Temporal dynamics of mouse hippocampal clock gene expression support memory processing

Abstract

Hippocampal plasticity and mnemonic processing exhibit a striking time-of-day dependence and likely implicate a temporally structured replay of memory traces. Molecular mechanisms fulfilling the requirements of sensing time and capturing time-related information are coded in dynamics of so-called clock genes and their protein products, first discovered and described in the hypothalamic suprachiasmatic nucleus. Using real-time PCR and immunohistochemical analyses, we show that in wildtype mice core clock components (mPer1/PER1, mPer2/PER2, mCry1/CRY1, mCry2/CRY2, mClock/CLOCK, mBmal1/BMAL1) are expressed in neurons of all subregions of the hippocampus in a time-locked fashion over a 24-h (diurnal) day/night cycle. Temporal profiling of these transcriptional regulators reveals distinct and parallel peaks, at times when memory traces are usually formed and/or consolidated. The coordinated rhythmic expression of hippocampal clock gene expression is greatly disordered in mice deficient for the clock gene mPer1, a key player implicated in both, maintenance and adaptative plasticity of circadian clocks. Moreover, Per1-knockout animals are severely handicapped in a hippocampus-dependent long-term spatial learning paradigm. We propose that the dynamics of hippocampal clock gene expression imprint a temporal structure on memory processing and shape at the same time the efficacy of behavioral learning.

The clock genePeriod1regulates innate routine behaviour in mice

“…Taken together, these findings point to a fundamental deficit in both a simple (this study) and a more complex, hippocampus-related behaviour [16] in male Per1 2/2 mice.…”

“…Per1-deficient (129S-Per1 tm1Drw /J) mice [12] and the corresponding WT were both bred back onto a melatonin-proficient C3H/ HeN genetic background [15,16]. Health status of the animals was monitored regularly as described previously [24,25].…”

“…Deletion of clock genes causes pronounced cognitive and behavioural effects throughout the animal kingdom [41]. Period1-deficient mice display alterations in glucocorticoid rhythmicity [42], addiction [43], muscle strength [44], colonic motility [45], fertility [17,46] and memory [16].…”

“…Owing to the habituation phenotype discussed above and the known learning deficit of Per1 2/2 mice [16], we also examined non-reproductive hippocampus-dependent innate routine behaviour.…”

Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration

“…BMAL1 has been implicated in hippocampal and astrocytic function (17)(18)(19)(20). In Drosophila, deletion of the Period gene exacerbates brain pathology in neurodegeneration-prone mutants (21).…”