Glucocorticoids (corticosterone in rodents, and cortisol in humans) are secreted in hourly pulses, establishing an ultradian pattern. We have previously shown in vitro and in vivo that ultradian glucocorticoid exposure induces a functional output in individual cells1-3. The intracellular glucocorticoid receptor (GR) is activated in distinct pulses and transmits this signal to the nucleus of cells, causing a gene pulsing effect4. In contrast, constant glucocorticoid treatment causes a highly aberrant overexpression of target genes in cell culture models3, however this has not yet been described in vivo. Therefore, here we assess the effect of altering the glucocorticoid ultradian pattern on transcriptional output in the rat hippocampus.
Male Sprague-Dawley rats were adrenalectomised and replaced with intravenous infusion of pulsatile or constant corticosterone at either physiological levels or double concentration to produce larger mass pulses, and each pulsatile infusion matched to the equivalent corticosterone in constant infusion. For the low physiological level infusions, we found differential pattern-dependent regulation of the glucocorticoid-targets Per1, KLF15 and SGK1 in the hippocampus, consistent with reports from cell culture experiments. When the pulse mass was increased the output of these three targets was not different between constant and pulsatile patterns. Therefore the large pulse mass caused a similar aberrant transcriptional output of hippocampal target genes to the highly abnormal constant infusion.
Our findings with the larger amplitude pulses may be of clinical relevance as the larger cortisol pulse mass has been reported in patients with obstructive sleep apneoa5. These patients also present with metabolic, cognitive and affective dysfunction. After treatment, their cortisol patterns normalise, along with an improvement in their clinical profile. Our data shows this larger pulse mass disrupts the timing of the ultradian transcriptional rhythm and loss of pulsatile activity, and therefore may contribute to the associated cognitive and affective dysfunction in these patients.