Glucocorticoids regulate hippocampal function in part by modulating gene expression through the glucocorticoid receptor (GR). GR binding is highly cell type specific, directed to accessible chromatin regions established during tissue differentiation. Distinct classes of GR binding sites are dependent on the activity of additional signal-activated transcription factors that prime chromatin toward context-specific organization. We hypothesized a stress context dependency for GR binding in hippocampus as a consequence of rapidly induced stress mediators priming chromatin accessibility. Using chromatin immunoprecipitation sequencing to interrogate GR binding, we found no effect of restraint stress context on GR binding, although analysis of sequences underlying GR binding sites revealed mechanistic detail for hippocampal GR function. We note enrichment of GR binding sites proximal to genes linked to structural and organizational roles, an absence of major tethering partners for GRs, and little or no evidence for binding at negative glucocorticoid response elements. A basic helix–loop–helix motif closely resembling a NeuroD1 or Olig2 binding site was found underlying a subset of GR binding sites and is proposed as a candidate lineage-determining transcription factor directing hippocampal chromatin access for GRs. Of our GR binding sites, 54% additionally contained half-sites for nuclear factor (NF)-1 that we propose as a collaborative or general transcription factor involved in hippocampal GR function. Our findings imply a dose-dependent and context-independent action of GRs in the hippocampus. Alterations in the expression or activity of NF-1/basic helix–loop–helix factors may play an as yet undetermined role in glucocorticoid-related disease susceptibility and outcome by altering GR access to hippocampal binding sites.
In this paper we report differential decoding of the ultradian corticosterone signal by glucocorticoid target tissues. Pulsatile corticosterone replacement in adrenalectomised rats resulted in different dynamics of Sgk1 mRNA production, with a distinct pulsatile mRNA induction profile observed in the pituitary in contrast to a non-pulsatile induction in the prefrontal cortex (PFC). We further report the first evidence for pulsatile transcriptional repression of a glucocorticoid-target gene in vivo, with pulsatile regulation of Pomc transcription in pituitary. We have explored a potential mechanism for differences in the induction dynamics of the same transcript (Sgk1) between the PFC and pituitary. Glucocorticoid receptor (GR) activation profiles were strikingly different in pituitary and prefrontal cortex, with a significantly greater dynamic range and shorter duration of GR activity detected in the pituitary, consistent with the more pronounced gene pulsing effect observed. In the prefrontal cortex, expression of Gilz mRNA was also non-pulsatile and exhibited a significantly delayed timecourse of increase and decrease when compared to Sgk1, additionally highlighting gene-specific regulatory dynamics during ultradian glucocorticoid treatment.
Ultradian glucocorticoid rhythms are highly conserved across mammalian species, however, their functional significance is not yet fully understood. Here we demonstrate that pulsatile corticosterone replacement in adrenalectomised rats induces a dynamic pattern of glucocorticoid receptor (GR) binding at ~3,000 genomic sites in liver at the pulse peak, subsequently not found during the pulse nadir. In contrast, constant corticosterone replacement induced prolonged binding at the majority of these sites. Additionally, each pattern further induced markedly different transcriptional responses. During pulsatile treatment, intragenic occupancy by active RNA polymerase II exhibited pulsatile dynamics with transient changes in enrichment, either decreased or increased depending on the gene, which mostly returned to baseline during the inter-pulse interval. In contrast, constant corticosterone exposure induced prolonged effects on RNA polymerase II occupancy at the majority of gene targets, thus acting as a sustained regulatory signal for both transactivation and repression of glucocorticoid target genes. The nett effect of these differences were consequently seen in the liver transcriptome as RNA-seq analysis indicated that despite the same overall amount of corticosterone infused, twice the number of transcripts were regulated by constant corticosterone infusion, when compared to pulsatile. Target genes that were found to be differentially regulated in a pattern-dependent manner were enriched in functional pathways including carbohydrate, cholesterol, glucose and fat metabolism as well as inflammation, suggesting a functional role for dysregulated glucocorticoid rhythms in the development of metabolic dysfunction.
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Glucocorticoid (GC) hormones play significant roles within homeostasis and the chrono-dynamics of their regulatory role has become increasingly recognised within dysregulated GC pathology, particularly with metabolic phenotypes. Within this article, we will discuss the relevance of the ultradian homeostatic rhythm, how its dysregulation effects glucocorticoid receptor and RNA polymeraseII recruitment and may play a significant role within aberrant metabolic action.
Neuropsychiatric disorders such as major depression and schizophrenia are highly prevalent and contribute substantially to disease burden worldwide. Despite this, progress understanding the pathophysiology has remained largely elusive, yet these disorders often exhibit a loss of regulation of biological rhythms, such as sleep/wake cycles and hormonal rhythms. Cushing's disease, a condition characterized by chronic corticosteroid (cortisol) hypersecretion is associated with psychiatric and neurocognitive disorders and disruption to the circadian release of cortisol can result in depression and neurocognitive impairment. In rats, we report that circadian regulation of the hippocampal transcriptome integrates crucial functional networks that link corticosteroid-inducible gene regulation to synaptic plasticity regulation via an intra-hippocampal circadian transcriptional clock. During the early active period, when corticosteroid availability is high, CA1 region excitatory and inhibitory post-synaptic currents were augmented along with long-term potentiation. In contrast, chronic corticosteroid exposure disturbed hippocampal function. The hippocampal transcriptome, as well as circadian regulation of synaptic plasticity were ablated, resulting in memory loss during hippocampal-dependent behavior. These findings identify how exposure to elevated levels of corticosteroid, that is often seen in neuropsychiatric illness, results in adverse critical hippocampal function. These data provide novel insights into the molecular mechanisms of neurocognitive disorders and provides evidence for corticosteroid-mediated intervention in disabling mental illnesses.
Disrupted circadian activity is associated with many neuropsychiatric disorders. A major coordinator of circadian biological systems is adrenal glucocorticoid secretion which exhibits a pronounced preawakening peak that regulates metabolic, immune, and cardiovascular processes, as well as mood and cognitive function. Loss of this circadian rhythm during corticosteroid therapy is often associated with memory impairment. Surprisingly, the mechanisms that underlie this deficit are not understood. In this study, in rats, we report that circadian regulation of the hippocampal transcriptome integrates crucial functional networks that link corticosteroid-inducible gene regulation to synaptic plasticity processes via an intrahippocampal circadian transcriptional clock. Further, these circadian hippocampal functions were significantly impacted by corticosteroid treatment delivered in a 5-d oral dosing treatment protocol. Rhythmic expression of the hippocampal transcriptome, as well as the circadian regulation of synaptic plasticity, was misaligned with the natural light/dark circadian-entraining cues, resulting in memory impairment in hippocampal-dependent behavior. These findings provide mechanistic insights into how the transcriptional clock machinery within the hippocampus is influenced by corticosteroid exposure, leading to adverse effects on critical hippocampal functions, as well as identifying a molecular basis for memory deficits in patients treated with long-acting synthetic corticosteroids.
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