The Sex-dependent Impact of PER2 Polymorphism on Sleep and Activity in a Novel Mouse Model of Cranial-irradiation-induced Hypersomnolence

Overview

Journal Neurooncol Adv

Publisher Oxford University Press

Date 2023 Oct 2

PMID 37781088

Authors

Kendra A Adegbesan

Francesco Tomassoni Ardori

Sudhirkumar Yanpallewar

Sean P Bradley

Yogita Chudasama

Elizabeth Vera

Nicole Briceno

Amanda L King

Lino Tessarollo

Mark R Gilbert

Vivian A Guedes

DeeDee K Smart

Terri S Armstrong

Dorela D Shuboni-Mulligan

Affiliations

Soon will be listed here.

Abstract

Background: Hypersomnolence is a common and disruptive side effect of cranial radiotherapy and is associated with fatigue and disturbances in mood and cognition in primary brain tumor (PBT) patients. The biological underpinnings of this effect are not understood. Our laboratory has previously found that the presence of a single nucleotide polymorphism (rs934945, G-E mutation) in the PERIOD2 (PER2) clock gene was associated with a decreased likelihood of fatigue in PBT patients. Here, we aim to understand the effects of PER2 polymorphism on radiation susceptibility within a murine model of cranial-irradiation-induced hypersomnolence (C-RIH).

Methods: Male and female transgenic mice were generated using CRISPR-Cas9, replacing the endogenous mouse PER2:CRY1 binding domain with its human isoform with (h1244 KI) or without the SNP rs934945 (h1244 KI). Activity and sleep were monitored continuously 10 days before and after cranial irradiation (whole brain, 15Gy, single fraction). Behavioral assessments measuring anxiety, depression, and working memory were used to assess mood and cognitive changes 2 months postradiation.

Results: During their active phase, h1244 knock-ins (KIs) had less radiation-induced suppression of activity relative to h1244 KIs and female h1244 KIs saw a reduction of hypersomnolence over 10 days. h1244 KIs displayed less anxiety behavior and were more ambulatory within all behavioral tests.

Conclusions: The PER2 rs934945 polymorphism had long-lasting behavioral effects associated with radiation toxicity, particularly in sleep in females and the activity of all animals. Our findings shed light on biological mechanisms underlying C-RIH.

References

King A, Shuboni-Mulligan D, Vera E, Crandon S, Acquaye A, Boris L . Exploring the prevalence and burden of sleep disturbance in primary brain tumor patients. Neurooncol Pract. 2022; 9(6):526-535. PMC: 9665069. DOI: 10.1093/nop/npac049. View

Wang Y, Xie C, Xu Y, Zhang Y, Zhu C, Zhou K . Cerebellar irradiation does not cause hyperactivity, fear, and anxiety-related disorders in the juvenile rat brain. Eur Radiol Exp. 2022; 6(1):57. PMC: 9663786. DOI: 10.1186/s41747-022-00307-8. View

Kim M, Custodio R, Lee H, Sayson L, Ortiz D, Kim B . Per2 Expression Regulates the Spatial Working Memory of Mice through DRD1-PKA-CREB Signaling. Mol Neurobiol. 2022; 59(7):4292-4303. DOI: 10.1007/s12035-022-02845-z. View

Hayashi J, Noguchi A, Nakashima K, Hayashi S, Kashiwagi S, Mayumi T . Human lymphoblastoid and fibroblast interferon in the treatment of chronic hepatitis B. Clin Ther. 1990; 12(1):12-21. View

Brown P, Buckner J, OFallon J, Iturria N, Brown C, ONeill B . Effects of radiotherapy on cognitive function in patients with low-grade glioma measured by the folstein mini-mental state examination. J Clin Oncol. 2003; 21(13):2519-24. DOI: 10.1200/JCO.2003.04.172. View

Shearman L, Sriram S, Weaver D, Maywood E, Chaves I, Zheng B . Interacting molecular loops in the mammalian circadian clock. Science. 2000; 288(5468):1013-9. DOI: 10.1126/science.288.5468.1013. View

Song H, Cho C, Lee H, Moon J, Kang S, Yoon H . Association of CLOCK, ARNTL, PER2, and GNB3 polymorphisms with diurnal preference in a Korean population. Chronobiol Int. 2016; 33(10):1455-1463. DOI: 10.1080/07420528.2016.1231199. View

Armstrong C, Hunter J, Ledakis G, Cohen B, Tallent E, Goldstein B . Late cognitive and radiographic changes related to radiotherapy: initial prospective findings. Neurology. 2002; 59(1):40-8. DOI: 10.1212/wnl.59.1.40. View

Kerns S, Kundu S, Oh J, Singhal S, Janelsins M, Travis L . The Prediction of Radiotherapy Toxicity Using Single Nucleotide Polymorphism-Based Models: A Step Toward Prevention. Semin Radiat Oncol. 2015; 25(4):281-91. PMC: 4576690. DOI: 10.1016/j.semradonc.2015.05.006. View

10.

Mitchell M, Engelbrecht A . Circadian Rhythms and Breast Cancer: The Role of Per2 in Doxorubicin-Induced Cell Death. J Toxicol. 2015; 2015:392360. PMC: 4548136. DOI: 10.1155/2015/392360. View

11.

Bae K, Jin X, Maywood E, Hastings M, Reppert S, Weaver D . Differential functions of mPer1, mPer2, and mPer3 in the SCN circadian clock. Neuron. 2001; 30(2):525-36. DOI: 10.1016/s0896-6273(01)00302-6. View

12.

Vieira E, Mirizio G, Barin G, de Andrade R, Nimer N, La Sala L . Clock Genes, Inflammation and the Immune System-Implications for Diabetes, Obesity and Neurodegenerative Diseases. Int J Mol Sci. 2020; 21(24). PMC: 7766955. DOI: 10.3390/ijms21249743. View

13.

Cleeland C, Bennett G, Dantzer R, Dougherty P, Dunn A, Meyers C . Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism? A cytokine-immunologic model of cancer symptoms. Cancer. 2003; 97(11):2919-25. DOI: 10.1002/cncr.11382. View

14.

Albrecht U, Eichele G . The mammalian circadian clock. Curr Opin Genet Dev. 2003; 13(3):271-7. DOI: 10.1016/s0959-437x(03)00055-8. View

15.

Kloehn I, Pillai S, Officer L, Klement C, Gasser P, Evans J . Sexual Differentiation of Circadian Clock Function in the Adrenal Gland. Endocrinology. 2016; 157(5):1895-904. DOI: 10.1210/en.2015-1968. View

16.

Hainfeld J, Ridwan S, Stanishevskiy Y, Panchal R, Slatkin D, Smilowitz H . Iodine nanoparticles enhance radiotherapy of intracerebral human glioma in mice and increase efficacy of chemotherapy. Sci Rep. 2019; 9(1):4505. PMC: 6418169. DOI: 10.1038/s41598-019-41174-5. View

17.

Lim A, Myers A, Yu L, Buchman A, Duffy J, De Jager P . Sex difference in daily rhythms of clock gene expression in the aged human cerebral cortex. J Biol Rhythms. 2013; 28(2):117-29. PMC: 3774838. DOI: 10.1177/0748730413478552. View

18.

Noll K, King A, Dirven L, Armstrong T, Taphoorn M, Wefel J . Neurocognition and Health-Related Quality of Life Among Patients with Brain Tumors. Hematol Oncol Clin North Am. 2021; 36(1):269-282. DOI: 10.1016/j.hoc.2021.08.011. View

19.

Leder K, Pitter K, LaPlant Q, Hambardzumyan D, Ross B, Chan T . Mathematical modeling of PDGF-driven glioblastoma reveals optimized radiation dosing schedules. Cell. 2014; 156(3):603-616. PMC: 3923371. DOI: 10.1016/j.cell.2013.12.029. View

20.

Smart D . Radiation Toxicity in the Central Nervous System: Mechanisms and Strategies for Injury Reduction. Semin Radiat Oncol. 2017; 27(4):332-339. PMC: 5657507. DOI: 10.1016/j.semradonc.2017.04.006. View