PERIOD1 coordinates hippocampal rhythms and memory processing with daytime

Abstract

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.

Synchrony and desynchrony in circadian clocks: impacts on learning and memory

“…Potentially, phase-specific coordination of physiological processes occurs locally in the brain regions generating or regulating those behaviors. Indeed, analysis of hippocampal circadian gene and protein expression reveals cyclic coordination of gene expression suggesting that hippocampal gene expression may form a temporal framework for memory formation (Jilg et al 2010;Rawashdeh et al 2014). In a mouse model used to represent evening-type individuals, the clock mutation in a Jcl/ICR background, in which the animals have long periods and Clocks and Memory www.learnmem.org phase delays, the animals demonstrate an impaired learning ability in the Morris water maze during the early dark phase (morning for the mice) along with damped hippocampal acetylcholine release (Sei et al 2003(Sei et al , 2006.…”

“…Basal rhythms in histone markers; learning-induction phase specific and absent in per1 mutants Rawashdeh et al (2014) Hormones Cortisol Mice Diurnal rhythms; peaks promote dendritic spine formation after learning; troughs promote dendritic spine maintenance.…”

“…In the hippocampus, phospho-CREB levels oscillate in phase with the pERK and cAMP (Eckel-Mahan et al 2008). More recently, hippocampal circadian rhythms in CREB activation have been shown to be dependent upon the Period1 gene (Rawashdeh et al 2014). In Aplysia, training animals during the subjective day results in significantly increased protein levels of the CREBdependent immediate early gene ApC/EBP (Lyons et al 2006), a transcription factor in nonassociative (Alberini et al 1994), and associative memory formation (Levitan et al 2008).…”

“…Acetylation of histone protein, particularly H3, enhances the induction and formation of long-term memory (Levenson et al 2004), while trimethylation of H3 at lysine 4 marks active transcription (Gupta et al 2010). The circadian clock regulates H3 acetylation at lysine 14 in phase with trimethylation of H3 at lysine 4 providing a mechanism for circadian regulation of learning-induced gene transcription (Rawashdeh et al 2014). SIRT1, a NAD-dependent deacetylase, which regulates CLOCK mediated chromatin remodeling and circadian rhythms (Asher et al 2008;Nakahata et al 2008) also functions in learning and memory (Gao et al 2010).…”

“…SIRT1, a NAD-dependent deacetylase, which regulates CLOCK mediated chromatin remodeling and circadian rhythms (Asher et al 2008;Nakahata et al 2008) also functions in learning and memory (Gao et al 2010). SIRT1 oscillates in the hippocampus with alterations in SIRT1 rhythm resulting in memory deficits (Rawashdeh et al 2014). Thus, circadian regulation of learninginduced transcription necessary for LTM through epigenetic mechanisms or transcription factor activation provides a key mechanism through which the circadian clock targets memory formation.…”