Circadian regulation of hippocampal function is disrupted with chronic corticosteroid treatment

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. ### Competing Interest Statement The authors have declared no competing interest. * AVP : Vasopressin BHLHE40 : Basic helix-loop-helix e40 CaMKII : Calcium/calmodulin-dependent protein kinase type II CORT : Corticosterone DBP : D-box protein DEGs : Differentially expressed genes GluN2B : Glutamate [NMDA] receptor subunit 2B GO : Gene ontology GR : Glucocorticoid receptor GRE : Glucocorticoid response element GRIN2 : Glutamate ionotropic receptor NMDA type subunit 2 HFS : High frequency stimulation KLF15 : Kruppel like factor 15 LTP : Long term potentiation mEPSC : miniature Excitatory Post-synaptic Currents mIPSC : miniature Inhibitory Post-synaptic Currents MPL : Methylprednisolone MR : Mineralocorticoid receptor NMDAR : N-methyl-D-aspartate receptor PER1 : Period 1 PER2 : Period 2 PER3 : Period 3 SCN : Suprachiasmatic nucleus SGK1 : Serum/Glucocorticoid regulated kinase 1 TSC22D3 : Glucocorticoid Induced Leucine Zipper VEH : Vehicle ZFP189 : Zinc finger protein 189 ZT : zeitgeber time