Molecular characterization of the stress network in individuals at risk for schizophrenia

Mandy Meijer,Arlin Keo,Judith M.C Van Leeuwen,Oleh Dzyubachyk,Onno C Meijer,Christiaan H Vinkers,Ahmed Mahfouz

doi:10.1016/j.ynstr.2021.100307

Abstract

The biological mechanisms underlying inter-individual differences in human stress reactivity remain poorly understood. We aimed to identify the molecular underpinning of aberrant neural stress sensitivity in individuals at risk for schizophrenia. Linking mRNA expression data from the Allen Human Brain Atlas to task-based fMRI revealed 201 differentially expressed genes in cortex-specific brain regions differentially activated by stress in individuals with low (healthy siblings of schizophrenia patients) or high (healthy controls) 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. ADCYAP1, GABRB1, SSTR1, and TNFRSF12A), neurotransmitter receptors (e.g. GRIN3A, SSTR1, GABRB1, and HTR1E), and signaling factors that interact with the corticosteroid receptor and hypothalamic-pituitary-adrenal axis (e.g. ADCYAP1, IGSF11, and PKIA). Overall, the identified genes potentially underlie altered stress reactivity in individuals at risk for schizophrenia and other psychiatric disorders and play a role in mounting an adaptive stress response in at-risk individuals, making them potentially druggable targets for stress-related diseases.

Highlights

Stress is a major risk factor for the development of a wide range of psychiatric disorders, including schizophrenia and depression (Tost et al, 2015)
Using a bootstrapping approach, we found the identified set of genes to be highly robust to the imbalance between the number of Allen Human Brain Atlas (AHBA) samples inside and outside our stress network
We identified the gene expression signatures of our stress network with altered stress-induced activity by determining which genes are differentially expressed in our stress network compared to the rest of the brain minus the cerebellum

Summary

Introduction

Stress is a major risk factor for the development of a wide range of psychiatric disorders, including schizophrenia and depression (Tost et al, 2015). Acute stress causes a shift in neural networks by suppressing the executive control network and activating the salience network and default mode network (DMN) (van Oort et al., 2017). Acute social stress de activates 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 (Argyropoulos et al, 2008; van Leeuwen et al, 2018). Understanding the molecular mechanisms that drive these differences in brain activity during the stress response, might give insight in the question why some individuals are more vulnerable to the development of schizophrenia and other psychiatric disorders like schizophrenia, with stress as known environmental risk factor. 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

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