:  The human pineal gland is a neuroendocrine transducer that forms an integral part of the brain. Through the nocturnally elevated synthesis and release of the neurohormone melatonin, the pineal gland encodes and disseminates information on circadian time, thus coupling the outside world to the biochemical and physiological internal demands of the body. Approaches to better understand molecular details behind the rhythmic signalling in the human pineal gland are limited but implicitly warranted, as human chronobiological dysfunctions are often associated with alterations in melatonin synthesis. Current knowledge on melatonin synthesis in the human pineal gland is based on minimally invasive analyses, and by the comparison of signalling events between different vertebrate species, with emphasis put on data acquired in sheep and other primates. Together with investigations using autoptic pineal tissue, a remnant silhouette of premortem dynamics within the hormone’s biosynthesis pathway can be constructed. The detected biochemical scenario behind the generation of dynamics in melatonin synthesis positions the human pineal gland surprisingly isolated. In this neuroendocrine brain structure, protein‐protein interactions and nucleo‐cytoplasmic protein shuttling indicate furthermore a novel twist in the molecular dynamics in the cells of this neuroendocrine brain structure. These findings have to be seen in the light that an impaired melatonin synthesis is observed in elderly and/or demented patients, in individuals affected by Alzheimer’s disease, Smith–Magenis syndrome, autism spectrum disorder and sleep phase disorders. Already, recent advances in understanding signalling dynamics in the human pineal gland have significantly helped to counteract chronobiological dysfunctions through a proper restoration of the nocturnal melatonin surge.

In species ranging from flies to mammals, parameters of memory processing, like acquisition, consolidation, and retrieval are clearly molded by time of day. However, mechanisms that regulate and adapt these temporal differences are elusive, with an involvement of clock genes and their protein products suggestive. Therefore, we analyzed initially in mouse hippocampus the daytime-dependent dynamics of parameters, known to be important for proper memory formation, like phosphorylation of the "memory molecule" cyclic adenosine monophosphate (cAMP) responsive element binding protein (CREB) and chromatin remodeling. Next, in an effort to characterize the mechanistic role of clock genes within hippocampal molecular dynamics, we compared the results obtained from wildtype (WT) -mice and mice deficient for the archetypical clock gene Period1 (Per1(-/-) -mice). We detected that the circadian rhythm of CREB phosphorylation in the hippocampus of WT mice disappeared completely in mice lacking Per1. Furthermore, we found that the here for the first time described profound endogenous day/night rhythms in histone modifications in the hippocampus of WT-mice are markedly perturbed in Per1(-/-) -mice. Concomitantly, both, in vivo recorded LTP, a cellular correlate for long-term memory, and hippocampal gene expression were significantly altered in the absence of Per1. Notably, these molecular perturbations in Per1(-/-) -mice were accompanied by the loss of daytime-dependent differences in spatial working memory performance. Our data provide a molecular blueprint for a novel role of PER1 in temporally shaping the daytime-dependency of memory performance, likely, by gating CREB signaling, and by coupling to downstream chromatin remodeling.

Memory performance varies over a 24-h day/night cycle. While the detailed underlying mechanisms are yet unknown, recent evidence suggests that in the mouse hippocampus, rhythmic phosphorylation of mitogen-activated protein kinase (MAPK) and cyclic adenosine monophosphate response elementbinding protein (CREB) are central to the circadian (~24 h) regulation of learning and memory. We recently identified the clock protein PERIOD1 (PER1) as a vehicle that translates information encoding time of day to hippocampal plasticity. We here elaborate how PER1 may gate the sensitivity of memoryrelevant hippocampal signaling pathways. We found that in wildtype mice (WT), spatial learning triggers CREB phosphorylation only during the daytime, and that this effect depends on the presence of PER1. The time-of-day-dependent induction of CREB phosphorylation can be reproduced pharmacologically in acute hippocampal slices prepared from WT mice, but is absent in preparations made from Per1-knockout (Per1 À/À ) mice. We showed that the PER1-dependent CREB phosphorylation is regulated downstream of MAPK. Stimulation of WT hippocampal neurons triggered the co-translocation of PER1 and the CREB kinase pP90RSK (pMAPK-activated ribosomal S6 kinase) into the nucleus. In hippocampal neurons from Per1 À/À mice, however, pP90RSK remained perinuclear. A coimmunoprecipitation assay confirmed a high-affinity interaction between PER1 and pP90RSK. Knocking down endogenous PER1 in hippocampal cells inhibited adenylyl cyclase-dependent CREB activation. Taken together, the PER1-dependent modulation of cytoplasmic-to-nuclear signaling in the murine hippocampus provides a molecular explanation for how the circadian system potentially shapes a temporal framework for daytime-dependent memory performance, and adds a novel facet to the versatility of the clock gene protein PER1.

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The mammalian pineal organ transduces light-dependent neural inputs into a hormonal output. This photoneuroendocrine transduction results in a largely elevated concentration of the pineal hormone melatonin at night. The rhythm in melatonin production and secretion depends on activation and inactivation of transcriptional, translational, and posttranslational mechanisms fundamentally linked to two second messenger systems, the cAMP- and the Ca(2+)-signal transduction pathways. Here we review molecular biological, immunocytochemical, and single-cell imaging studies, which demonstrate a time- and substance-specific activation of these signaling pathways in rat pinealocytes. The data provide a framework for understanding the complex interactions between second messengers (cAMP, Ca2+), transcription factors (CREB, ICER), and their role in regulation of melatonin synthesis. The data have proven the rat pinealocyte to be an interesting model to study transmembrane signaling pathways which may be common to both neuroendocrine and neuronal cells.

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