Objective: To observe the expression of circadian rhythm related genes Bmal1 and melatonin receptors in different brain regions of 6-OHDA-induced acute Parkinson’s disease rats.

Background: More and more studies have found that there is a close relationship between dopamine system and circadian rhythm system. On the one hand, the key rate-limiting enzyme tyrosine hydroxylase that synthesizes dopamine is controlled by circadian rhythms, resulting in diurnal fluctuations in dopamine levels in the striatum. On the other hand, dopamine can pass through Dependent pathways regulate the expression of the clock gene and regulate the activity of BMAL1 / CLOCK dimers that play an important role in circadian rhythm mechanisms. These findings mean that the dopaminergic system and the circadian rhythm system play a role in the regulation of each other, both in the occurrence and development of Parkinson’s disease plays a role, is a very interesting research direction.

Methods: Taking western blot to test Bmal1 and MT2 expression in both substantia nigra and corpus striatum of the rats. Using immunohistochemistry to test MT1 and MT2 expression in pineal gland of the rats.

Results: A significant circadian rhythm of Bmal1 and MT2 is found in the striatum of normal rats. Bmal1 is also found to be rhythmic in substantia nigra but with smaller amplitude. Comparing with the control group, the normal circadian rhythm of Bmal1 and MT2 expression is lost in Parkinson disease rats. A general decrease of Bmal1 and MT2 is found in Parkinson disease rats. MT2 expression is not rhythmic in pineal gland but MT1 is expressed rhythmically. MT1 is significantly increased in pineal gland in Parkinson disease rats in contrast with control group.

Conclusions: 1. A much larger amplitude of circadian rhythm is found in stratum comparing to substantia nigra. 2. A decrease of circadian amplitude is found in both substantia nigra and corpus striatum in Parkinson disease model rats comparing to that in the control group rats. A general decrease of Bmal1 and MT2 are found in both substantia nigra and corpus striatum in Parkinson model rats, indicating that circadian rhythm dysfunction is closely related to Parkinson’s disease. MT1 is increased in pineal gland in Parkinson disease rats. It may be due to the compensatory response of pineal gland to decrease circadian amplitude.

References: 1. Hayes J, Tipton KF, Bianchi L, Corte LD. Complexities in the neurotoxic actions of 6-hydroxydopamine in relation to the cytoprotective properties of taurine. Brain research bulletin 2001; 55(2): 239-45. 2. Sarre S, Herregodts P, Deleu D, et al. Biotransformation of L-dopa in striatum and substantia nigra of rats with a unilateral, nigrostriatal lesion: a microdialysis study. Naunyn-Schmiedeberg’s archives of pharmacology 1992; 346(3): 277-85. 3. Lee CS, Sauer H, Bjorklund A. Dopaminergic neuronal degeneration and motor impairments following axon terminal lesion by instrastriatal 6-hydroxydopamine in the rat. Neuroscience 1996; 72(3): 641-53. 4. Yuan H, Sarre S, Ebinger G, Michotte Y. Neuroprotective and neurotrophic effect of apomorphine in the striatal 6-OHDA-lesion rat model of Parkinson’s disease. Brain research 2004; 1026(1): 95-107. 5. George Paxinos CW. The rat brain in stereotaxic coordinates. London, UK: Elsevier; 2007. 6. Iuvone PM, Galli CL, Garrison-Gund CK, Neff NH. Light stimulates tyrosine hydroxylase activity and dopamine synthesis in retinal amacrine neurons. Science 1978; 202(4370): 901-2. 7. Masri S, Rigor P, Cervantes M, et al. Partitioning circadian transcription by SIRT6 leads to segregated control of cellular metabolism. Cell 2014; 158(3): 659-72. 8. Doi M, Yujnovsky I, Hirayama J, et al. Impaired light masking in dopamine D2 receptor-null mice. Nature neuroscience 2006; 9(6): 732-4. 9. Yujnovsky I, Hirayama J, Doi M, Borrelli E, Sassone-Corsi P. Signaling mediated by the dopamine D2 receptor potentiates circadian regulation by CLOCK:BMAL1. Proceedings of the National Academy of Sciences of the United States of America 2006; 103(16): 6386-91. 10. Videnovic A, Golombek D. Circadian and sleep disorders in Parkinson’s disease. Experimental neurology 2013; 243: 45-56. 11. Mendoza J, Challet E. Circadian insights into dopamine mechanisms. Neuroscience 2014; 282: 230-42. 12. Hampp G, Ripperger JA, Houben T, et al. Regulation of monoamine oxidase A by circadian-clock components implies clock influence on mood. Current biology : CB 2008; 18(9): 678-83. 13. McClung CA, Sidiropoulou K, Vitaterna M, et al. Regulation of dopaminergic transmission and cocaine reward by the Clock gene. Proceedings of the National Academy of Sciences of the United States of America 2005; 102(26): 9377-81. 14. McGeer EG, McGeer PL. Circadian rhythm in pineal tyrosine hydroxylase. Science 1966; 153(3731): 73-4. 15. Sidor MM, Spencer SM, Dzirasa K, et al. Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice. Molecular psychiatry 2015; 20(11): 1479-80. 16. Gonzalez S, Moreno-Delgado D, Moreno E, et al. Circadian-related heteromerization of adrenergic and dopamine D(4) receptors modulates melatonin synthesis and release in the pineal gland. PLoS biology 2012; 10(6): e1001347. 17. Sellix MT, Freeman ME. Circadian rhythms of neuroendocrine dopaminergic neuronal activity in ovariectomized rats. Neuroendocrinology 2003; 77(1): 59-70. 18. Sellix MT, Egli M, Poletini MO, et al. Anatomical and functional characterization of clock gene expression in neuroendocrine dopaminergic neurons. American journal of physiology Regulatory, integrative and comparative physiology 2006; 290(5): R1309-23. 19. Owasoyo JO, Walker CA, Whitworth UG. Diurnal variation in the dopamine level of rat brain areas: effect of sodium phenobarbital. Life sciences 1979; 25(2): 119-22. 20. Paulson PE, Robinson TE. Relationship between circadian changes in spontaneous motor activity and dorsal versus ventral striatal dopamine neurotransmission assessed with on-line microdialysis. Behavioral neuroscience 1994; 108(3): 624-35. 21. Hood S, Cassidy P, Cossette MP, et al. Endogenous dopamine regulates the rhythm of expression of the clock protein PER2 in the rat dorsal striatum via daily activation of D2 dopamine receptors. The Journal of neuroscience : the official journal of the Society for Neuroscience 2010; 30(42): 14046-58. 22. Verwey M, Dhir S, Amir S. Circadian influences on dopamine circuits of the brain: regulation of striatal rhythms of clock gene expression and implications for psychopathology and disease. F1000Research 2016; 5. 23. Moore RY. Neural control of the pineal gland. Behavioural brain research 1996; 73(1-2): 125-30. 24. Rosell A, Gimenez-Amaya JM. Anatomical re-evaluation of the corticostriatal projections to the caudate nucleus: a retrograde labeling study in the cat. Neuroscience research 1999; 34(4): 257-69. 25. Witkovsky P. Dopamine and retinal function. Documenta ophthalmologica Advances in ophthalmology 2004; 108(1): 17-40. 26. Kawarai T, Kawakami H, Yamamura Y, Nakamura S. Structure and organization of the gene encoding human dopamine transporter. Gene 1997; 195(1): 11-8.

« Back to 2018 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/circadian-modifications-in-parkinson-disease/