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The clock gene Per1 may exert diurnal control over hippocampal memory consolidation

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Abstract

The circadian system influences many different biological processes, including memory performance. While the suprachiasmatic nucleus (SCN) functions as the brain’s central pacemaker, downstream “satellite clocks” may also regulate local functions based on the time of day. Within the dorsal hippocampus (DH), for example, local molecular oscillations may contribute to time-of-day effects on memory. Here, we used the hippocampus-dependent Object Location Memory task to determine how memory is regulated across the day/night cycle in mice. First, we systematically determined which phase of memory (acquisition, consolidation, or retrieval) is modulated across the 24 h day. We found that mice show better long-term memory performance during the day than at night, an effect that was specifically attributed to diurnal changes in memory consolidation, as neither memory acquisition nor memory retrieval fluctuated across the day/night cycle. Using RNA-sequencing we identified the circadian clock gene Period1 (Per1) as a key mechanism capable of supporting this diurnal fluctuation in memory consolidation, as learning-induced Per1 oscillates in tandem with memory performance in the hippocampus. We then show that local knockdown of Per1 within the DH impairs spatial memory without affecting either the circadian rhythm or sleep behavior. Thus, Per1 may independently function within the DH to regulate memory in addition to its known role in regulating the circadian system within the SCN. Per1 may therefore exert local diurnal control over memory consolidation within the DH.

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Fig. 1: Memory performance oscillates over the diurnal cycle with better memory performance during the day.
Fig. 2: Memory acquisition and memory retrieval are unaffected by the time of day.
Fig. 3: Learning during the day drives major changes in gene expression that do not occur at night.
Fig. 4: Knockdown of Per1 in the dorsal hippocampus disrupts long-term spatial memory formation.
Fig. 5: Knocking down Per1 in the dorsal hippocampus does not affect circadian rhythms or sleep behavior.

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Acknowledgements

We would like to thank Dr. Rachael Neve and the Gene Delivery Technology Core at Massachusetts General Hospital for help designing and packaging all HSV viruses described here. We would also like to thank the Huck Institutes of the Life Sciences at Penn State for funding, Dr. Craig Praul and the Huck Genomics Core Facility for library construction, Dr. Yuka Imamura and the Penn State Hershey Genome Sciences Facility for sequencing, and the Penn State Bioinformatics Consulting Center for assistance with the RNA-seq.

Funding

This research was funded by NIH grants R01AG074041 (JLK), K99/R00AG056586 (JLK) and R21AG068444 (JLK), Whitehall Foundation Grant #2020-05-06 (JLK), American Federation for Aging Research Grant #A21105 (JLK), startup funds from the Eberly College of Science and Department of Biology at Pennsylvania State University (JLK) and the National Institute on Aging under Grant T32 AG049676 to The Pennsylvania State University (LB).

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Authors and Affiliations

  1. Department of Biology, Pennsylvania State University, University Park, PA, 16802, USA

    Lauren Bellfy, Chad W. Smies, Alicia R. Bernhardt, Kasuni K. Bodinayake, Emily M. Stuart, Destiny S. Wright, Chen-Yu Lo, Shoko Murakami, Hannah M. Boyd, Megan J. von Abo & Janine L. Kwapis

  2. Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, 16802, USA

    Lauren Bellfy, Aswathy Sebastian, Hannah M. Boyd, Istvan Albert & Janine L. Kwapis

  3. Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, 16802, USA

    Istvan Albert

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Contributions

Study concept and design: LB and JLK. Acquisition of data: LB, CWS, ARB, KKB, EMS, DSW, CL, SM, HMB, and MJV. Analysis of data: LB, ARB, KKB, MJV, AS, and IA. Drafting of manuscript: LB and JLK. Final approval of manuscript: All authors.

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Correspondence to Janine L. Kwapis.

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Bellfy, L., Smies, C.W., Bernhardt, A.R. et al. The clock gene Per1 may exert diurnal control over hippocampal memory consolidation. Neuropsychopharmacol. 48, 1789–1797 (2023). https://doi.org/10.1038/s41386-023-01616-1

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