Promene u gustini GFAP imunopozitivnih ćelija u mozgu  pacova uslovljene pojedinačnim produženim stresom

Sava Ivaz

doi:10.5937/mp75-50087

Sava Ivaz Medicinski fakultet u Beogradu

DOI: https://doi.org/10.5937/mp75-50087

Ključne reči: Post-traumatski stresni poremećaj, astrociti, GFAP, hipokampus, medijalni prefrontalni korteks

Sažetak

Uvod: Posttraumatski stresni poremećaj (PTSP) je hronični sindrom izazvan traumatskim događajem i nesposobnošću osobe da se oporavi od normalne negativne emocionalne reakcije na traumatski stres. Značajan broja pacijenata ne reaguje na standardnu terapiju, što ukazuje da je patofiziološki mehanizam ovog poremećaja nedovoljno istražen. PTSP je povezan sa anksioznošću, oštećenjem pamćenja, pojačanim strahom i gubitkom volumena hipokampusa, ali odnos između ovih promena je ostao nepoznat. Malo studija je proučavalo ulogu glijalnih ćelija u PTSP-u, dok nedavni nalazi ukazuju da bi patologija astrocita mogla biti karakteristika ovog poremećaja. Jedan od animalnih modela PTSP-a je pojedinačni produženi stres (PPS) koji se sastoji od mehaničkog sputavanja, forsiranog plivanja i izlaganja životinje etarskoj anesteziji do gubitka refleksa repa.

Cilj rada: Cilj je uporediti gustinu astrocita u gyrus dentatus-u (GD), CA1/2 i CA3 regionima hipokampusa i medijalnom prefrontalnom korteksu (mPFC) mozga pacova izloženih PPS-u u odnosu na kontrolnu grupu.

Materijal i metode: U istraživanju su Wistar pacovi (n=5) bili izloženi PPS-u i žrtvovani nakon 7 dana uporedo sa kontrolnim životinjama (n=5). Određivanje broja astrocita u datim regionima vršeno je imunohistohemijskim bojenjem glijalnog fibrilarnog kiselog proteina (engl. glial fibrillary acidic protein-GFAP). Statistička analiza je urađena korišćenjem statističkog programa SPSS (IBM SPSS Statistics for Windows,v23.0).

Rezultati: Gustina GFAP imunopozitivnih astrocita u hipokampusu pacova izloženih PPS-u je

statistički značajno niža u odnosu na kontrolne životinje u CA1/2 (p<0,01) i GD (p<0,05)

regionima; CA3 region nema zapaženih promena. Gustina GFAP imunopozitivnih astrocita je bila statistički značajno niža u mPFC-u mozga pacova izloženih PPS-u u odnosu na kontrolnu grupu (p<0,01).

Zaključak: Rezultati ovog istraživanja jasno ukazuju da PPS uzrokuje značajno smanjenje gustine astrocita u hipokampusu i mPFC-u što govori u prilog tome da promene u astrocitima mogu imati ulogu u razvoju morfoloških i funkcionalnih poremećaja koje pokreće PTSP. Sagledavanje uloge astrocita u PTSP-u može doprineti razvoju savremenih terapijskih meta za lečenje ove bolesti.

Reference

1. Schoenfeld TJ, Rhee D, Martin L, Smith JA, Sonti AN, Padmanaban V et al. New neurons restore structural and behavioral abnormalities in a rat model of PTSD. Hippocampus. 2019 Sep;29(9):848-861.
2. Ballenger JC, Davidson JR, Lecrubier Y, Nutt DJ, Foa EB, Kessler RC et al. Consensus statement on posttraumatic stress disorder from the International Consensus Group on Depression and Anxiety. J Clin Psychiatry. 2000;61 Suppl 5:60-6.
3. Bingham BC, Sheela Rani CS, Frazer A, Strong R, Morilak DA. Exogenous prenatal corticosterone exposure mimics the effects of prenatal stress on adult brain stress response systems and fear extinction behavior. Psychoneuroendocrinology. 2013 Nov;38(11):2746-57.
4. Sapolsky RM. Stress and plasticity in the limbic system. Neurochem Res. 2003 Nov;28(11):1735-42.
5. Hughes KC, Shin LM. Functional neuroimaging studies of post-traumatic stress disorder. Expert Rev Neurother. 2011 Feb;11(2):275-85.
6. Bremner JD, Randall P, Scott TM, Bronen RA, Seibyl JP, Southwick SM, Delaney RC, McCarthy G, Charney DS, Innis RB. MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am J Psychiatry. 1995 Jul;152(7):973-81.
7. Stein MB, Koverola C, Hanna C, Torchia MG, McClarty B. Hippocampal volume in women victimized by childhood sexual abuse. Psychol Med. 1997 Jul;27(4):951-9.
8. Li B, Zhang D, Verkhratsky A. Astrocytes in Post-traumatic Stress Disorder. Neurosci Bull. 2022 Aug;38(8):953-965.
9. Semyanov A, Verkhratsky A. Astrocytic processes: from tripartite synapses to the active
milieu. Trends Neurosci. 2021 Oct;44(10):781
10. Verkhratsky A, Nedergaard M. Astroglial cradle in the life of the synapse. Philos Trans R Soc Lond B Biol Sci. 2014 Oct 19;369(1654):20130595.
11. Li Y, Li L, Wu J, Zhu Z, Feng X, Qin L et. al. Activation of astrocytes in hippocampus decreases fear memory through adenosine A1 receptors. Elife.2020Sep1;9:e57155.
12. Izquier I, Furini CR, Myskiw JC. Fear Memory. Physiol Rev. 2016 Apr;96(2):695-750.
13. Saur L, Baptista PP, Bagatini PB, Neves LT, de Oliveira RM, Vaz SP et al. Experimental Post-traumatic Stress Disorder Decreases Astrocyte Density and Changes Astrocytic Polarity in the CA1 Hippocampus of Male Rats. Neurochem Res. 2016 Apr;41(4):892-904.
14. Yamamoto S, Morinobu S, Takei S, Fuchikami M, Matsuki A, Yamawaki S, Liberzon I. Single prolonged stress: toward an animal model of posttraumatic stress disorder. Depress Anxiety. 2009;26(12):1110-7.
15. Liberzon I, Krstov M, Young EA. Stress-restress: effects on ACTH and fast feedback. Psychoneuroendocrinology. 1997 Aug;22(6):443-53.
16. Romana Petrović. Medicinski B. Morfološke i biohemijske promene u prefrontalnom korteksu, amigdaloidnom telu i hipokampalnoj formaciji mozga pacova uslovljene pojedinačnim produženim stresom. 2018;
17. Kitayama N, Vaccarino V, Kutner M, Weiss P, Bremner JD. Magnetic resonance imaging (MRI) measurement of hippocampal volume in posttraumatic stress disorder: a meta-analysis. J Affect Disord. 2005 Sep;88(1):79-86.
18. Lindauer RJ, Olff M, van Meijel EP, Carlier IV, Gersons BP. Cortisol, learning, memory, and attention in relation to smaller hippocampal volume in police officers with posttraumatic stress disorder. Biol Psychiatry. 2006 Jan 15;59(2):171-7.
19. Czéh B, Simon M, Schmelting B, Hiemke C, Fuchs E. Astroglial plasticity in the hippocampus is affected by chronic psychosocial stress and concomitant fluoxetine treatment. Neuropsychopharmacology. 2006 Aug;31(8):1616-26.
20. Han F, Xiao B, Wen L. Loss of Glial Cells of the Hippocampus in a Rat Model of Post-traumatic Stress Disorder. Neurochem Res. 2015 May;40(5):942-51.
21. Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M et al. Sleep drives metabolite clearance from the adult brain. Science. 2013 Oct 18;342(6156):373-7.
22. Friedman WJ, Black IB, Kaplan DR. Distribution of the neurotrophins brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5 in the postnatal rat brain: an immunocytochemical study. Neuroscience. 1998 May;84(1):101-14.
23. Kelley KW, Ben Haim L, Schirmer L, Tyzack GE, Tolman M, Miller JG et al. Kir4.1-Dependent Astrocyte-Fast Motor Neuron Interactions Are Required for Peak Strength. Neuron. 2018 Apr 18;98(2):306-319.e7.
24. Perez-urrutia N, Mendoza C, Alvarez-ricartes N, Oliveros-matus P, Echeverria F, Grizzell JA, et al.

Intranasal cotinine improves memory , and reduces depressive-like behavior , and GFAP + cells loss induced by restraint stress in mice. Exp Neurol. 2017;295:211–21.
25. Adami P, König P, Vetter Z, Hausmann A, Conca A. Post-traumatic stress disorder and amygdala-hippocampectomy. Acta Psychiatr Scand. 2006 Apr;113(4):360-3; discussion 363-4.
26. Anand KS, Dhikav V. Hippocampus in health and disease: An overview. Ann Indian Acad Neurol. 2012 Oct;15(4):239-46.
27. Kerr KM, Agster KL, Furtak SC, Burwell RD. Functional neuroanatomy of the parahippocampal region: the lateral and medial entorhinal areas. Hippocampus. 2007;17(9):697-708.
28. Ohm TG. The dentate gyrus in Alzheimer's disease. Prog Brain Res. 2007;163:723-40.
29. O'Reilly RC, McClelland JL. Hippocampal conjunctive encoding, storage, and recall: avoiding a trade-off. Hippocampus. 1994 Dec;4(6):661-82.
30. Kheirbek MA, Klemenhagen KC, Sahay A, Hen R. Neurogenesis and generalization: a new approach to stratify and treat anxiety disorders. Nat Neurosci. 2012 Dec;15(12):1613-20.
31. Hayes JP, Hayes S, Miller DR, Lafleche G, Logue MW, Verfaellie M. Automated measurement of hippocampal subfields in PTSD: Evidence for smaller dentate gyrus volume. J Psychiatr Res. 2017 Dec;95:247-252.
32. Harnett NG, Goodman AM, Knight DC. PTSD-related neuroimaging abnormalities in brain function, structure, and biochemistry. Exp Neurol. 2020 Aug;330:113331.
33. Chen F, Ke J, Qi R, Xu Q, Zhong Y, Liu T et al. Increased Inhibition of the Amygdala by the mPFC may Reflect a Resilience Factor in Post-traumatic Stress Disorder: A Resting-State fMRI Granger Causality Analysis. Front Psychiatry. 2018 Oct 22;9:516.
34. Henigsberg N, Kalember P, Petrović ZK, Šečić A. Neuroimaging research in posttraumatic stress disorder - Focus on amygdala, hippocampus and prefrontal cortex. Prog Neuropsychopharmacol Biol Psychiatry. 2019 Mar 2;90:37-42.
35. Zheng S, Wang H, Han F, Chu J, Zhang F, Zhang X et al. Detection of Microstructural Medial Prefrontal Cortex Changes Using Magnetic Resonance Imaging Texture Analysis in a Post-Traumatic Stress Disorder Rat Model. Front Psychiatry. 2022 Apr 21;13:805851.
36. Pawlyk AC, Morrison AR, Ross RJ, Brennan FX. Stress-induced changes in sleep in rodents: models and mechanisms. Neurosci Biobehav Rev. 2008;32(1):99-117.
37. Lou T, Ma J, Wang Z, Terakoshi Y, Lee CY, Asher G et al. Hyper-Activation of mPFC Underlies Specific Traumatic Stress-Induced Sleep-Wake EEG Disturbances. Front Neurosci. 2020 Aug 18;14:883.