcortical and 34 cortical regions. We compared amygdala degree centrality, a measure of hubness, between those exposed to high vs. low (median split) prenatal stress, defined by maternal reports of stressful life events during the first (n = 93, 57% female) and second (n = 125, 54% female) half of pregnancy. Group differences were tested across network density thresholds (5-40%) using 10,000 permutations, with sex and intracranial volume as covariates, followed by sex-specific analyses. Finally, we sought to replicate our results in an independent all-male sample (n = 450, age 18-20) from the Avon Longitudinal Study of Parents and Children (ALSPAC)., Results: The high-stress during the first half of pregnancy ELSPAC group showed lower amygdala degree particularly in men, who demonstrated this difference at 10 consecutive thresholds, with no significant differences in global network properties. At the lowest significant density threshold, amygdala volume was positively correlated with hippocampus, putamen, rostral anterior and posterior cingulate, transverse temporal, and pericalcarine cortex in the low-stress (p(FDR) < 0.027), but not the high-stress (p(FDR) > 0.882) group. Although amygdala degree was nominally lower across thresholds in the high-stress ALSPAC group, these results were not significant., Conclusion: Unlike childhood trauma, prenatal stress may shift SCN towards a less amygdala-centric SCN pattern, particularly in men. These findings did not replicate in an all-male ALSPAC sample, possibly due to the sample's younger age and lower prenatal stress exposure., (Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.)

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.)

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.

Prior work suggests that there may be two distinct pathways of alcohol use disorder (AUD) risk: one associated with positive emotion enhancement and behavioral impulsivity, and another associated with negative emotion relief and coping. We sought to map these two pathways onto individual differences in neural reward and threat processing assessed using blood-oxygen-level-dependent functional magnetic resonance imaging in a sample of 759 undergraduate students (426 women, mean age 19.65±1.24 years) participating in the Duke Neurogenetics Study. We demonstrate that problem drinking is highest in the context of stress and in those with one of two distinct neural phenotypes: (1) a combination of relatively low reward-related activity of the ventral striatum (VS) and high threat-related reactivity of the amygdala; or (2) a combination of relatively high VS activity and low amygdala reactivity. In addition, we demonstrate that the relationship between stress and problem alcohol use is mediated by impulsivity, as reflected in monetary delay discounting rates, for those with high VS-low amygdala reactivity, and by anxious/depressive symptomatology for those with the opposite neural risk phenotype. Across both neural phenotypes, we found that greater divergence between VS and amygdala reactivity predicted greater risk for problem drinking. Finally, for those individuals with the low VS-high amygdala risk phenotype we found that stress not only predicted the presence of AUD diagnosis at the time of neuroimaging but also subsequent problem drinking reported 3 months following study completion. These results offer new insight into the neural basis of AUD risk and suggest novel biological targets for early individualized treatment or prevention.

We examined epigenetic regulation in regards to behaviorally and clinically relevant human brain function. Specifically, we found that increased promoter methylation of the serotonin transporter gene predicted increased threat-related amygdala reactivity and decreased mRNA expression in postmortem amygdala tissue. These patterns were independent of functional genetic variation in the same region. Furthermore, the association with amygdala reactivity was replicated in a second cohort and was robust to both sampling methods and age.

Essential for detection of relevant external stimuli and for fear processing, the amygdala is under modulatory influence of dopamine (DA). The DA transporter (DAT) is of fundamental importance for the regulation of DA transmission by mediating reuptake inactivation of extracellular DA. This study examined if a common functional variable number tandem repeat polymorphism in the 3' untranslated region of the DAT gene (SLC6A3) influences amygdala function during the processing of aversive emotional stimuli. Amygdala reactivity was examined by comparing regional cerebral blood flow, measured with positron emission tomography and [(15)O]water, during exposure to angry and neutral faces, respectively, in a Swedish sample comprising 32 patients with social anxiety disorder and 17 healthy volunteers. In a separate US sample, comprising 85 healthy volunteers studied with blood oxygen level-dependent functional magnetic resonance imaging, amygdala reactivity was assessed by comparing the activity during exposure to threatening faces and neutral geometric shapes, respectively. In both the Swedish and the US sample, 9-repeat carriers displayed higher amygdala reactivity than 10-repeat homozygotes. The results suggest that this polymorphism contributes to individual variability in amygdala reactivity.

Background: Evolutionarily conserved genes and their associated molecular pathways can serve as a translational bridge between human and mouse research, extending our understanding of biological pathways mediating individual differences in behavior and risk for psychopathology., Methods: Comparative gene array analysis in the amygdala and cingulate cortex between the serotonin transporter knockout mouse, a genetic animal model replicating features of human depression, and existing brain transcriptome data from postmortem tissue derived from clinically depressed humans was conducted to identify genes with similar changes across species (i.e., conserved) that may help explain risk of depressive-like phenotypes. Human neuroimaging analysis was then used to investigate the impact of a common single-nucleotide polymorphism (rs1064448) in a gene with identified conserved human-mouse changes, adenylate cyclase 7 (ADCY7), on threat-associated amygdala reactivity in two large independent samples., Results: Comparative analysis identified genes with conserved transcript changes in amygdala (n = 29) and cingulate cortex (n = 19), both critically involved in the generation and regulation of emotion. Selected results were confirmed by real-time quantitative polymerase chain reaction, including upregulation in the amygdala of transcripts for ADCY7, a gene previously implicated in human depression and associated with altered emotional responsiveness in mouse models. Translating these results back to living healthy human subjects, we show that genetic variation (rs1064448) in ADCY7 biases threat-related amygdala reactivity., Conclusions: This converging cross-species evidence implicates ADCY7 in the modulation of mood regulatory neural mechanisms and, possibly, risk for and pathophysiology of depression, together supporting a continuous dimensional approach to major depressive disorder and other affective disorders., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)