Memories are not static but continue to be processed after encoding. This is thought to allow the integration of related episodes via the identification of patterns. Although this idea lies at the heart of contemporary theories of systems consolidation, it has yet to be demonstrated experimentally. Using a modified water-maze paradigm in which platforms are drawn stochastically from a spatial distribution, we found that mice were better at matching platform distributions 30 d compared to 1 d after training. Post-training time-dependent improvements in pattern matching were associated with increased sensitivity to new platforms that conflicted with the pattern. Increased sensitivity to pattern conflict was reduced by pharmacogenetic inhibition of the medial prefrontal cortex (mPFC). These results indicate that pattern identification occurs over time, which can lead to conflicts between new information and existing knowledge that must be resolved, in part, by computations carried out in the mPFC.
Shiftwork is associated with adverse metabolic pathophysiology, and the rising incidence of shiftwork in modern societies is thought to contribute to the worldwide increase in obesity and metabolic syndrome. The underlying mechanisms are largely unknown, but may involve direct physiological effects of nocturnal light exposure, or indirect consequences of perturbed endogenous circadian clocks. This study employs a two-week paradigm in mice to model the early molecular and physiological effects of shiftwork. Two weeks of timed sleep restriction has moderate effects on diurnal activity patterns, feeding behavior, and clock gene regulation in the circadian pacemaker of the suprachiasmatic nucleus. In contrast, microarray analyses reveal global disruption of diurnal liver transcriptome rhythms, enriched for pathways involved in glucose and lipid metabolism and correlating with first indications of altered metabolism. Although altered food timing itself is not sufficient to provoke these effects, stabilizing peripheral clocks by timed food access can restore molecular rhythms and metabolic function under sleep restriction conditions. This study suggests that peripheral circadian desynchrony marks an early event in the metabolic disruption associated with chronic shiftwork. Thus, strengthening the peripheral circadian system by minimizing food intake during night shifts may counteract the adverse physiological consequences frequently observed in human shift workers.
The mammalian circadian timing system consists of a master pacemaker in the suprachiasmatic nucleus (SCN), which is thought to synchronize peripheral clocks in various organs with each other and with external time. Our knowledge about the role of the SCN clock is based mainly on SCN lesion and transplantation studies. We have now directly deleted the SCN clock using the Cre/LoxP system and investigated how this affects synchronization of peripheral rhythms. Impaired locomotor activity and arrhythmic clock gene expression in the SCN confirm that the SCN clockwork was efficiently abolished in our mouse model. Nonetheless, under light-dark (LD) conditions, peripheral clocks remained rhythmic and synchronized to the LD cycle, and phase relationships between peripheral clocks were sustained. Adaptation to a shifted LD cycle was accelerated in SCN clock-deficient mice. Moreover, under zeitgeber-free conditions, rhythmicity of the peripheral clock gene expression was initially dampened, and after several days peripheral clocks were desynchronized. These findings suggest that the SCN clock is dispensable for the synchronization of peripheral clocks to the LD cycle. A model describing an SCN clock-independent pathway that synchronizes peripheral clocks with the LD cycle is discussed.-Husse, J., Leliavski, A., Tsang, A. H., Oster, H., Eichele, G. The light-dark cycle controls peripheral rhythmicity in mice with a genetically ablated suprachiasmatic nucleus clock. FASEB J. 28, 4950 -4960 (2014). www.fasebj.org Key Words: circadian ⅐ synaptotagmin10Circadian clocks coordinate a broad range of physiological processes such as the sleep-wake cycle, endocrine functions, locomotion, and various aspects of metabolism. The mammalian circadian timing system is hierarchically organized with a master pacemaker residing in the suprachiasmatic nucleus (SCN) and subordinate peripheral clocks present in most tissues (1). How different tissue clocks interact to orchestrate circadian rhythms and how this network of clocks is synchronized to external time remains one of the most intensely investigated areas of chronobiology.Circadian clockwork in the SCN and in the periphery is based on interlocked transcriptional-translational feedback loops driven by a common set of circadian clock genes (2). The circadian clockwork drives the rhythmic expression of tissue-specific clock output genes, some of which encode signaling molecules, which, in the case of the SCN, include neuropeptides (e.g., prokineticin 2 or arginine vasopressin; refs. 3, 4). SCN neurons are tightly coupled via gap junctions and neuropeptidergic signaling, resulting in coherent rhythms of electrical activity (5, 6). Both electrical activity and neuropeptide rhythms serve to transmit time information from the SCN to subordinate clocks in the brain and in the periphery (7,8).The function of the circadian timing system is to adapt an organism's physiology to changes in the environment caused by the rotation of the Earth. Thus, synchronization of the circadian system to the...
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