Withdrawn: Dexamethasone resets the circadian clock in hippocampus via multiple mechanisms involving lithium-independent GSK3ß signalling.

The above article from British Journal of Pharmacology, published online as an Accepted Article on 19 August 2019 in Wiley Online Library (wileyonlinelibrary.com), has been withdrawn by agreement between the authors, the journal Editor-in-Chief Professor Amrita Ahluwalia, and John Wiley & Sons Limited. The withdrawal has been agreed owing to new findings that necessitate re-interpretation of the results.

Development and Entrainment of the Fetal Clock in the Suprachiasmatic Nuclei: The Role of Glucocorticoids.

The adult circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus is resilient to glucocorticoids (GCs). The fetal rodent SCN resembles that of the adult in its organization of GC-sensitive peripheral tissues. We tested the hypothesis that the fetal SCN clock is sensitive to changes in GC levels. Maternal GCs must pass through the placenta to reach the fetal SCN. We show that the maternal but not the fetal part of the placenta harbors the autonomous circadian clock, which is reset by dexamethasone (DEX) and rhythmically expresses Hsd11b2. The results suggest the presence of a mechanism for rhythmic GC passage through the placental barrier, which is adjusted according to actual GC levels. GC receptors are expressed rhythmically in the laser-dissected fetal SCN samples. We demonstrate that hypothalamic explants containing the SCN of the mPer2 Luc mouse prepared at embryonic day (E)15 spontaneously develop rhythmicity within several days of culture, with dynamics varying among fetuses from the same litter. Culturing these explants in media enriched with DEX accelerates the development. At E17, treatment of the explants with DEX induces phase advances and phase delays of the rhythms depending on the timing of treatments, and the shifts are completely blocked by the GC receptor antagonist, mifepristone. The DEX-induced phase-response curve differs from that induced by the vehicle. The fetal SCN is sensitive to GCs in vivo because DEX administration to pregnant rats acutely downregulates c-fos expression specifically in the laser-dissected fetal SCN. Our results provide evidence that the rodent fetal SCN clock may respond to changes in GC levels.

Implicit time-place conditioning alters Per2 mRNA expression selectively in striatum without shifting its circadian clocks.

Animals create implicit memories of the time of day that significant events occur then anticipate the recurrence of those conditions at the same time on subsequent days. We tested the hypothesis that implicit time memory for daily encounters relies on the setting of the canonical circadian clockwork in brain areas involved in the formation or expression of context memories. We conditioned mice to avoid locations paired with a mild foot shock at one of two Zeitgeber times set 8 hours apart. Place avoidance was exhibited only when testing time matched the prior training time. The suprachiasmatic nucleus, dorsal striatum, nucleus accumbens, cingulate cortex, hippocampal complex, and amygdala were assessed for clock gene expression. Baseline phase dependent differences in clock gene expression were found in most tissues. Evidence for conditioned resetting of a molecular circadian oscillation was found only in the striatum (dorsal striatum and nucleus accumbens shell), and specifically for Per2 expression. There was no evidence of glucocorticoid stress response in any tissue. The results are consistent with a model where temporal conditioning promotes a selective Per2 response in dopamine-targeted brain regions responsible for sensorimotor integration, without resetting the entire circadian clockwork.