Stress and Its Impact on the Transcriptome

Abstract

Exposure to stress during the course of a lifetime is inevitable in the animal kingdom. It is the response to stress, the valence of the exposure, and the developmental time point that largely determine the consequences to the initial and subsequent exposures. The versatility of transcriptomic methods to yield rich, high-resolution, information-laden datasets from entire brain regions to single cells makes it a powerful approach to investigate the effects of stress from several angles. Dysregulation of the transcriptome is now a phenotypic signature of many neuropsychiatric disorders. New insight has been gained from examining stress-induced changes in gene expression at a global scale. Human postmortem datasets from depression and posttraumatic stress disorder studies have identified major gene expression changes in the diseased brain, including sex-specific changes and marked differences in male and female molecular profiles for the same disorder. Extensions of this work into animal models have explored the impact of transcriptomic dysregulation on early-life stress, chronic stress, and transgenerational impact of stress. Here, we explore the findings of human postmortem genomic studies of neuropsychiatric disorders and comparable animal models through the lens of transcriptomic dysregulation and how these findings have contributed to our understanding of stress.

Keywords: Circuit; Glucocorticoid; Neurotrophic; Posttraumatic stress disorder; Resilience.

Figure 1:. Sex specificity in postmortem transcriptomes of MDD and PTSD

Divergent profiles were observed between male and female transcriptomes in MDD and PTSD. Comparative analysis of MDD and PTSD revealed sparse overlap in transcriptome profiles despite high incidence of MDD in PTSD diagnoses. Animal model studies of genes dysregulated in male or female MDD exhibit depressive-like behavior only in animals of the matching and not the opposite sex.

Figure 2:. Model of stress actions in psychiatric disease.

Stress-induced molecular signaling in brain regions such as the hippocampus and prefrontal cortex elevate vulnerability to development of major depressive and posttraumatic stress disorder. Disease progression can continue to drive dysfunction in these brain regions.