High Sensitivity of the Circadian Clock in the Hippocampal Dentate Gyrus to Glucocorticoid- and GSK3-Beta-Dependent Signals

Jun 10, 2021Neuroendocrinology

The Brain's Daily Rhythm in Memory Areas Responds Strongly to Stress Hormones and a Key Cell Regulator

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Abstract

Circadian rhythms of clock gene expression in all hippocampal regions were abolished by adrenalectomy.

Dexamethasone injections rescued circadian rhythms in the dentate gyrus after adrenalectomy.
Dexamethasone treatment significantly lengthened bioluminescence rhythm periods in all hippocampal regions, with the most pronounced effect in the dentate gyrus.
The GSK3β inhibitor CHIR-99021 significantly shortened bioluminescence rhythm periods, especially in the dentate gyrus.
Co-treatment with CHIR-99021 and dexamethasone produced the shortening effect associated with CHIR-99021.
GSK3β- and glucocorticoid-dependent pathways may entrain the clock in different hippocampal regions by modulating rhythm periods in opposite directions.

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AIMS: Circadian clocks in the hippocampus (HPC) align memory processing with appropriate time of day. Our study was aimed at ascertaining the specificity of glycogen synthase kinase 3-beta (GSK3β)- and glucocorticoid (GC)-dependent pathways in the entrainment of clocks in individual HPC regions, CA1-3, and dentate gyrus (DG).

METHODS: The role of GCs was addressed in vivo by comparing the effects of adrenalectomy (ADX) and subsequent dexamethasone (DEX) supplementation on clock gene expression profiles (Per1, Per2, Nr1d1, and Bmal1). In vitro the effects of DEX and the GSK3β inhibitor, CHIR-99021, were assessed from recordings of bioluminescence rhythms in HPC organotypic explants of mPER2Luc mice.

RESULTS: Circadian rhythms of clock gene expression in all HPC regions were abolished by ADX, and DEX injections to the rats rescued those rhythms in DG. The DEX treatment of the HPC explants significantly lengthened periods of the bioluminescence rhythms in all HPC regions with the most significant effect in DG. In contrast to DEX, CHIR-99021 significantly shortened the period of bioluminescence rhythm. Again, the effect was most significant in DG which lacks the endogenously inactivated (phosphorylated) form of GSK3β. Co-treatment of the explants with CHIR-99021 and DEX produced the CHIR-99021 response. Therefore, the GSK3β-mediated pathway had dominant effect on the clocks.

CONCLUSION: GSK3β- and GC-dependent pathways entrain the clock in individual HPC regions by modulating their periods in an opposite manner. The results provide novel insights into the mechanisms connecting the arousal state-relevant signals with temporal control of HPC-dependent memory and cognitive functions.

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High Sensitivity of the Circadian Clock in the Hippocampal Dentate Gyrus to Glucocorticoid- and GSK3-Beta-Dependent Signals

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