title: Expression profiling associates blood and brain glucocorticoid receptor signaling with trauma-related individual differences in both sexes.
abstract: Delineating the molecular basis of individual differences in the stress response is critical to understanding the pathophysiology and treatment of posttraumatic stress disorder (PTSD). In this study, 7 d after predator-scent-stress (PSS) exposure, male and female rats were classified into vulnerable (i.e., "PTSD-like") and resilient (i.e., minimally affected) phenotypes on the basis of their performance on a variety of behavioral measures. Genome-wide expression profiling in blood and two limbic brain regions (amygdala and hippocampus), followed by quantitative PCR validation, was performed in these two groups of animals, as well as in an unexposed control group. Differentially expressed genes were identified in blood and brain associated with PSS-exposure and with distinct behavioral profiles postexposure. There was a small but significant between-tissue overlap (4-21%) for the genes associated with exposure-related individual differences, indicating convergent gene expression in both sexes. To uncover convergent signaling pathways across tissue and sex, upstream activated/deactivated transcription factors were first predicted for each tissue and then the respective pathways were identified. Glucocorticoid receptor (GR) signaling was the only convergent pathway associated with individual differences when using the most stringent statistical threshold. Corticosterone treatment 1 h after PSS-exposure prevented anxiety and hyperarousal 7 d later in both sexes, confirming the GR involvement in the PSS behavioral response. In conclusion, genes and pathways associated with extreme differences in the traumatic stress behavioral response can be distinguished from those associated with trauma exposure. Blood-based biomarkers can predict aspects of brain signaling. GR signaling is a convergent signaling pathway, associated with trauma-related individual differences in both sexes.
authors.affiliation: Departments of Psychiatry, Mental Health Patient Care Center, James J. Peters Veterans Affairs Medical Center, Bronx, NY 10468; and nikolaos.daskalakis@mssm.edu.
authors.forename: Nikolaos P
authors.identifier: http://orcid.org/0000-0003-1660-9112
authors.initials: NP
authors.lastname: Daskalakis
authors.affiliation: Anxiety and Stress Research Unit, Ministry of Health Mental Health Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84170, Israel.
authors.forename: Hagit
authors.initials: H
authors.lastname: Cohen
authors.affiliation: Departments of Psychiatry, Genetics and Genomic Sciences, and.
authors.forename: Guiqing
authors.initials: G
authors.lastname: Cai
authors.affiliation: Departments of Psychiatry, Genetics and Genomic Sciences, and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.affiliation: Departments of Psychiatry, Mental Health Patient Care Center, James J. Peters Veterans Affairs Medical Center, Bronx, NY 10468; and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Rachel
authors.initials: R
authors.lastname: Yehuda
mesh_terms: D000679:Amygdala / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D003345:Corticosterone / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D011235:Predatory Behavior / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000097:blood* / Q000235:genetics*; D012727:Sex Characteristics; D015398:Signal Transduction; D013313:Stress Disorders, Post-Traumatic / Q000097:blood* / Q000188:drug therapy / Q000235:genetics*
chemical_list: D011965:Receptors, Glucocorticoid; D003345:Corticosterone
keywords: NR3C1; predator stress; preventive treatment; psychiatry; transcription regulation
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