Dokument: Der Einfluss einer Bmal1-Defizienz auf die Infarktbildung und strukturelle Regeneration nach Photothrombose in männlichen und weiblichen Mäusen.

Titel:

Der Einfluss einer Bmal1-Defizienz auf die Infarktbildung und strukturelle Regeneration nach Photothrombose in männlichen und weiblichen Mäusen.

Weiterer Titel:

The effect of Bmal1-Deficiency on infarction and structural regeneration in response to photothrombotic stroke in male and female mice

URL für Lesezeichen:

https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=49536

URN (NBN):

urn:nbn:de:hbz:061-20190510-080746-6

Kollektion:

Dissertationen

Sprache:

Deutsch

Dokumententyp:

Wissenschaftliche Abschlussarbeiten » Dissertation

Medientyp:

Text

Autor:

Lembach, Anne [Autor]

Dateien:

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Dateien vom 08.05.2019 / geändert 08.05.2019

Beitragende:

Prof. Dr. von Gall, Charlotte [Gutachter]
Prof. Dr. med. Albrecht, Philipp [Gutachter]

Stichwörter:

Photothrombose, Regeneration, Bmal1-Defizienz

Dokumententyp (erweitert):

Dissertation

Beschreibungen:

Schlaganfall ist auch heute noch die zweithäufigste Todesursache weltweit. Aktuelle Untersuchungen deuten auf einen Zusammenhang zwischen dem Auftreten von ischämischen Ereignissen und dem zirkadianen System hin. Eine Deletion des Uhrengens Bmal1 führt zu einem Verlust zirkadianer Rhythmik in Mäusen.
Diese Arbeit untersuchte die Auswirkungen einer Deletion von Bmal1 auf die Infarktbildung und strukturelle Regeneration während der subakuten Phase nach Induktion fokaler kortikaler Infarkte mittels Photothrombose (PT). Dabei wurden das Volumen des Infarktkerns und der Glianarbe sowie das Volumen der Mikrogliaaktivierung in männlichen und weiblichen Wildtyp- [Bmal1+/+] und Bmal1-defizienten [Bmal1-/-] Mäusen 7 Tage (d) und 14 d nach PT untersucht. Zusätzlich wurde die Neubildung von Zellen, insbesondere von Astrozyten und Mikroglia, quantifiziert. Es wurde eine zeitabhängige Abnahme des Infarktvolumens sowie der Mikrogliaaktivierung und Proliferation bei den Gesamtgruppen der Bmal1+/+- und Bmal1-/--Mäuse festgestellt. Das Volumen der Glianarbe war hingegen ausschließlich bei der Gesamtgruppe der Bmal1-/--Mäuse 14 d gegenüber 7 d signifikant kleiner. Bei geschlechtsabhängiger Untersuchung wurde eine zeitabhängige Abnahme dieser Volumina ausschließlich bei den weiblichen Bmal1-/--Mäusen bestätigt, was auf einen geschlechtsspezifischen Einfluss einer Bmal1-Defizienz hinweist. Während das Volumen von Infarktkern, Glianarbe und Mikrogliaaktivierung 7 d nach PT bei den weiblichen Bmal1-/--Mäusen im Vergleich zu den männlichen Bmal1-/--Mäusen noch signifikant größer war, waren diese 14 d nach PT gleich klein. Zudem waren diese Parameter 14 d nach PT bei den weiblichen Bmal1-/--Mäusen im Vergleich zu den Bmal1+/+-Mäusen signifikant kleiner. Es konnte jedoch kein Einfluss des Geschlechts auf die Proliferation nach fokaler Ischämie festgestellt werden, sodass die hier beobachteten geschlechtsabhängigen Veränderungen am ehesten durch bereits vorhandene und nicht neu gebildete Zellen bedingt zu sein scheinen.
In Zusammenschau mit der aktuellen Datenlage sowie weiterführenden Untersuchungen dieser Arbeitsgruppe, die erhöhte Östrogenkonzentrationen bei weiblichen Bmal1-/--Mäusen nachwiesen, deutet die Gesamtheit der hier erfassten Ergebnisse auf einen positiven und protektiven Einfluss einer Bmal1-Defizienz auf die Infarktbildung und strukturelle Regeneration bei weiblichen Mäusen hin.

Stroke is still the second most common cause of death worldwide. Current research suggests a link between the occurrence of ischemic events and the circadian system. The deletion of the clock gene Bmal1 leads to a loss of circadian rhythms in mice.
This work studied the effects of Bmal1-deficiency on infarction and structural recovery during the subacute phase after induction of focal cortical infarcts by photothrombosis (PT). Therefore, the volumes of infarct core and glial scar, as well as the volume of microglial activation in male and female wildtype [Bmal1+/+] and Bmal1-deficient [Bmal1-/-] mice were analyzed 7 days (d) and 14 d after PT. In addition, proliferation, especially of astrocytes and microglia, was quantified. A time-dependent decrease in the volumes of infarct core and microglial activation as well as proliferation in Bmal1+/+- and Bmal1-/--mice was observed. However, the volume of the glial scar was only significantly smaller in Bmal1-/--mice 14 d compared to 7 d after PT. When sexes were analyzed separately, a time-dependent decrease in these volumes was only confirmed in female Bmal1-/--mice, indicating a gender-specific influence of a Bmal1-deficiency. While volumes of infarct core, glial scar and microglial activation were significantly larger in female Bmal1-/--mice compared to male Bmal1-/--mice 7 d after PT, they were equally reduced 14 d after PT. In addition, these parameters were significantly smaller 14 d after PT in female Bmal1-/-- mice compared to Bmal1+/+-mice. A sex-dependent effect on proliferation after focal ischemia was, however, not found, suggesting that the sex-related differences observed in this work are most likely caused by already existing, yet not newly formed cells.
Together with current data and further investigations of this group, confirming increased estrogen levels in female Bmal1-/--mice, the present findings suggest a positive and protective effect of Bmal1-deficiency on infarction and structural recovery in female mice.

Quelle:

1. Balami JS, Chen RL, Grunwald IQ, Buchan AM. Neurological complications of acute ischaemic stroke. Lancet Neurol. 2011;10(4):357-71.

2. Khaw KT. Epidemiology of stroke. J Neurol Neurosurg Psychiatry. 1996;61(4):333-8.

3. Petrea RE, Beiser AS, Seshadri S, Kelly-Hayes M, Kase CS, Wolf PA. Gender differences in stroke incidence and poststroke disability in the Framingham heart study. Stroke. 2009;40(4):1032-7.

4. Weimar C, Roth MP, Zillessen G, Glahn J, Wimmer ML, Busse O, et al. Complications following acute ischemic stroke. Eur Neurol. 2002;48(3):133-40.

5. Barres BA. The mystery and magic of glia: a perspective on their roles in health and disease. Neuron. 2008;60(3):430-40.

6. Allaman I, Belanger M, Magistretti PJ. Astrocyte-neuron metabolic relationships: for better and for worse. Trends Neurosci. 2011;34(2):76-87.

7. Earnest DJ, Neuendorff N, Coffman J, Selvamani A, Sohrabji F. Sex Differences in the Impact of Shift Work Schedules on Pathological Outcomes in an Animal Model of Ischemic Stroke. Endocrinology. 2016;157(7):2836-43.

8. Winget CM, DeRoshia CW, Markley CL, Holley DC. A review of human physiological and performance changes associated with desynchronosis of biological rhythms. Aviat Space Environ Med. 1984;55(12):1085-96.

9. Cho K, Ennaceur A, Cole JC, Suh CK. Chronic jet lag produces cognitive deficits. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2000;20(6):RC66.

10. Bracci M, Manzella N, Copertaro A, Staffolani S, Strafella E, Barbaresi M, et al. Rotating-shift nurses after a day off: peripheral clock gene expression, urinary melatonin, and serum 17-beta-estradiol levels. Scand J Work Environ Health. 2014;40(3):295-304.

11. Cho K. Chronic 'jet lag' produces temporal lobe atrophy and spatial cognitive deficits. Nature neuroscience. 2001;4(6):567-8.

12. Bonde JP, Hansen J, Kolstad HA, Mikkelsen S, Olsen JH, Blask DE, et al. Work at night and breast cancer--report on evidence-based options for preventive actions. Scand J Work Environ Health. 2012;38(4):380-90.

13. Bunney WE, Bunney BG. Molecular clock genes in man and lower animals: possible implications for circadian abnormalities in depression. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2000;22(4):335-45.

14. Nicoletti C, Muller C, Hayashi C, Nakaseko M, Tobita I, Laubli T. Circadian rhythm of heart rate and physical activity in nurses during day and night shifts. European journal of applied physiology. 2015.

15. Vitaterna MH, Pinto LH, Turek FW. Chapter 30 - Molecular Genetic Basis for Mammalian Circadian Rhythms. In: Dement MHKRC, editor. Principles and Practice of Sleep Medicine (Fourth Edition). Philadelphia: W.B. Saunders; 2005. p. 363-74.

16. Bollinger T, Schibler U. Circadian rhythms - from genes to physiology and disease. Swiss Med Wkly. 2014;144:w13984.

17. Halberg F, Halberg E, Barnum C, Bittner J, Withrow R. Photoperiodism and related phenomena in plants and animals. AAAS 1959. 1959.

18. Reppert SM, Weaver DR. Coordination of circadian timing in mammals. Nature. 2002;418(6901):935-41.

19. Aschoff J. CIRCADIAN RHYTHMS IN MAN. Science (New York, NY). 1965;148(3676):1427-32.

20. Albrecht U, Eichele G. The mammalian circadian clock. Current opinion in genetics & development. 2003;13(3):271-7.

21. Dibner C, Schibler U. Circadian timing of metabolism in animal models and humans. J Intern Med. 2015;277(5):513-27.

22. Yamaguchi S, Isejima H, Matsuo T, Okura R, Yagita K, Kobayashi M, et al. Synchronization of cellular clocks in the suprachiasmatic nucleus. Science (New York, NY). 2003;302(5649):1408-12.

23. Reppert SM, Weaver DR. Molecular analysis of mammalian circadian rhythms. Annu Rev Physiol. 2001;63:647-76.

24. Prolo LM, Takahashi JS, Herzog ED. Circadian rhythm generation and entrainment in astrocytes. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2005;25(2):404-8.

25. Dibner C, Schibler U, Albrecht U. The mammalian circadian timing system: organization and coordination of central and peripheral clocks. Annu Rev Physiol. 2010;72:517-49.

26. Albrecht U. Timing to perfection: the biology of central and peripheral circadian clocks. Neuron. 2012;74(2):246-60.

27. Fonken LK, Nelson RJ. The effects of light at night on circadian clocks and metabolism. Endocr Rev. 2014;35(4):648-70.

28. Bunger MK, Wilsbacher LD, Moran SM, Clendenin C, Radcliffe LA, Hogenesch JB, et al. Mop3 is an essential component of the master circadian pacemaker in mammals. Cell. 2000;103(7):1009-17.

29. Kume K, Zylka MJ, Sriram S, Shearman LP, Weaver DR, Jin X, et al. mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell. 1999;98(2):193-205.

30. Shearman LP, Sriram S, Weaver DR, Maywood ES, Chaves I, Zheng B, et al. Interacting molecular loops in the mammalian circadian clock. Science (New York, NY). 2000;288(5468):1013-9.

31. Musiek ES, Lim MM, Yang G, Bauer AQ, Qi L, Lee Y, et al. Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration. The Journal of clinical investigation. 2013;123(12):5389-400.

32. Ruan GX, Gamble KL, Risner ML, Young LA, McMahon DG. Divergent roles of clock genes in retinal and suprachiasmatic nucleus circadian oscillators. PLoS One. 2012;7(6):e38985.

33. Shi S, Hida A, McGuinness OP, Wasserman DH, Yamazaki S, Johnson CH. Circadian clock gene Bmal1 is not essential; functional replacement with its paralog, Bmal2. Curr Biol. 2010;20(4):316-21.

34. Pfeffer M, Muller CM, Mordel J, Meissl H, Ansari N, Deller T, et al. The mammalian molecular clockwork controls rhythmic expression of its own input pathway components. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2009;29(19):6114-23.

35. Shimba S, Ogawa T, Hitosugi S, Ichihashi Y, Nakadaira Y, Kobayashi M, et al. Deficient of a clock gene, brain and muscle Arnt-like protein-1 (BMAL1), induces dyslipidemia and ectopic fat formation. PLoS One. 2011;6(9):e25231.

36. Kennaway DJ. The role of circadian rhythmicity in reproduction. Hum Reprod Update. 2005;11(1):91-101.

37. Boden MJ, Varcoe TJ, Voultsios A, Kennaway DJ. Reproductive biology of female Bmal1 null mice. Reproduction. 2010;139(6):1077-90.

38. Kondratov RV, Kondratova AA, Gorbacheva VY, Vykhovanets OV, Antoch MP. Early aging and age-related pathologies in mice deficient in BMAL1, the core componentof the circadian clock. Genes Dev. 2006;20(14):1868-73.

39. Rudic RD, McNamara P, Curtis AM, Boston RC, Panda S, Hogenesch JB, et al. BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLoS Biol. 2004;2(11):e377.

40. Bunger MK, Walisser JA, Sullivan R, Manley PA, Moran SM, Kalscheur VL, et al. Progressive arthropathy in mice with a targeted disruption of the Mop3/Bmal- 1 locus. Genesis. 2005;41(3):122-32.
41. Chang L, Xiong W, Zhao X, Fan Y, Guo Y, Garcia-Barrio M, et al. Bmal1 in Perivascular Adipose Tissue Regulates Resting-Phase Blood Pressure Through Transcriptional Regulation of Angiotensinogen. Circulation. 2018;138(1):67-79.

42. Kondratova AA, Dubrovsky YV, Antoch MP, Kondratov RV. Circadian clock proteins control adaptation to novel environment and memory formation. Aging (Albany NY). 2010;2(5):285-97.

43. Ali AA, Schwarz-Herzke B, Stahr A, Prozorovski T, Aktas O, von Gall C. Premature aging of the hippocampal neurogenic niche in adult Bmal1-deficient mice. Aging (Albany NY). 2015;7(6):435-49.

44. Verkhratsky A, Butt A. Introduction to Glia. Glial Neurobiology: John Wiley & Sons, Ltd; 2007. p. 1-12.

45. Somjen GG. Nervenkitt: notes on the history of the concept of neuroglia. Glia. 1988;1(1):2-9.

46. Barres BA. What is a glial cell? Glia. 2003;43(1):4-5.

47. Verkhratsky A, Butt A. Morphology of Glial Cells. Glial Neurobiology: John Wiley & Sons, Ltd; 2007. p. 21-8.

48. Parpura V, Heneka MT, Montana V, Oliet SH, Schousboe A, Haydon PG, et al. Glial cells in (patho)physiology. Journal of neurochemistry. 2012;121(1):4-27.

49. Reichenbach A, Siegel A, Senitz D, Smith TG, Jr. A comparative fractal analysis of various mammalian astroglial cell types. Neuroimage. 1992;1(1):69-77.

50. Panickar KS, Norenberg MD. Astrocytes in cerebral ischemic injury: morphological and general considerations. Glia. 2005;50(4):287-98.

51. Kimelberg HK. Functions of mature mammalian astrocytes: a current view. Neuroscientist. 2010;16(1):79-106.

52. Nedergaard M, Ransom B, Goldman SA. New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci. 2003;26(10):523-30.

53. Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol. 2010;119(1):7-35.

54. Verkhratsky A, Butt A. Astrocytes. Glial Neurobiology: John Wiley & Sons, Ltd; 2007. p. 93-123.

55. Magistretti PJ. Neuron-glia metabolic coupling and plasticity. J Exp Biol. 2006;209(Pt 12):2304-11.

56. Verkhratsky A, Nedergaard M, Hertz L. Why are Astrocytes Important? Neurochem Res. 2014.

57. Verkhratsky A, Butt A. General Physiology of Glial Cells. Glial Neurobiology: John Wiley & Sons, Ltd; 2007. p. 39-81.

58. Araque A, Parpura V, Sanzgiri RP, Haydon PG. Tripartite synapses: glia, the unacknowledged partner. Trends Neurosci. 1999;22(5):208-15.

59. Vesce S, Bezzi P, Volterra A. The active role of astrocytes in synaptic transmission. Cell Mol Life Sci. 1999;56(11-12):991-1000.

60. Bergersen LH, Gundersen V. Morphological evidence for vesicular glutamate release from astrocytes. Neuroscience. 2009;158(1):260-5.

61. Wenker I. An active role for astrocytes in synaptic plasticity? J Neurophysiol. 2010;104(3):1216-8.

62. Malarkey EB, Parpura V. Mechanisms of glutamate release from astrocytes. Neurochem Int. 2008;52(1-2):142-54.

63. Parpura V, Basarsky TA, Liu F, Jeftinija K, Jeftinija S, Haydon PG. Glutamate- mediated astrocyte-neuron signalling. Nature. 1994;369(6483):744-7.

64. Amiri M, Bahrami F, Janahmadi M. Functional contributions of astrocytes in synchronization of a neuronal network model. J Theor Biol. 2012;292:60-70.

65. Belanger M, Magistretti PJ. The role of astroglia in neuroprotection. Dialogues Clin Neurosci. 2009;11(3):281-95.

66. Ng FS, Tangredi MM, Jackson FR. Glial cells physiologically modulate clock neurons and circadian behavior in a calcium-dependent manner. Curr Biol. 2011;21(8):625-34.

67. Jackson FR, Ng FS, Sengupta S, You S, Huang Y. Glial cell regulation of rhythmic behavior. Methods Enzymol. 2015;552:45-73.

68. Marpegan L, Swanstrom AE, Chung K, Simon T, Haydon PG, Khan SK, et al. Circadian regulation of ATP release in astrocytes. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2011;31(23):8342-50.

69. Halassa MM, Florian C, Fellin T, Munoz JR, Lee SY, Abel T, et al. Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss. Neuron. 2009;61(2):213-9.

70. Ullian EM, Sapperstein SK, Christopherson KS, Barres BA. Control of synapse number by glia. Science (New York, NY). 2001;291(5504):657-61.

71. Ullian EM, Christopherson KS, Barres BA. Role for glia in synaptogenesis. Glia. 2004;47(3):209-16.

72. Christopherson KS, Ullian EM, Stokes CC, Mullowney CE, Hell JW, Agah A, et al. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell. 2005;120(3):421-33.

73. Barres BA. A new role for glia: generation of neurons! Cell. 1999;97(6):667-70.

74. Barres BA, Barde Y. Neuronal and glial cell biology. Curr Opin Neurobiol. 2000;10(5):642-8.

75. Sofroniew MV. Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci. 2009;32(12):638-47.

76. Huang L, Wu ZB, Zhuge Q, Zheng W, Shao B, Wang B, et al. Glial scar formation occurs in the human brain after ischemic stroke. Int J Med Sci. 2014;11(4):344-8.

77. Verkhratsky A, Butt A. General Pathophysiology of Glia. Glial Neurobiology: John Wiley & Sons, Ltd; 2007. p. 153-65.

78. Buffo A, Rite I, Tripathi P, Lepier A, Colak D, Horn AP, et al. Origin and progeny of reactive gliosis: A source of multipotent cells in the injured brain. Proc Natl Acad Sci U S A. 2008;105(9):3581-6.

79. Wagner DC, Scheibe J, Glocke I, Weise G, Deten A, Boltze J, et al. Object- based analysis of astroglial reaction and astrocyte subtype morphology after ischemic brain injury. Acta Neurobiol Exp (Wars). 2013;73(1):79-87.

80. Ridet JL, Malhotra SK, Privat A, Gage FH. Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci. 1997;20(12):570-7.

81. Fawcett JW, Asher RA. The glial scar and central nervous system repair. Brain Res Bull. 1999;49(6):377-91.

82. Cervos-Navarro J, Lafuente JV. Traumatic brain injuries: structural changes. J Neurol Sci. 1991;103 Suppl:S3-14.

83. Cekanaviciute E, Buckwalter MS. Astrocytes: Integrative Regulators of Neuroinflammation in Stroke and Other Neurological Diseases. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2016;13(4):685-701.

84. Farina C, Aloisi F, Meinl E. Astrocytes are active players in cerebral innate immunity. Trends Immunol. 2007;28(3):138-45.

85. John GR, Lee SC, Brosnan CF. Cytokines: powerful regulators of glial cell activation. Neuroscientist. 2003;9(1):10-22.

86. Silver J, Miller JH. Regeneration beyond the glial scar. Nat Rev Neurosci. 2004;5(2):146-56.

87. Buffo A, Rolando C, Ceruti S. Astrocytes in the damaged brain: molecular and cellular insights into their reactive response and healing potential. Biochem Pharmacol. 2010;79(2):77-89.

88. Pekny M, Wilhelmsson U, Pekna M. The dual role of astrocyte activation and reactive gliosis. Neurosci Lett. 2014;565:30-8.

89. Sims NR, Yew WP. Reactive astrogliosis in stroke: Contributions of astrocytes to recovery of neurological function. Neurochem Int. 2017.

90. Li H, Zhang N, Lin HY, Yu Y, Cai QY, Ma L, et al. Histological, cellular and behavioral assessments of stroke outcomes after photothrombosis-induced ischemia in adult mice. BMC Neurosci. 2014;15:58.

91. Rolls A, Shechter R, Schwartz M. The bright side of the glial scar in CNS repair. Nat Rev Neurosci. 2009;10(3):235-41.

92. Sofroniew MV. Reactive astrocytes in neural repair and protection. Neuroscientist. 2005;11(5):400-7.

93. Burda JE, Sofroniew MV. Reactive gliosis and the multicellular response to CNS damage and disease. Neuron. 2014;81(2):229-48.

94. Loane DJ, Kumar A. Microglia in the TBI brain: The good, the bad, and the dysregulated. Exp Neurol. 2016;275 Pt 3:316-27.

95. Crotti A, Ransohoff RM. Microglial Physiology and Pathophysiology: Insights from Genome-wide Transcriptional Profiling. Immunity. 2016;44(3):505-15.

96. Ginhoux F, Guilliams M. Tissue-Resident Macrophage Ontogeny and Homeostasis. Immunity. 2016;44(3):439-49.

97. Verkhratsky A, Butt A. Glial Development. Glial Neurobiology: John Wiley & Sons, Ltd; 2007. p. 29-38.

98. Kempermann G, Neumann H. Neuroscience. Microglia: the enemy within? Science (New York, NY). 2003;302(5651):1689-90.

99. Salter MW, Beggs S. Sublime microglia: expanding roles for the guardians of the CNS. Cell. 2014;158(1):15-24.

100. Soulet D, Rivest S. Microglia. Curr Biol. 2008;18(12):R506-8.

101. Hayashi Y, Koyanagi S, Kusunose N, Okada R, Wu Z, Tozaki-Saitoh H, et al. The intrinsic microglial molecular clock controls synaptic strength via the circadian expression of cathepsin S. Sci Rep. 2013;3:2744.

102. Fonken LK, Frank MG, Kitt MM, Barrientos RM, Watkins LR, Maier SF. Microglia inflammatory responses are controlled by an intrinsic circadian clock. Brain Behav Immun. 2015;45:171-9.
103. Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nature neuroscience. 2007;10(11):1387-94.

104. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science (New York, NY). 2005;308(5726):1314-8.

105. Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 1996;19(8):312-8.

106. Allan SM, Rothwell NJ. Inflammation in central nervous system injury. Philos Trans R Soc Lond B Biol Sci. 2003;358(1438):1669-77.

107. Schroeter M, Jander S, Witte OW, Stoll G. Heterogeneity of the microglial response in photochemically induced focal ischemia of the rat cerebral cortex. Neuroscience. 1999;89(4):1367-77.

108. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, et al. ATP mediates rapid microglial response to local brain injury in vivo. Nature neuroscience. 2005;8(6):752-8.

109. Olson JK, Miller SD. Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol. 2004;173(6):3916-24.

110. Lyons SA, Pastor A, Ohlemeyer C, Kann O, Wiegand F, Prass K, et al. Distinct physiologic properties of microglia and blood-borne cells in rat brain slices after permanent middle cerebral artery occlusion. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2000;20(11):1537-49.

111. Jin R, Yang G, Li G. Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. Journal of leukocyte biology. 2010;87(5):779-89.

112. Ohsawa K, Imai Y, Sasaki Y, Kohsaka S. Microglia/macrophage-specific protein Iba1 binds to fimbrin and enhances its actin-bundling activity. Journal of neurochemistry. 2004;88(4):844-56.

113. Magnus T, Chan A, Grauer O, Toyka KV, Gold R. Microglial phagocytosis of apoptotic inflammatory T cells leads to down-regulation of microglial immune activation. J Immunol. 2001;167(9):5004-10.

114. Hausler KG, Prinz M, Nolte C, Weber JR, Schumann RR, Kettenmann H, et al. Interferon-gamma differentially modulates the release of cytokines and chemokines in lipopolysaccharide- and pneumococcal cell wall-stimulated mouse microglia and macrophages. Eur J Neurosci. 2002;16(11):2113-22.

115. Watson BD, Dietrich WD, Busto R, Wachtel MS, Ginsberg MD. Induction of reproducible brain infarction by photochemically initiated thrombosis. Ann Neurol. 1985;17(5):497-504.
116. Labat-gest V, Tomasi S. Photothrombotic ischemia: a minimally invasive and reproducible photochemical cortical lesion model for mouse stroke studies. Journal of visualized experiments : JoVE. 2013(76).

117. Nordin N, Xie SQ, Wunsche B. Assessment of movement quality in robot- assisted upper limb rehabilitation after stroke: a review. J Neuroeng Rehabil. 2014;11:137.

118. Verkhratsky A, Butt A. Glia and Diseases of the Nervous System. Glial Neurobiology: John Wiley & Sons, Ltd; 2007. p. 167-96.

119. Traystman RJ. Animal models of focal and global cerebral ischemia. ILAR journal / National Research Council, Institute of Laboratory Animal Resources. 2003;44(2):85-95.

120. Sommer CJ. Ischemic stroke: experimental models and reality. Acta Neuropathol. 2017;133(2):245-61.

121. Durukan A, Tatlisumak T. Acute ischemic stroke: overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia. Pharmacol Biochem Behav. 2007;87(1):179-97.

122. Lee JK, Park MS, Kim YS, Moon KS, Joo SP, Kim TS, et al. Photochemically induced cerebral ischemia in a mouse model. Surg Neurol. 2007;67(6):620-5; discussion 5.

123. Dietrich WD, Watson BD, Busto R, Ginsberg MD, Bethea JR. Photochemically induced cerebral infarction. I. Early microvascular alterations. Acta Neuropathol. 1987;72(4):315-25.

124. Schroeter M, Jander S, Stoll G. Non-invasive induction of focal cerebral ischemia in mice by photothrombosis of cortical microvessels: characterization of inflammatory responses. Journal of neuroscience methods. 2002;117(1):43-9.

125. Carmichael ST. Rodent models of focal stroke: size, mechanism, and purpose. NeuroRx. 2005;2(3):396-409.

126. Roof RL, Schielke GP, Ren X, Hall ED. A comparison of long-term functional outcome after 2 middle cerebral artery occlusion models in rats. Stroke. 2001;32(11):2648-57.

127. Belayev L, Alonso OF, Busto R, Zhao W, Ginsberg MD. Middle cerebral artery occlusion in the rat by intraluminal suture. Neurological and pathological evaluation of an improved model. Stroke. 1996;27(9):1616-22; discussion 23.

128. Barone FC, Knudsen DJ, Nelson AH, Feuerstein GZ, Willette RN. Mouse strain differences in susceptibility to cerebral ischemia are related to cerebral vascular anatomy. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 1993;13(4):683- 92.
129. Kleim JA, Boychuk JA, Adkins DL. Rat models of upper extremity impairment in stroke. ILAR journal / National Research Council, Institute of Laboratory Animal Resources. 2007;48(4):374-84.

130. Uzdensky AB. Photothrombotic Stroke as a Model of Ischemic Stroke. Transl Stroke Res. 2017.

131. Demyanenko SV, Panchenko SN, Uzdensky AB. Expression of neuronal and signaling proteins in penumbra around a photothrombotic infarction core in rat cerebral cortex. Biochemistry Biokhimiia. 2015;80(6):790-9.

132. Nowakowski RS, Lewin SB, Miller MW. Bromodeoxyuridine immunohistochemical determination of the lengths of the cell cycle and the DNA-synthetic phase for an anatomically defined population. Journal of neurocytology. 1989;18(3):311-8.

133. Smit JW, Meijer CJ, Decary F, Feltkamp-Vroom TM. Paraformaldehyde fixation in immunofluorescence and immunoelectron microscopy. Preservation of tissue and cell surface membrane antigens. J Immunol Methods. 1974;6(1- 2):93-8.

134. Mulisch M, Welsch U, Romeis B. Romeis Mikroskopische Technik. 19. Auflage ed2015. XVIII, 603 Seiten p.

135. Fonken LK, Weil ZM, Nelson RJ. Mice exposed to dim light at night exaggerate inflammatory responses to lipopolysaccharide. Brain Behav Immun. 2013;34:159-63.

136. Kennaway DJ, Boden MJ, Varcoe TJ. Circadian rhythms and fertility. Mol Cell Endocrinol. 2012;349(1):56-61.

137. Hemmeryckx B, Van Hove CE, Fransen P, Emmerechts J, Kauskot A, Bult H, et al. Progression of the prothrombotic state in aging Bmal1-deficient mice. Arterioscler Thromb Vasc Biol. 2011;31(11):2552-9.

138. Nowicka D, Rogozinska K, Aleksy M, Witte OW, Skangiel-Kramska J. Spatiotemporal dynamics of astroglial and microglial responses after photothrombotic stroke in the rat brain. Acta Neurobiol Exp (Wars). 2008;68(2):155-68.

139. Shanina EV, Redecker C, Reinecke S, Schallert T, Witte OW. Long-term effects of sequential cortical infarcts on scar size, brain volume and cognitive function. Behavioural brain research. 2005;158(1):69-77.

140. Fitzek S, Fitzek C, Urban PP, Marx J, Hopf HC, Stoeter P. Time course of lesion development in patients with acute brain stem infarction and correlation with NIHSS score. European journal of radiology. 2001;39(3):180-5.

141. Lansberg MG, O'Brien MW, Tong DC, Moseley ME, Albers GW. Evolution of cerebral infarct volume assessed by diffusion-weighted magnetic resonance imaging. Archives of neurology. 2001;58(4):613-7.

142. Schwamm LH, Koroshetz WJ, Sorensen AG, Wang B, Copen WA, Budzik R, et al. Time course of lesion development in patients with acute stroke: serial diffusion- and hemodynamic-weighted magnetic resonance imaging. Stroke. 1998;29(11):2268-76.

143. Haupt C, Witte OW, Frahm C. Up-regulation of Connexin43 in the glial scar following photothrombotic ischemic injury. Mol Cell Neurosci. 2007;35(1):89- 99.

144. Schroeter M, Schiene K, Kraemer M, Hagemann G, Weigel H, Eysel UT, et al. Astroglial responses in photochemically induced focal ischemia of the rat cortex. Exp Brain Res. 1995;106(1):1-6.

145. Westgate EJ, Cheng Y, Reilly DF, Price TS, Walisser JA, Bradfield CA, et al. Genetic components of the circadian clock regulate thrombogenesis in vivo. Circulation. 2008;117(16):2087-95.

146. Krityakiarana W, Sompup K, Jongkamonwiwat N, Mukda S, Pinilla FG, Govitrapong P, et al. Effects of melatonin on severe crush spinal cord injury- induced reactive astrocyte and scar formation. J Neurosci Res. 2016;94(12):1451-9.

147. Beker MC, Caglayan B, Yalcin E, Caglayan AB, Turkseven S, Gurel B, et al. Time-of-Day Dependent Neuronal Injury After Ischemic Stroke: Implication of Circadian Clock Transcriptional Factor Bmal1 and Survival Kinase AKT. Mol Neurobiol. 2017.

148. Cotrina ML, Lou N, Tome-Garcia J, Goldman J, Nedergaard M. Direct comparison of microglial dynamics and inflammatory profile in photothrombotic and arterial occlusion evoked stroke. Neuroscience. 2017;343:483-94.

149. Herrmann JE, Imura T, Song B, Qi J, Ao Y, Nguyen TK, et al. STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2008;28(28):7231-43.

150. Okada S, Nakamura M, Katoh H, Miyao T, Shimazaki T, Ishii K, et al. Conditional ablation of Stat3 or Socs3 discloses a dual role for reactive astrocytes after spinal cord injury. Nat Med. 2006;12(7):829-34.

151. Lalancette-Hebert M, Gowing G, Simard A, Weng YC, Kriz J. Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2007;27(10):2596-605.

152. Imai F, Suzuki H, Oda J, Ninomiya T, Ono K, Sano H, et al. Neuroprotective effect of exogenous microglia in global brain ischemia. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2007;27(3):488-500.

153. Jin WN, Shi SX, Li Z, Li M, Wood K, Gonzales RJ, et al. Depletion of microglia exacerbates postischemic inflammation and brain injury. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2017:271678x17694185.

154. Tian DS, Dong Q, Pan DJ, He Y, Yu ZY, Xie MJ, et al. Attenuation of astrogliosis by suppressing of microglial proliferation with the cell cycle inhibitor olomoucine in rat spinal cord injury model. Brain Res. 2007;1154:206- 14.

155. Curtis AM, Bellet MM, Sassone-Corsi P, O'Neill LA. Circadian clock proteins and immunity. Immunity. 2014;40(2):178-86.

156. Curtis AM, Fagundes CT, Yang G, Palsson-McDermott EM, Wochal P, McGettrick AF, et al. Circadian control of innate immunity in macrophages by miR-155 targeting Bmal1. Proc Natl Acad Sci U S A. 2015;112(23):7231-6.

157. Weil ZM, Karelina K, Su AJ, Barker JM, Norman GJ, Zhang N, et al. Time-of- day determines neuronal damage and mortality after cardiac arrest. Neurobiol Dis. 2009;36(2):352-60.

158. Gibbs JE, Blaikley J, Beesley S, Matthews L, Simpson KD, Boyce SH, et al. The nuclear receptor REV-ERBalpha mediates circadian regulation of innate immunity through selective regulation of inflammatory cytokines. Proc Natl Acad Sci U S A. 2012;109(2):582-7.

159. Castanon-Cervantes O, Wu M, Ehlen JC, Paul K, Gamble KL, Johnson RL, et al. Dysregulation of inflammatory responses by chronic circadian disruption. J Immunol. 2010;185(10):5796-805.

160. Thau-Zuchman O, Shohami E, Alexandrovich AG, Trembovler V, Leker RR. The anti-inflammatory drug carprofen improves long-term outcome and induces gliogenesis after traumatic brain injury. Journal of neurotrauma. 2012;29(2):375- 84.

161. Hish GA, Jr., Diaz JA, Hawley AE, Myers DD, Jr., Lester PA. Effects of analgesic use on inflammation and hematology in a murine model of venous thrombosis. Journal of the American Association for Laboratory Animal Science : JAALAS. 2014;53(5):485-93.

162. Ferrer I, Planas AM. Signaling of cell death and cell survival following focal cerebral ischemia: life and death struggle in the penumbra. J Neuropathol Exp Neurol. 2003;62(4):329-39.

163. Yamashima T. Ca2+-dependent proteases in ischemic neuronal death: a conserved 'calpain-cathepsin cascade' from nematodes to primates. Cell calcium. 2004;36(3-4):285-93.

164. Ferrer I, Friguls B, Dalfo E, Justicia C, Planas AM. Caspase-dependent and caspase-independent signalling of apoptosis in the penumbra following middle cerebral artery occlusion in the adult rat. Neuropathology and applied neurobiology. 2003;29(5):472-81.

165. Chan PH. Mitochondria and neuronal death/survival signaling pathways in cerebral ischemia. Neurochem Res. 2004;29(11):1943-9.

166. Barreto GE, Sun X, Xu L, Giffard RG. Astrocyte proliferation following stroke in the mouse depends on distance from the infarct. PLoS One. 2011;6(11):e27881.

167. Shimada IS, LeComte MD, Granger JC, Quinlan NJ, Spees JL. Self-renewal and differentiation of reactive astrocyte-derived neural stem/progenitor cells isolated from the cortical peri-infarct area after stroke. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2012;32(23):7926-40.

168. Carlen M, Meletis K, Goritz C, Darsalia V, Evergren E, Tanigaki K, et al. Forebrain ependymal cells are Notch-dependent and generate neuroblasts and astrocytes after stroke. Nature neuroscience. 2009;12(3):259-67.

169. Ohab JJ, Carmichael ST. Poststroke neurogenesis: emerging principles of migration and localization of immature neurons. Neuroscientist. 2008;14(4):369- 80.

170. Manwani B, Bentivegna K, Benashski SE, Venna VR, Xu Y, Arnold AP, et al. Sex differences in ischemic stroke sensitivity are influenced by gonadal hormones, not by sex chromosome complement. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2015;35(2):221-9.

171. Li L, Lundkvist A, Andersson D, Wilhelmsson U, Nagai N, Pardo AC, et al. Protective role of reactive astrocytes in brain ischemia. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2008;28(3):468-81.

172. Bush TG, Puvanachandra N, Horner CH, Polito A, Ostenfeld T, Svendsen CN, et al. Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron. 1999;23(2):297-308.

173. Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV. Reactive astrocytes protect tissue and preserve function after spinal cord injury. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2004;24(9):2143-55.

174. Liu Z, Li Y, Cui Y, Roberts C, Lu M, Wilhelmsson U, et al. Beneficial effects of gfap/vimentin reactive astrocytes for axonal remodeling and motor behavioral recovery in mice after stroke. Glia. 2014.

175. Hayakawa K, Nakano T, Irie K, Higuchi S, Fujioka M, Orito K, et al. Inhibition of reactive astrocytes with fluorocitrate retards neurovascular remodeling and recovery after focal cerebral ischemia in mice. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2010;30(4):871-82.

176. Hill JJ, Jin K, Mao XO, Xie L, Greenberg DA. Intracerebral chondroitinase ABC and heparan sulfate proteoglycan glypican improve outcome from chronic stroke in rats. Proc Natl Acad Sci U S A. 2012;109(23):9155-60.

177. Lenz KM, McCarthy MM. A starring role for microglia in brain sex differences. Neuroscientist. 2015;21(3):306-21.

178. Wimmer I, Zrzavy T, Lassmann H. Neuroinflammatory responses in experimental and human stroke lesions. Journal of neuroimmunology. 2018;323:10-8.

179. Wilson ME. Stroke: Understanding the Differences between Males and Females. Pflugers Archiv : European journal of physiology. 2013;465(5):595-600.

180. Ritzel RM, Capozzi LA, McCullough LD. Sex, stroke, and inflammation: the potential for estrogen-mediated immunoprotection in stroke. Horm Behav. 2013;63(2):238-53.

181. Liu F, McCullough LD. Interactions between Age, Sex, and Hormones in Experimental Ischemic Stroke. Neurochem Int. 2012;61(8):1255-65.

182. Engler-Chiurazzi EB, Brown CM, Povroznik JM, Simpkins JW. Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury. Progress in neurobiology. 2016.

183. Broughton BR, Brait VH, Kim HA, Lee S, Chu HX, Gardiner-Mann CV, et al. Sex-dependent effects of G protein-coupled estrogen receptor activity on outcome after ischemic stroke. Stroke. 2014;45(3):835-41.

184. McCullough LD, Hurn PD. Estrogen and ischemic neuroprotection: an integrated view. Trends in endocrinology and metabolism: TEM. 2003;14(5):228-35.

185. Dubal DB, Wise PM. Neuroprotective effects of estradiol in middle-aged female rats. Endocrinology. 2001;142(1):43-8.

186. Stoop W, De Geyter D, Verachtert S, Brouwers S, Verdood P, De Keyser J, et al. Post-stroke treatment with 17beta-estradiol exerts neuroprotective effects in both normotensive and hypertensive rats. Neuroscience. 2017;348:335-45.

187. Nadkarni S, McArthur S. Oestrogen and immunomodulation: new mechanisms that impact on peripheral and central immunity. Curr Opin Pharmacol. 2013;13(4):576-81.

188. Petrone AB, Simpkins JW, Barr TL. 17β-Estradiol and Inflammation: Implications for Ischemic Stroke. Aging and Disease. 2014;5(5):340-5.

189. Wu SY, Chen YW, Tsai SF, Wu SN, Shih YH, Jiang-Shieh YF, et al. Estrogen ameliorates microglial activation by inhibiting the Kir2.1 inward-rectifier K(+) channel. Sci Rep. 2016;6:22864.

190. Li X, Blizzard KK, Zeng Z, DeVries AC, Hurn PD, McCullough LD. Chronic behavioral testing after focal ischemia in the mouse: functional recovery and the effects of gender. Exp Neurol. 2004;187(1):94-104.

191. Dubal DB, Zhu H, Yu J, Rau SW, Shughrue PJ, Merchenthaler I, et al. Estrogen receptor alpha, not beta, is a critical link in estradiol-mediated protection against brain injury. Proc Natl Acad Sci U S A. 2001;98(4):1952-7.

192. Blurton-Jones M, Tuszynski MH. Reactive astrocytes express estrogen receptors in the injured primate brain. The Journal of comparative neurology. 2001;433(1):115-23.

193. Liu X, Fan XL, Zhao Y, Luo GR, Li XP, Li R, et al. Estrogen provides neuroprotection against activated microglia-induced dopaminergic neuronal injury through both estrogen receptor-alpha and estrogen receptor-beta in microglia. J Neurosci Res. 2005;81(5):653-65.

194. Perez-Alvarez MJ, Mateos L, Alonso A, Wandosell F. Estradiol and Progesterone Administration After pMCAO Stimulates the Neurological Recovery and Reduces the Detrimental Effect of Ischemia Mainly in Hippocampus. Mol Neurobiol. 2015;52(3):1690-703.

195. Perez-Alvarez MJ, Maza Mdel C, Anton M, Ordonez L, Wandosell F. Post- ischemic estradiol treatment reduced glial response and triggers distinct cortical and hippocampal signaling in a rat model of cerebral ischemia. Journal of neuroinflammation. 2012;9:157.

196. Lembach A, Stahr A, Ali A, Ingenwerth M, von Gall C. Sex-Dependent Effects of Bmal1-Deficiency on Mouse Cerebral Cortex Infarction in Response to Photothrombotic Stroke. International Journal of Molecular Sciences. 2018;19(10):3124.

197. Nakamura TJ, Sellix MT, Kudo T, Nakao N, Yoshimura T, Ebihara S, et al. Influence of the estrous cycle on clock gene expression in reproductive tissues: effects of fluctuating ovarian steroid hormone levels. Steroids. 2010;75(3):203- 12.

198. Monteiro R, Teixeira D, Calhau C. Estrogen Signaling in Metabolic Inflammation. Mediators Inflamm. 2014;2014.
199. Bailey M, Silver R. Sex differences in circadian timing systems: implications for disease. Frontiers in neuroendocrinology. 2014;35(1):111-39.

200. Yan L, Silver R. Neuroendocrine underpinnings of sex differences in circadian timing systems. J Steroid Biochem Mol Biol. 2016;160:118-26.

201. Clarkson AN, Lopez-Valdes HE, Overman JJ, Charles AC, Brennan KC, Thomas Carmichael S. Multimodal examination of structural and functional remapping in the mouse photothrombotic stroke model. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2013;33(5):716-23.

202. Clarkson AN, Huang BS, Macisaac SE, Mody I, Carmichael ST. Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature. 2010;468(7321):305-9.

Lizenz:

Urheberrechtsschutz

Bezug:

Beginn der Arbeit 2013, Abgabe der Arbeit 10/2018 und Disputation 02.05.2019

Fachbereich / Einrichtung:

Medizinische Fakultät » Institute » Institut für Anatomie I

Dokument erstellt am:

10.05.2019

Dateien geändert am:

10.05.2019

Promotionsantrag am:

25.10.2018

Datum der Promotion:

02.05.2019

Heinrich-Heine-Universität Düsseldorf

Dokument: Der Einfluss einer Bmal1-Defizienz auf die Infarktbildung und strukturelle Regeneration nach Photothrombose in männlichen und weiblichen Mäusen.