Acute Activation of Glucocorticoid Receptors Increases Transcription of Serotonin-Related mRNA Transcripts in the Dorsal Raphe

Presentation Number: MON 376
Date of Presentation: April 3rd, 2017

Allie Holschbach*1, Ashley Turnidge2 and Robert J Handa1
1Colorado State University, Fort Collins, CO, 2Colorado State University

Abstract

Stress has profound effects on the physiology and behavior of mammals, and these effects are orchestrated by activation of glucocorticoid receptors (GR) in the brain following stress-induced elevations in corticosteroid secretion from the adrenal gland. Acute stress and/or activation of GRs results in many adaptive reactions that are necessary for survival, but chronic activation can become problematic, often resulting in the presentation of neuropsychiatric disorders such as depression and anxiety. Stress-related disorders are twice as prevalent in women compared to men, and this sex difference may be related in how the serotonin system responds to stress. Serotonin is a neurochemical that has been strongly implicated in depression and anxiety, and the serotonin system is exquisitely sensitive to stress and glucocorticoid action. Most of the brain’s serotonin is produced by neurons in the dorsal raphe (DR), a brain region that densely expresses GR. To explore the effects of glucocorticoids on serotonin neurons in the DR, we adrenalectomized adult male and female C57bl6 mice to remove endogenous glucocorticoids then after two days of recovery, injected a selective GR agonist, RU28362 (40 µg/kg, ip) or vehicle. Mice were decapitated 30 minutes later, and blood and brains were collected for later examination. Absolute levels of mRNA were measured in microdissected DR using digital droplet PCR. RU28362 increased the transcription of several serotonin-related genes within the DR within 30 minutes. These included mRNA levels of the serotonin-synthesizing enzyme, tryptophan hydroxylase 2 (p = .01), the serotonin-metabolizing enzyme, monoamine oxidase a (p = .05), and serotonin receptor 1a (p = .02). There was a trend to increase serotonin transporter mRNA levels (p = .09) in male mice. This treatment did not affect mRNA levels of GR (p = .70), although a longer treatment time might be necessary. Ongoing experiments will test additional mRNA transcripts, including other serotonin receptors and the GR-regulated circadian clock gene, period 1. Increased serotonin signaling following these acute increases in serotonin-related mRNA transcripts may contribute to adaptive responses to acute stressors. These data indicate a new role for GRs in adjusting serotonin synthesis and sensitivity acutely in response to a stressor. A deeper understanding of sex differences in the response of DR neurons to activation of GRs could reveal neurochemical changes underlying the development of neuropsychiatric disorders.

 

Nothing to Disclose: AH, AT, RJH