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Per2 Expression Regulates the Spatial Working Memory of Mice through DRD1-PKA-CREB Signaling

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Abstract

Several individuals worldwide show cognitive impairment due to various reasons, including a prolonged lifespan and an altered lifestyle. Various causes, such as broken circadian rhythms and dopamine-related factors, have been proposed to be involved in the development of cognitive impairment. However, the underlying pathways remain elusive. Humans with circadian misalignment often face cognitive impairments, and animals with mutations in circadian rhythm-related genes display impaired cognitive functions. To analyze this in detail, this study aimed to investigate the pathways potentially involved in cognitive impairment using Period2 (Per2) transgenic animals. Spatial working memory performance in Per2 knockout (KO) and wild-type mice was assessed using the Barnes maze and Y-maze. The dopamine-related protein expression levels in the hippocampus were measured by Western blotting and enzyme-linked immunosorbent assay (ELISA). Per2 KO mice exhibited impaired spatial working memory, and the expression levels of dopamine receptor D1 (DRD1), protein kinase A (PKA), and cAMP response element-binding protein (CREB) were higher in Per2 KO mice than in control mice. Additionally, DRD1 expression levels were inversely proportional to those of PER2. Thus, memory tests were again conducted after administration of the DRD1 antagonist SCH-23390. Per2 KO mice recovered from memory impairment, and the levels of PKA and CREB decreased after treatment. The effects of Aβ on memory in Per2 mice were also investigated, and we found the increased Aβ levels did not influence the memory performance of Per2 mice after SCH-23390 treatment. These results indicate that Per2 expression levels might influence spatial working memory performance via DRD1-PKA-CREB-dependent signaling.

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References

  1. Wang LMC, Dragich JM, Kudo T et al (2009) Expression of the circadian clock gene Period2 in the hippocampus: Possible implications for synaptic plasticity and learned behaviour. ASN Neuro 1:139–152. https://doi.org/10.1042/AN20090020

    Article  CAS  Google Scholar 

  2. Fisk AS, Tam SKE, Brown LA et al (2018) Light and cognition: Roles for circadian rhythms, sleep, and arousal. Front Neurol 9:1–18. https://doi.org/10.3389/fneur.2018.00056

    Article  Google Scholar 

  3. Kyriacou CP, Hastings MH (2010) Circadian clocks: genes, sleep, and cognition. Trends Cogn Sci 14:259–267. https://doi.org/10.1016/j.tics.2010.03.007

    Article  PubMed  Google Scholar 

  4. Ruby NF, Hwang CE, Wessells C et al (2008) Hippocampal-dependent learning requires a functional circadian system. Proc Natl Acad Sci U S A 105:15593–15598. https://doi.org/10.1073/pnas.0808259105

    Article  PubMed  PubMed Central  Google Scholar 

  5. Schmidt C, Collette F, Cajochen C, Peigneux P (2007) A time to think: Circadian rhythms in human cognition. Cogn Neuropsychol 24:755–789. https://doi.org/10.1080/02643290701754158

    Article  PubMed  Google Scholar 

  6. Chellappa SL, Morris CJ, Scheer FAJL (2019) Effects of circadian misalignment on cognition in chronic shift workers. Sci Rep 9:1–9. https://doi.org/10.1038/s41598-018-36762-w

    Article  CAS  Google Scholar 

  7. Wright KP, Lowry CA, leBourgeois MK (2012) Circadian and wakefulness-sleep modulation of cognition in humans. Front Mol Neurosci 5:1–12. https://doi.org/10.3389/fnmol.2012.00050

    Article  Google Scholar 

  8. Chellappa SL, Morris CJ, Scheer FAJL (2018) Daily circadian misalignment impairs human cognitive performance task-dependently. Sci Rep 8:1–11. https://doi.org/10.1038/s41598-018-20707-4

    Article  CAS  Google Scholar 

  9. Barca-Mayo O, Pons-Espinal M, Follert P et al (2017) Astrocyte deletion of Bmal1 alters daily locomotor activity and cognitive functions via GABA signalling. Nat Commun 8:1–14. https://doi.org/10.1038/ncomms14336

    Article  CAS  Google Scholar 

  10. De Bundel D, Gangarossa G, Biever A et al (2013) Cognitive dysfunction, elevated anxiety, and reduced cocaine response in circadian clock-deficient cryptochrome knockout mice. Front Behav Neurosci 7:1–11. https://doi.org/10.3389/fnbeh.2013.00152

    Article  CAS  Google Scholar 

  11. Garcia JA, Zhang D, Estill SJ, et al (2000) Impaired cued and contextual memory in NPAS2-deficient mice. Science (80- ) 288:2226–2230. https://doi.org/10.1126/science.288.5474.2226

  12. Kim M, de la Peña JB, Cheong JH, Kim HJ (2018) Neurobiological functions of the period circadian clock 2 gene, per2. Biomol Ther 26:358–367. https://doi.org/10.4062/biomolther.2017.131

    Article  CAS  Google Scholar 

  13. Ripperger JA, Jud C, Albrecht U (2011) The daily rhythm of mice. FEBS Lett 585:1384–1392. https://doi.org/10.1016/j.febslet.2011.02.027

    Article  CAS  PubMed  Google Scholar 

  14. Ripperger JA, Albrecht U (2012) The circadian clock component PERIOD2: From molecular to cerebral functions. Prog Brain Res 199:233–245. https://doi.org/10.1016/B978-0-444-59427-3.00014-9

    Article  CAS  PubMed  Google Scholar 

  15. Kwon I, Lee J, Chang SH et al (2006) BMAL1 Shuttling Controls Transactivation and Degradation of the CLOCK/BMAL1 Heterodimer. Mol Cell Biol 26:7318–7330. https://doi.org/10.1128/mcb.00337-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Shearman LP, Sriram S, Weaver DR, et al (2000) Interacting molecular loops in the mammalian circadian clock. Science (80- ) 288:1013–1019. https://doi.org/10.1126/science.288.5468.1013

  17. Nieoullon A (2002) Dopamine and the regulation of cognition and attention. Prog Neurobiol 67:53–83. https://doi.org/10.1016/S0301-0082(02)00011-4

    Article  CAS  PubMed  Google Scholar 

  18. Nyberg L, Karalija N, Salami A et al (2016) Dopamine D2 receptor availability is linked to hippocampal-caudate functional connectivity and episodic memory. Proc Natl Acad Sci U S A 113:7918–7923. https://doi.org/10.1073/pnas.1606309113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Takahashi H, Kato M, Takano H et al (2008) Differential contributions of prefrontal and hippocampal dopamine D 1 and D2 receptors in human cognitive functions. J Neurosci 28:12032–12038. https://doi.org/10.1523/JNEUROSCI.3446-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Vijayraghavan S, Wang M, Birnbaum SG et al (2007) Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat Neurosci 10:376–384. https://doi.org/10.1038/nn1846

    Article  CAS  PubMed  Google Scholar 

  21. El-Ghundi M, Fletcher PJ, Drago J et al (1999) Spatial learning deficit in dopamine D1 receptor knockout mice. Eur J Pharmacol 383:95–106. https://doi.org/10.1016/S0014-2999(99)00573-7

    Article  CAS  PubMed  Google Scholar 

  22. Morice E, Billard J, Mathieu F et al (2007) HAL author manuscript Parallel Loss of Hippocampal LTD and Cognitive Flexibility in a Genetic Model of Hyperdopaminergia. Neuropsychopharmacology:1–19

  23. Zhao L, Lin Y, Lao G et al (2015) Association study of dopamine receptor genes polymorphism with cognitive functions in bipolar i disorder patients. J Affect Disord 170:85–90. https://doi.org/10.1016/j.jad.2014.08.039

    Article  CAS  PubMed  Google Scholar 

  24. Bae K, Jin X, Maywood ES et al (2001) Differential functions of mPer1, mPer2, and mPer3 in the SCN circadian clock. Neuron 30:525–536. https://doi.org/10.1016/S0896-6273(01)00302-6

    Article  CAS  PubMed  Google Scholar 

  25. Abarca C, Albrecht U, Spanagel R (2002) Cocaine sensitization and reward are under the influence of circadian genes and rhythm. Proc Natl Acad Sci 99:9026–9030

    Article  CAS  Google Scholar 

  26. Kim M, Custodio RJ, Botanas CJ et al (2019) The circadian gene, Per2, influences methamphetamine sensitization and reward through the dopaminergic system in the striatum of mice. Addict Biol 24:946–957. https://doi.org/10.1111/adb.12663

    Article  CAS  PubMed  Google Scholar 

  27. Coburn-Litvak PS, Pothakos K, Tata DA et al (2003) Chronic administration of corticosterone impairs spatial reference memory before spatial working memory in rats. Neurobiol Learn Mem 80:11–23. https://doi.org/10.1016/S1074-7427(03)00019-4

    Article  CAS  PubMed  Google Scholar 

  28. Pitts MW (2018) Barnes Maze Procedure for Spatial Learning and Memory in Mice. Bio-protocol 8:1–15. https://doi.org/10.21769/bioprotoc.2744.Barnes

    Article  CAS  Google Scholar 

  29. Kraeuter A, Guest PC, Sarnyai Z (2019) The Y-maze for assessment of spatial working and reference memory in mice. Hum Press 1916:105–111. https://doi.org/10.1007/978-1-4939-8994-2_10

    Article  CAS  Google Scholar 

  30. Wardlaw SM, Phan TX, Saraf A et al (2014) Genetic disruption of the core circadian clock impairs hippocampus- dependent memory. Learn Mem 21:417–423. https://doi.org/10.1101/lm.035451.114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rawashdeh O, Parsons R, Maronde E (2018) Clocking in Time to Gate Memory Processes: The Circadian Clock Is Part of the Ins and Outs of Memory. Neural Plast 2018. https://doi.org/10.1155/2018/6238989

  32. Song H, Moon M, Choe HK et al (2015) Aβ-induced degradation of BMAL1 and CBP leads to circadian rhythm disruption in Alzheimer’s disease. Mol Neurodegener 10:1–15. https://doi.org/10.1186/s13024-015-0007-x

    Article  CAS  Google Scholar 

  33. Duncan MJ, Smith JT, Franklin KM et al (2012) Effects of aging and genotype on circadian rhythms, sleep, and clock gene expression in APPxPS1 knock-in mice, a model for Alzheimer’s disease. Exp Neurol 236:249–258. https://doi.org/10.1016/j.expneurol.2012.05.011

    Article  CAS  PubMed  Google Scholar 

  34. Fusilier AR, Davis JA, Paul JR, et al (2021) Impaired clock gene expression and abnormal diurnal regulation of hippocampal inhibitory transmission and spatial memory in a mouse model of Alzheimer’s disease. bioArXiv

  35. Remodes M, Schuman EM (2004) Role for a cortical input to hippocampal area CA1 in the consolidation of a long-tem memory. Nature 431:699–703. https://doi.org/10.1038/nature02965

    Article  CAS  Google Scholar 

  36. Yoon T, Okada J, Jung MW, Kim JJ (2008) Prefrontal cortex and hippocampus subserve different components of working memory in rats. Learn Mem 15:97–105. https://doi.org/10.1101/lm.850808

    Article  PubMed  PubMed Central  Google Scholar 

  37. McNamara CG, Dupret D (2017) Two sources of dopamine for the hippocampus. Trends Neurosci 40:383–384. https://doi.org/10.1016/j.tins.2017.05.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Duszkiewicz AJ, McNamara CG, Takeuchi T, Genzel L (2019) Novelty and Dopaminergic Modulation of Memory Persistence: A Tale of Two Systems. Trends Neurosci 42:102–114. https://doi.org/10.1016/j.tins.2018.10.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kempadoo KA, Mosharov EV, Choi SJ et al (2016) Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory. Proc Natl Acad Sci U S A 113:14835–14840. https://doi.org/10.1073/pnas.1616515114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Gangarossa G, Longueville S, De Bundel D et al (2012) Characterization of dopamine D1 and D2 receptor-expressing neurons in the mouse hippocampus. Hippocampus 22:2199–2207. https://doi.org/10.1002/hipo.22044

    Article  CAS  PubMed  Google Scholar 

  41. Xing B, Kong H, Meng X et al (2010) Dopamine D1 but not D3 receptor is critical for spatial learning and related signaling in the hippocampus. Neuroscience 169:1511–1519. https://doi.org/10.1016/j.neuroscience.2010.06.034

    Article  CAS  PubMed  Google Scholar 

  42. Silva WCN d, Köhler CC, Radiske A, Cammarota M (2012) D 1/D 5 dopamine receptors modulate spatial memory formation. Neurobiol Learn Mem 97:271–275. https://doi.org/10.1016/j.nlm.2012.01.005

    Article  CAS  PubMed  Google Scholar 

  43. Broussard JI, Yang K, Levine AT et al (2016) Dopamine Regulates Aversive Contextual Learning and Associated In Vivo Synaptic Plasticity in the Hippocampus. Cell Rep 14:1930–1939. https://doi.org/10.1016/j.celrep.2016.01.070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cools R, D’Esposito M (2011) Inverted-U-shaped dopamine actions on human working memory and cognitive control. Biol Psychiatry 69. https://doi.org/10.1016/j.biopsych.2011.03.028

  45. Lidow MS, Koh PO, Arnsten AFT (2003) D1 dopamine receptors in the mouse prefrontal cortex: Immunocytochemical and cognitive neuropharmacological analyses. Synapse 47:101–108. https://doi.org/10.1002/syn.10143

    Article  CAS  PubMed  Google Scholar 

  46. Zahrt J, Taylor JR, Mathew RG, Arnsten AFT (1997) Supranormal stimulation of D1 dopamine receptors in the rodent prefrontal cortex impairs spatial working memory performance. J Neurosci 17:8528–8535. https://doi.org/10.1523/jneurosci.17-21-08528.1997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wearick-Silva LE, Orso R, Martins LA et al (2019) Dual influences of early life stress induced by limited bedding on walking adaptability and Bdnf/TrkB and Drd1/Drd2 gene expression in different mouse brain regions. Behav Brain Res 359:66–72. https://doi.org/10.1016/j.bbr.2018.10.025

    Article  CAS  PubMed  Google Scholar 

  48. Hampp G, Ripperger JA, Houben T et al (2008) Regulation of Monoamine Oxidase A by Circadian-Clock Components Implies Clock Influence on Mood. Curr Biol 18:678–683. https://doi.org/10.1016/j.cub.2008.04.012

    Article  CAS  PubMed  Google Scholar 

  49. Zhang J, Ko SY, Liao Y et al (2018) Activation of the dopamine D1 receptor can extend long-term spatial memory persistence via PKA signaling in mice. Neurobiol Learn Mem 155:568–577. https://doi.org/10.1016/j.nlm.2018.05.016

    Article  CAS  PubMed  Google Scholar 

  50. Arnsten AFT, Ramos BP, Birnbaum SG, Taylor JR (2005) Protein kinase A as a therapeutic target for memory disorders: Rationale and challenges. Trends Mol Med 11:121–128. https://doi.org/10.1016/j.molmed.2005.01.006

    Article  CAS  PubMed  Google Scholar 

  51. Abel T, Nguyen PV, Barad M et al (1997) Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell 88:615–626. https://doi.org/10.1016/S0092-8674(00)81904-2

    Article  CAS  PubMed  Google Scholar 

  52. Kimura R, Ohno M (2009) Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5XFAD Alzheimer mouse model. Neurobiol Dis 33:229–235. https://doi.org/10.1016/j.nbd.2008.10.006

    Article  CAS  PubMed  Google Scholar 

  53. Westerman MA, Cooper-Blacketer D, Mariash A et al (2002) The relationship between Aβ and memory in the Tg2576 mouse model of Alzheimer’s disease. J Neurosci 22:1858–1867. https://doi.org/10.1523/jneurosci.22-05-01858.2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Manczak M, Kandimalla R, Yin X, Reddy PH (2018) Hippocampal mutant APP and amyloid beta-induced cognitive decline, dendritic spine loss, defective autophagy, mitophagy and mitochondrial abnormalities in a mouse model of Alzheimer’s disease. Hum Mol Genet 27:1332–1342. https://doi.org/10.1093/hmg/ddy042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ali T, Kim MO (2015) Melatonin ameliorates amyloid beta-induced memory deficits, tau hyperphosphorylation and neurodegeneration via PI3/Akt/GSk3β pathway in the mouse hippocampus. J Pineal Res 59:47–59. https://doi.org/10.1111/jpi.12238

    Article  CAS  PubMed  Google Scholar 

  56. Shen YX, Xu SY, Wei W et al (2002) The protective effects of melatonin from oxidative damage induced by amyloid beta-peptide 25-35 in middle-aged rats. J Pineal Res 32:85–89. https://doi.org/10.1034/j.1600-079x.2002.1819.x

    Article  CAS  PubMed  Google Scholar 

  57. Olcese JM, Cao C, Mori T et al (2009) Protection against cognitive deficits and markers of neurodegeneration by long-term oral administration of melatonin in a transgenic model of Alzheimer disease. J Pineal Res 47:82–96. https://doi.org/10.1111/j.1600-079X.2009.00692.x

    Article  CAS  PubMed  Google Scholar 

  58. Zisapel N (2002) Melatonin – Dopamine Interactions : From Basic Neurochemistry to a Clinical Setting 21:605–616

  59. Iuvone PM, Gan J (1995) Functional interaction of melatonin receptors and D1 dopamine receptors in cultured chick retinal neurons. J Neurosci 15:2179–2185. https://doi.org/10.1523/jneurosci.15-03-02179.1995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Cleal M, Fontana BD, Ranson DC et al (2021) The Free-movement pattern Y-maze: A cross-species measure of working memory and executive function. Behav Res Methods 53:536–557. https://doi.org/10.3758/s13428-020-01452-x

    Article  PubMed  Google Scholar 

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Funding

This research was supported by the National Research Foundation (NRF) of Korea (NRF-2021R1G1A1093620; 2020M3E5D9080791).

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Authors and Affiliations

  1. Uimyung Research Institute for Neuroscience, Department of Pharmacy, Sahmyook University, Hwarangro 815, Nowongu, Seoul, 01795, Republic of Korea

    Mikyung Kim, Raly James Custodio, Hyun Jun Lee, Leandro Val Sayson, Darlene Mae Ortiz & Hee Jin Kim

  2. BioScience Research Institute, Department of Chemistry & Life Science, Sahmyook University, Hwarangro 815, Nowongu, Seoul, 01795, Republic of Korea

    Mikyung Kim

  3. Division of Child & Adolescent Psychiatry, Department of Psychiatry and Institute of Human Behavioral Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea

    Bung-Nyun Kim

  4. School of Pharmacy, Jeonbuk National University, Badkje-daero 567, Jeonju-si, Jeollabuk-do, 54896, Republic of Korea

    Jae Hoon Cheong

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Contributions

MK, HJK, and JHC were responsible for the study concept and design. MK, RJC, LVS, and DMO conducted the experiments and collected the data. MK, RJC, and BNK analyzed the data. MK wrote the manuscript. All authors reviewed the manuscript.

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Correspondence to Mikyung Kim or Jae Hoon Cheong.

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All animal treatments and maintenance were performed in accordance with the Principles of Laboratory Animal Care (NIH Publication No. 85–23, revised 1985) and the Animal Care and Use Guidelines of Sahmyook University, South Korea (SYUIACUC2021-020).

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Supplementary Information

Supplementary figure 1.

Dopamine-related protein levels in the hippocampus of drug-naïve Per2 KO, OE, and WT mice. (A)-(D) Protein expression levels of DRD1, DRD2, DAT, and TH by Western blotting. The expression levels of DRD1 were significantly different in Per2 KO, OE, and WT mice. * p < 0.05, ** p < 0.01, significantly different (PNG 190 kb)

High Resolution Image (TIF 338 kb)

Supplementary figure 2.

Spatial working memory of drug-naïve Per2 KO, OE, and WT mice. (A) Total entry and (B) percentage of spontaneous alternation during the Y-maze. (C-D) Latency time and (E-F) errors during the Barnes maze. Per2 KO and OE mice impaired spatial working memory on the Y-maze and Barnes maze. Red arrows indicate long-term memory on the next day after introducing the goal box. Per2 KO mice showed worse long-term memory compared to Per2 OE and WT mice. ** p < 0.01, significantly different to the WT (PNG 265 kb)

High Resolution Image (TIF 362 kb)

Supplementary figure 3.

The expression levels of Drd1 and Drd2 in HPC of drug-naïve Per2 KO and WT mice by RT-qPCR. Drd1 (A) and Drd2 (B) expression levels in Per2 KO and WT mice (PNG 65 kb)

High Resolution Image (TIF 174 kb)

Supplementary figure 4.

The expression levels of circadian-related genes in HPC of drug-naïve Per2 KO and WT mice by RT-qPCR. The expression levels of Clock (A), Bmal1 (B), Cry1 (C), and Cry2 (D) in Per2 KO and WT mice. * p < 0.05, significantly different compared to the WT (PNG 104 kb)

High Resolution Image (TIF 226 kb)

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Kim, M., Custodio, R.J., Lee, H.J. et al. Per2 Expression Regulates the Spatial Working Memory of Mice through DRD1-PKA-CREB Signaling. Mol Neurobiol 59, 4292–4303 (2022). https://doi.org/10.1007/s12035-022-02845-z

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