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Biological and Behavioral Patterns of Post-Stroke Depression in Rats

  • Gal Ifergane (a1), Matthew Boyko (a2), Dmitri Frank (a2), Honore N. Shiyntum (a3), Julia Grinshpun (a2), Ruslan Kuts (a2), Amir B. Geva (a4), Zeev Kaplan (a5), Vladimir Zeldetz (a6) and Hagit Cohen (a5)...

Abstract

Background: Post-stroke depression (PSD) is the most frequent psychiatric complication following ischemic stroke. It affects up to 60% of all patients and is associated with increased morbidity and mortality following ischemic stroke. The pathophysiology of PSD remains elusive and appears to be multifactorial, rather than “purely” biological or psychosocial in origin. Thus, valid animal models of PSD would contribute to the study of the etiology (and treatment) of this disorder. Methods: The present study depicts a rat model for PSD, using middle cerebral artery occlusion (MCAO). The two-way shuttle avoidance task, Porsolt forced-swim test, and sucrose preference test were employed to assess any depression-like behavior. Localized brain expressions of brain-derived neurotrophic factor (BDNF) protein levels were evaluated to examine the possible involvement of the brain neuronal plasticity in the observed behavioral syndrome. The raw data were subjected to unsupervised fuzzy clustering (UFC) algorithms to assess the sensitivity of bio-behavioral measures indicative of depressive symptoms post MCAO. Results : About 56% of the rats developed significant depressive-like behavioral disruptions as a result of MCAO compared with 4% in the sham-operated control rats. A pattern of a depressive-like behavioral response was common to all affected MCAO animals, characterized by significantly more escape failures and reduced number of total avoidance shuttles, a significant elevation in immobility duration, and reduced sucrose preference. Significant downregulations of BDNF protein levels in the hippocampal sub-regions, frontal cortex, and hypothalamus were observed in all affected MCAO animals. Conclusion: The UFC analysis supports the behavioral analysis and thus, lends validity to our results.

Profils biologiques et modes comportementaux chez des rats atteints de dépression post-AVC. Contexte: La dépression demeure la complication psychiatrique la plus courante à la suite d’un AVC. Elle affecte jusqu’à 60 % de tous les patients qui en sont victimes et est associée à une augmentation de leur morbidité et de leur mortalité. La pathophysiologie de la dépression post-AVC est toutefois difficile à établir ; il semblerait que ses causes, plutôt que seulement biologiques ou psychosociales, sont multifactorielles. Du coup, des modèles animaux valides et appliqués à la dépression post-AVC pourraient contribuer à l’étude de l’étiologie de ce trouble mental et paver la voie à un traitement. Méthodes: La présente étude vise à décrire un modèle de dépression post-AVC chez des rats en se basant sur l’occlusion de leur artère cérébrale moyenne (OACM). On a ainsi utilisé trois tests pour mesurer tout type de comportement de nature dépressive: l’évitement d’une tâche dans une boîte à deux compartiments (two-way shuttle avoidance task), le test de Porsolt et le test de préférence au saccharose. L’activité locale du cerveau en lien avec les taux de protéines du facteur neurotrophique a été évaluée pour comprendre le rôle possible de la plasticité neuronale eu égard aux syndromes comportementaux observés. On a ensuite soumis nos données brutes à des algorithmes non supervisés par regroupements flous afin d’évaluer la sensibilité des résultats bio-comportementaux révélateurs de symptômes dépressifs post-OACM. Résultats: Environ 56 % des rats ont manifesté d’importantes perturbations comportementales de nature dépressive à la suite d’une OACM. Chez des rats témoins opérés de manière fictive, ce taux fut de 4 %. Un mode de réaction comportementale s’apparentant à la dépression a donc été observé systématiquement chez tous les rats affectés par une OACM. Ce mode s’est caractérisé par un nombre nettement plus grand de défaillances au moment de s’échapper, par un nombre réduit de déplacements d’un compartiment à l’autre, par une augmentation notable de leur durée d’immobilité et par une réduction de leur préférence en saccharose. Une importante régulation négative liée aux taux de protéines du facteur neurotrophique a aussi été observée chez tous les rats « OACM » dans leurs sous-régions hippocampiques, leur cortex frontal et l’hypothalamus. Conclusion: L’analyse menée au moyen d’algorithmes non supervisés par regroupements flous tend à corroborer notre analyse comportementale et à renforcer ainsi la validité de nos résultats.

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Copyright

Corresponding author

Correspondence to: Matthew Boyko, Brain Research Lab, Division of Anesthesiology and Critical Care, Soroka Medical Center, Ben-Gurion University of the Negev, P.O. Box 151, Beer-Sheva 98105, Israel. Email: matewboyko@gmail.com

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These authors contributed equally.

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References

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1. Hyman, C, Hofer, M, Barde, YA, et al. BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature. 1991;350:230-232.
2. McAllister, AK. Subplate neurons: a missing link among neurotrophins, activity, and ocular dominance plasticity? Proc Natl Acad Sci U S A. 1999;96:13600-13602.
3. Shimada, A, Mason, CA, Morrison, ME. TrkB signaling modulates spine density and morphology independent of dendrite structure in cultured neonatal Purkinje cells. Neuroscience. 1998;18:8559-8570.
4. Solomon, Z, Shklar, R, Mikulincer, M. Frontline treatment of combat stress reaction: a 20-year longitudinal evaluation study. Am J Psychiatry. 2005;162:2309-2314.
5. Yacoubian, TA, Lo, DC. Truncated and full-length TrkB receptors regulate distinct modes of dendritic growth. Nat Neurosci. 2000;3:342-349.
6. Rutherford, LC, Nelson, SB, Turrigiano, GG. BDNF has opposite effects on the quantal amplitude of pyramidal neuron and interneuron excitatory synapses. Neuron. 1998;21:521-530.
7. Seil, FJ, Drake-Baumann, R. TrkB receptor ligands promote activity-dependent inhibitory synaptogenesis. Neuroscience. 2000;20:5367-5373.
8. Vicario-Abejon, C, Collin, C, McKay, RD, Segal, M. Neurotrophins induce formation of functional excitatory and inhibitory synapses between cultured hippocampal neurons. Neuroscience. 1998;18:7256-7271.
9. Comelli, MC, Seren, MS, Guidolin, D, et al. Photochemical stroke and brain-derived neurotrophic factor (BDNF) mRNA expression. Neuroreport. 1992;3:473-476.
10. Kokaia, Z, Andsberg, G, Yan, Q, Lindvall, O. Rapid alterations of BDNF protein levels in the rat brain after focal ischemia: evidence for increased synthesis and anterograde axonal transport. Exp Neurol. 1998;154:289-301.
11. Kokaia, Z, Zhao, Q, Kokaia, M, et al. Regulation of brain-derived neurotrophic factor gene expression after transient middle cerebral artery occlusion with and without brain damage. Exp Neurol. 1995;136:73-88.
12. Madinier, A, Bertrand, N, Mossiat, C, et al. Microglial involvement in neuroplastic changes following focal brain ischemia in rats. PLoS One. 2009;4:e8101.
13. Sulejczak, D, Ziemlinska, E, Czarkowska-Bauch, J, Nosecka, E, Strzalkowski, R, Skup, M. Focal photothrombotic lesion of the rat motor cortex increases BDNF levels in motor-sensory cortical areas not accompanied by recovery of forelimb motor skills. Neurotrauma. 2007;24:1362-1377.
14. Chen, J, Zhang, C, Jiang, H, et al. Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice. Cereb Blood Flow Metab. 2005;25:281-290.
15. Yanamoto, H, Nagata, I, Sakata, M, et al. Infarct tolerance induced by intra-cerebral infusion of recombinant brain-derived neurotrophic factor. Brain Res. 2000;859:240-248.
16. Nakao, N, Kokaia, Z, Odin, P, Lindvall, O. Protective effects of BDNF and NT-3 but not PDGF against hypoglycemic injury to cultured striatal neurons. Exp Neurol. 1995;131:1-10.
17. Petersen, AA, Larsen, KE, Behr, GG, et al. Brain-derived neurotrophic factor inhibits apoptosis and dopamine-induced free radical production in striatal neurons but does not prevent cell death. Brain Res Bull. 2001;56:331-335.
18. Shimohama, S, Tamura, Y, Akaike, A, et al. Brain-derived neurotrophic factor pretreatment exerts a partially protective effect against glutamate-induced neurotoxicity in cultured rat cortical neurons. Neurosci Lett. 1993;164:55-58.
19. Schabitz, W, Sommer, C, Zoder, W, Kiessling, M, Schwaninger, M, Schwab, S. Intravenous brain-derived neurotrophic factor reduces infarct size and counterregulates Bax and Bcl-2 expression after temporary focal cerebral ischemia. Stroke. 2000;31:2212-2217.
20. Astrom, M, Adolfsson, R, Asplund, K. Major depression in stroke patients: a three year longitudinal study. Stroke. 1993;24:976-982.
21. Eastwood, MR, Rifat, SL, Nobbs, H, Ruderman, J. Mood disorder following cerebrovascular accident. Br J Psychiatry. 1989;154:195-200.
22. Robinson, R, Bolduc, P, Price, T. Two-year longitudinal study of poststroke mood disorders: diagnosis and outcome at one and two years. Stroke. 1987;18:837-843.
23. Duman, R. Synaptic plasticity and mood disorders. Mol Psychiatry. 2002;7:29-34.
24. Duman, R. Depression: a case of neuronal life and death? Biol Psychiatry. 2004;56:140-145.
25. Manji, H, Drevets, W, Charney, D. The cellular neurobiology of depression. Nat Med. 2001;7:541-547.
26. Boyko, M, Zlotnik, A, Gruenbaum, BF, et al. An experimental model of focal ischemia using an internal carotid artery approach. Neurosci Methods. 2010;193:246-253.
27. Longa, Z, Weinstein, PR, Carlson, S, Cummins, R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 1989;20:84-91.
28. Dittmar, M, Spruss, T, Schuierer, G, Horn, M. External carotid artery territory ischemia impairs outcome in the endovascular filament model of middle cerebral artery occlusion in rats. Stroke. 2003;34:2252-2257.
29. Boyko, M, Ohayon, S, Goldsmith, T, et al. Morphological and neuro-behavioral parallels in the rat model of stroke. Behav Brain Res. 2011;223(1):17-23.
30. Boyko, M, Ohayon, S, Goldsmith, T, et al. Cell-free DNAFA marker to predict ischemic brain damage in a rat stroke experimental model. Neurosurg Anesthesiol. 2011;23:222-228.
31. Ohayon, S, Boyko, M, Saad, A, et al. Cell-free DNA as a marker for prediction of brain damage in traumatic brain injury in rats. Neurotrauma. 2012;29:261-267.
32. Boyko, M, Kutz, R, Gruenbaum, BF, et al. The influence of aging on poststroke depression using a rat model via middle cerebral artery occlusion. Cogn Affect Behav Neurosci. 2013;13(4):847-859.
33. Association, AP. Diagnostic and statistical manual of mental disorders, 4th edn., text revised edn. Washington, DC: American Psychiatric Association; 2000.
34. Boyko, M, Kutza, R, Grinshpun, G, et al. Establishment of an animal model of depression contagion. Behav Brain Res. 2015;281:358-363.
35. Porsolt, RD, Anton, G, Blavet, N, Jalfre, M. Behavioral despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol. 1978;48:379-391.
36. Boyko, M, Azabb, AN, Kutsa, R, et al. The neuro-behavioral profile in rats after subarachnoid hemorrhage. Brain Res. 2013;1491:109-116.
37. Porsolt, RD, Le Pichon, M, Jalfre, M. Depression: a new animal model sensitive to antidepressant treatments. Nature. 1977;266:730.
38. Paxinos, G, Watson, C. The rat brain in stereotaxic coordinates, 5th edn. Elsevier Academic Press; 2005.
39. Berg, A, Palomäki, H, Lehtihalmes, M, Lönnqvist, J, Kaste, M. Poststroke depression: an 18-month follow-up. Stroke. 2003;34:138-143.
40. Bezdek, JC, Castelaz, PF. Prototype classification and feature selection with fuzzy sets. IEEE Trans Syst Man Cybern Syst. 1971;17:87-92.
41. Bezdek, JC, Pal, NR. Some new validity indexes of cluster validity. IEEE Trans Syst Man Cybern Syst. 1998;28(3):301-315.
42. Gath, I, Geva, AB. Fuzzy clustering for the estimation of the parameters of the components of mixtures of normal distributions. Pattern Recognit Lett. 1989;9:77-86.
43. Rezaee, MR, Lelieveldt, BPF, Reiber, JHC. A new cluster validity for the fuzzy c-mean. Pattern Recognit Lett. 1998:237-246.
44. Cohen, H, Zohar, J, Matar, MA, Kaplan, Z, Geva, AB. Unsupervised fuzzy clustering analysis supports behavioral cutoff criteria in an animal model of posttraumatic stress disorder. Biol Psychiatry. 2005;58:640-650.
45. Cryan, JF, Markou, A, Lucki, I. Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol Sci. 2002;23:238-245.
46. Nestler, EJ, Gould, E, Manji, H, et al. Preclinical models: status of basic research in depression. Biol Psychiatry. 2002;52:503-528.
47. Geva, AB. Feature extraction and state identification in biomedical signals using hierarchical fuzzy clustering. Med Biol Eng Comput. 1998;36:608-614.
48. Geva, AB. Hierarchical-fuzzy clustering of temporal-patterns and its application for time-series prediction. Pattern Recognit Lett. 1999;20:1519-1532.
49. Geva, AB, Pratt, H. Unsupervised clustering of evoked potentials by waveform. Med Biol Eng Comput. 1994;32:543-550.
50. Kotila, M, Numminen, H, Waltimo, O, Kaste, M. Depression after stroke: results of the FINNSTROKE Study. Stroke. 1998;29:368-372.
51. Ramasubbu, R, Robinson, R, Flint, A, Kosier, T, Price, T. Functional impairment associated with acute poststroke depression: the Stroke Data Bank Study. J Neuropsychiatry Clin Neurosci. 1998;10:26-33.
52. Nibuya, M, Morinobu, S, Duman, R. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. Neuroscience. 1995;15:7539-7547.
53. Kronenberg, G, Gertz, K, Heinz, A, Endres, M. Of mice and men: modelling post-stroke depression experimentally. Br J Pharmacol. 2014;171(20):4673-4689.
54. Malberg, J, Eisch, A, Nestler, E, Duman, R. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. Neuroscience. 2000;20:9104-9110.
55. Schwartz, JA, Speed, NM, Brunberg, JA, Brewer, TL, Brown, M, Greden, JF. Depression in stroke rehabilitation. Biol Psychiatry. 1993;33:694-699.
56. Kauhanen, M, Korpelainen, JT, Hiltunen, P, et al. Poststroke depression correlates with cognitive impairment and neurological deficits. Stroke. 1999;30:1875-1880.
57. Morris, PL, Robinson, RG, Andrzejewski, P, Samuels, J, Price, TR. Association of depression with 10-year poststroke mortality. Am J Psychiatry. 1993;150:124-129.
58. Williams, LS, Ghose, SS, Swindle, RW. Depression and other mental health diagnoses increase mortality risk after ischemic stroke. Am J Psychiatry. 2004;161:1090-1095.
59. Jorgensen, L, Engstad, T, Jacobsen, B. Higher incidence of falls in long-term stroke survivors than in population controls: depressive symptoms predict falls after stroke. Stroke. 2002;33:542-547.
60. Paolucci, S, Antonucci, G, Grasso, MG, et al. Post-stroke depression, antidepressant treatment and rehabilitation results. A case-control study. Cerebrovasc Dis. 2001;12:264-271.
61. Zhou, Z, Lu, T, Xu, G, et al. Decreased serum brain-derived neurotrophic factor (BDNF) is associated with post-stroke depression but not with BDNF gene Val66Met polymorphism. Clin Chem Lab Med. 2011;49(2):185-9.
62. Andersen, G, Vestergaard, K, Lauritzen, L. Effective treatment of poststroke depression with the selective serotonin reuptake inhibitor citalopram. Stroke. 1994;25:1099-1104.
63. Currier, M, Murray, G, Welch, C. Electroconvulsive therapy for poststroke depressed geriatric patients. Neuropsychiatry Clin Neurosci. 1992;4:140-144.
64. Robinson, RG, Lipsey, JR, Pearlson, GD. The occurrence and treatment of poststroke mood disorders. Compr Ther. 1984;10:19-24.
65. Wiart, L, Petit, H, Joseph, PA, Mazaux, JM, Barat, M. Fluoxetine in early poststroke depression: a double-blind placebo-controlled study. Stroke. 2000;31:1829-1832.

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