Molecular characterization of the stress network in the human brain

Abstract

The biological mechanisms underlying inter-individual differences in human stress reactivity remain poorly understood. We aimed to identify the molecular underpinning of neural stress sensitivity.Linking mRNA expression data from the Allen Human Brain Atlas to task-based fMRI revealed 261 differentially expressed genes in brain regions differentially activated by stress in individuals with low or high stress sensitivity. These genes are associated with stress-related psychiatric disorders (e.g. schizophrenia and anxiety) and include markers for specific neuronal populations (e.g. VIP, CCK, and NPY), neurotransmitter receptors (e.g. HTR1A, CHRNA3), and signaling factors that interact with the glucocorticoid receptor and hypothalamic-pituitary-adrenal axis (e.g. CRH, NEUROD2, PACAP).Overall, the identified genes potentially underlie altered stress reactivity in individuals at risk for psychiatric disorders and play a role in mounting an adaptive stress response, making them potentially druggable targets for stress-related diseases. SIGNIFICANCE STATEMENTEven though stress increases the risk for almost all psychiatric disorders, large inter-individual differences exist. The molecular mechanisms in humans underlying the heterogeneity in stress sensitivity remain poorly understood. Therefore, this study aimed to disentangle the brain underpinning of stress reactivity in individuals at increased risk for psychiatric disorders. To this end, we used a novel approach by combining neuroimaging data with gene expression data. Overall, we report new molecular pathways that determine how individuals respond to stress and that may be involved in the increased risk for psychiatric disorders. Identifying the molecular mechanisms how the brain can elicit an adaptive stress response is important to understand who is at risk, but also reveal potentially druggable targets for stress-related disorders.control network and activating the salience network and default mode network (DMN). 6, 7 One hypothesis is that stress vulnerability is the result of maladaptive changes in the dynamic response of these neural networks, either during the acute phase, during the recovery period in the aftermath of stress, or both. 2 Moreover, acute social stress deactivates the DMN in the aftermath of stress during emotion processing in healthy controls but not in siblings of schizophrenia patients who are at-risk for several psychiatric disorders. 8,9 Yet, the molecular mechanisms underlying differences in brain reactivity to stress in humans remain unknown as access to the tissue of interest in humans is limited.Nevertheless, stress-related brain regions and networks as identified by fMRI can be further characterized based on transcriptomic signatures. Mapping gene expression atlases of the healthy brain to imaging data allows the identification of the molecular mechanisms underlying imaging phenotypes. Previous studies have identified gene expression patterns associated with structural brain changes in autism spectrum disorders, Huntington's disease a...

Overcoming bias in gene-set enrichment analyses of brain-wide transcriptomic data

“…Despite investigating very different phenomena, these studies reported similar sets of significant GO categories, most frequently implicating categories related to metabolic, neuronal, and generic biological and behavioral processes. The most reported GO category in our survey was 'chemical synaptic transmission' (GO:000726), which has been reported in 15 human analyses from 10 different studies (21,26,32,(69)(70)(71)(72)(73)(74)(75) and four different mouse analyses from three different studies ( organization of human resting-state functional connectivity (21), human adolescent cortical shrinkage and myelination (26), and tract-traced structural connectivity in the mouse brain (17). Some other commonly reported categories include 'potassium ion transmembrane transport' (22,26,32,74,77,78), 'learning or memory' (15,74,75,79,80), and 'electron transport chain' (18,19,23,26,74)…”