Circadian regulation of hippocampal function is disrupted with corticosteroid treatment

Abstract

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.

Circadian Clock Genes Are Regulated by Rhythmic Corticosterone at Physiological Levels in the Rat Hippocampus

“…The two receptor types bind the same downstream response elements, but studies in rats detect a high occupancy of the mineralocorticoid receptor even at circadian trough levels due to a strong binding affinity of corticosterone [47, 50, 51]. However, even with a high basic occupancy, the amount of mineralocorticoid receptor bound to the glucocorticoid response element in the Per1 promoter still exhibits a circadian rhythm [47] as does the binding of the glucocorticoid receptor [30], indicating that under physiological conditions, both receptor types are susceptible to corticosterone activation during the daily hormone increase, thus highlighting the biological importance of the endogenous ligand. The receptor binding patterns of corticosterone and dexamethasone also vary between brain regions, so while corticosterone is bound in higher concentrations in the hippocampus as compared to the anterior pituitary, the opposite pattern was the case for dexamethasone [52, 53].…”

“…The glucocorticoid receptor is widely distributed in the brain with a high concentration in the hippocampus [26–29]. At the molecular level, a functional glucocorticoid receptor response element has been identified in the promoter of the clock genes Per1 [30] and Per2 [31]. A set of studies combining adrenalectomy and injection of corticosterone in rats have reported glucocorticoid-dependent effects on the expression of clock genes in the prefrontal cortex [32], the bed nucleus of the stria terminalis, and the amygdala [7, 33], whereas timely controlled rhythmic infusion of corticosterone at physiological levels has been shown to drive clock gene rhythms in the cerebellum [34].…”

“…Further, hippocampal clock gene expression is influenced by high-dose injections of the synthetic steroid dexamethasone [10]. On the other hand, chronic exposure to glucocorticoids in rats has been shown to disrupt rhythms in hippocampal clock gene transcription accompanied by altered synaptic plasticity and memory impairment [30].…”

Phase-shifting the circadian glucocorticoid profile induces disordered feeding behaviour by dysregulating hypothalamic neuropeptide gene expression

“…This evidence for GR’s involvement in the transcriptional regulation of Npy in the arcuate nucleus does not preclude an additional involvement of the MR since both GR and MR are highly expressed in the arcuate nucleus 33 – 35 . However, because MR has 10 fold higher affinity for CORT than GR it is near maximally bound even at low CORT levels circulating during the circadian nadir, while in contrast the lower affinity GR becomes activated with the higher CORT levels of an ultradian pulse peak within the circadian active phase 36 – 39 and therefore provides a more responsive and dynamic sensor of fluctuating CORT levels over the day. Accordingly, GR is generally thought to be more likely to initiate transcriptional responses to higher CORT levels.…”

Timing Matters: The Interplay between Early Mealtime, Circadian Rhythms, Gene Expression, Circadian Hormones, and Metabolism—A Narrative Review

“…In order to stay synchronized with the external environment, circadian clocks rely on external signals called zeitgebers or timing cues to undergo phase resetting [ 32 , 34 ]. The retinohypothalamic tract primarily entrains the SCN through exposure to external light, whereas neurohormonal factors exert an influence on peripheral clocks and mealtimes [ 35 , 36 ], and peripheral tissues can be moderately affected by nonphotic signals, such as food intake and glucocorticoids [ 37 , 38 ]. The nervous and endocrine systems both regulate the peripheral clocks in vivo.…”