Neurocritical Care

, Volume 25, Issue 2, pp 293–305 | Cite as

Long-Term Cognitive Deficits After Subarachnoid Hemorrhage in Rats

  • Toshihiro Sasaki
  • Ulrike Hoffmann
  • Motomu Kobayashi
  • Huaxin Sheng
  • Abdelkader Ennaceur
  • Frederick W. Lombard
  • David S. WarnerEmail author
Translational research



Cognitive dysfunction can be a long-term complication following subarachnoid hemorrhage (SAH). Preclinical models have been variously characterized to emulate this disorder. This study was designed to directly compare long-term cognitive deficits in the context of similar levels of insult severity in the cisterna magna double-blood (DB) injection versus prechiasmatic blood (PB) injection SAH models.


Pilot work identified blood injectate volumes necessary to provide similar mortality rates (20–25 %). Rats were then randomly assigned to DB or PB insults. Saline injection and naïve rats were used as controls. Functional and cognitive outcome was assessed over 35 days.


DB and PB caused similar transient rotarod deficits. PB rats exhibited decreased anxiety behavior on the elevated plus maze, while anxiety was increased in DB. DB and PB caused differential deficits in the novel object recognition and novel object location tasks. Morris water maze performance was similarly altered in both models (decreased escape latency and increased swimming speed). SAH caused histologic damage in the medial prefrontal cortex, perirhinal cortex, and hippocampal CA1, although severity of injury in the respective regions differed between DB and PB.


Both SAH models caused long-term cognitive deficits in the context of similar insult severity. Cognitive deficits differed between the two models, as did distribution of histologic injury. Each model offers unique properties and both models may be useful for study of SAH-induced cognitive deficits.


Subarachnoid hemorrhage Cognitive dysfunction Prechiasmatic blood injection model Cisterna magna double blood injection model Rat 



This research was funded by the Department of Anesthesiology, Duke University Medical Center.

Compliance with Ethical Standards

Conflicts of Interest


Human and Animal Rights

All applicable institutional and/or national guidelines for the care and use of animals were followed.


  1. 1.
    Mayer SA, Kreiter KT, Copeland D, Bernardini GL, Bates JE, Peery S, et al. Global and domain-specific cognitive impairment and outcome after subarachnoid hemorrhage. Neurology. 2002;59(11):1750–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Kreiter KT, Copeland D, Bernardini GL, Bates JE, Peery S, Claassen J, et al. Predictors of cognitive dysfunction after subarachnoid hemorrhage. Stroke. 2002;33(1):200–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Sheldon S, Macdonald RL, Cusimano M, Spears J, Schweizer TA. Long-term consequences of subarachnoid hemorrhage: examining working memory. J Neurol Sci. 2013;332(1–2):145–7.PubMedCrossRefGoogle Scholar
  4. 4.
    Latimer SF, Wilson FC, McCusker CG, Caldwell SB, Rennie I. Subarachnoid haemorrhage (SAH): long-term cognitive outcome in patients treated with surgical clipping or endovascular coiling. Disabil Rehabil. 2013;35(10):845–50.PubMedCrossRefGoogle Scholar
  5. 5.
    Al-Khindi T, Macdonald RL, Schweizer TA. Cognitive and functional outcome after aneurysmal subarachnoid hemorrhage. Stroke. 2010;41(8):e519–36.PubMedCrossRefGoogle Scholar
  6. 6.
    Prunell GF, Mathiesen T, Diemer NH, Svendgaard NA. Experimental subarachnoid hemorrhage: subarachnoid blood volume, mortality rate, neuronal death, cerebral blood flow, and perfusion pressure in three different rat models. Neurosurgery. 2003;52(1):165–75 (discussion 75–6).PubMedGoogle Scholar
  7. 7.
    Lee JY, Huang DL, Keep R, Sagher O. Characterization of an improved double hemorrhage rat model for the study of delayed cerebral vasospasm. J Neurosci Methods. 2008;168(2):358–66.PubMedCrossRefGoogle Scholar
  8. 8.
    Lee JY, Sagher O, Keep R, Hua Y, Xi G. Comparison of experimental rat models of early brain injury after subarachnoid hemorrhage. Neurosurgery. 2009;65(2):331–43 (discussion 43).PubMedCrossRefGoogle Scholar
  9. 9.
    Takata K, Sheng H, Borel CO, Laskowitz DT, Warner DS, Lombard FW. Long-term cognitive dysfunction following experimental subarachnoid hemorrhage: new perspectives. Exp Neurol. 2008;213(2):336–44.PubMedCrossRefGoogle Scholar
  10. 10.
    Takata K, Sheng H, Borel CO, Laskowitz DT, Warner DS, Lombard FW. Simvastatin treatment duration and cognitive preservation in experimental subarachnoid hemorrhage. J Neurosurg Anesthesiol. 2009;21(4):326–33.PubMedCrossRefGoogle Scholar
  11. 11.
    Jeon H, Ai J, Sabri M, Tariq A, Macdonald RL. Learning deficits after experimental subarachnoid hemorrhage in rats. Neuroscience. 2010;169(4):1805–14.PubMedCrossRefGoogle Scholar
  12. 12.
    Liu Y, Li J, Wang Z, Yu Z, Chen G. Attenuation of early brain injury and learning deficits following experimental subarachnoid hemorrhage secondary to cystatin C: possible involvement of the autophagy pathway. Mol Neurobiol. 2014;49(2):1043–54.PubMedCrossRefGoogle Scholar
  13. 13.
    Liu Y, Qiu J, Wang Z, You W, Wu L, Ji C, et al. Dimethylfumarate alleviates early brain injury and secondary cognitive deficits after experimental subarachnoid hemorrhage via activation of Keap1-Nrf2-ARE system. J Neurosurg. 2015;123(4):915–23.PubMedCrossRefGoogle Scholar
  14. 14.
    Han SM, Wan H, Kudo G, Foltz WD, Vines DC, Green DE, et al. Molecular alterations in the hippocampus after experimental subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2014;34(1):108–17.PubMedCrossRefGoogle Scholar
  15. 15.
    Macdonald RL. Subarachnoid hemorrhage and outcome. J Neurosurg. 2013;119(3):603–4.PubMedCrossRefGoogle Scholar
  16. 16.
    Silasi G, Colbourne F. Long-term assessment of motor and cognitive behaviours in the intraluminal perforation model of subarachnoid hemorrhage in rats. Behav Brain Res. 2009;198(2):380–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Xie Y, Liu W, Zhang X, Wang L, Xu L, Xiong Y, et al. Human albumin improves long-term behavioral sequelae after subarachnoid hemorrhage through neurovascular remodeling. Crit Care Med. 2015;43(10):e440–9.PubMedCrossRefGoogle Scholar
  18. 18.
    Milner E, Holtzman JC, Friess S, Hartman RE, Brody DL, Han BH, et al. Endovascular perforation subarachnoid hemorrhage fails to cause Morris water maze deficits in the mouse. J Cereb Blood Flow Metab. 2014;34:e1–e9. doi: 10.1038/jcbfm.2014.108.CrossRefGoogle Scholar
  19. 19.
    Boyko M, Azab AN, Kuts R, Gruenbaum BF, Gruenbaum SE, Melamed I, et al. The neuro-behavioral profile in rats after subarachnoid hemorrhage. Brain Res. 2013;1491:109–16.PubMedCrossRefGoogle Scholar
  20. 20.
    Shen H, Chen Z, Wang Y, Gao A, Li H, Cui Y, et al. Role of neurexin-1beta and neuroligin-1 in cognitive dysfunction after subarachnoid hemorrhage in rats. Stroke. 2015;46(9):2607–15.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Handley SL, Mithani S. Effects of alpha-adrenoceptor agonists and antagonists in a maze-exploration model of ‘fear’-motivated behaviour. Naunyn Schmiedebergs Arch Pharmacol. 1984;327(1):1–5.PubMedCrossRefGoogle Scholar
  22. 22.
    Ennaceur A. One-trial object recognition in rats and mice: methodological and theoretical issues. Behav Brain Res. 2010;215(2):244–54.PubMedCrossRefGoogle Scholar
  23. 23.
    Antunes M, Biala G. The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process. 2012;13(2):93–110.PubMedCrossRefGoogle Scholar
  24. 24.
    Morris R. Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods. 1984;11(1):47–60.PubMedCrossRefGoogle Scholar
  25. 25.
    Samra SK, Giordani B, Caveney AF, Clarke WR, Scott PA, Anderson S, et al. Recovery of cognitive function after surgery for aneurysmal subarachnoid hemorrhage. Stroke. 2007;38(6):1864–72.PubMedCrossRefGoogle Scholar
  26. 26.
    Guresir E, Schuss P, Borger V, Vatter H. Experimental subarachnoid hemorrhage: double cisterna magna injection rat model–assessment of delayed pathological effects of cerebral vasospasm. Transl Stroke Res. 2015;6(3):242–51.PubMedCrossRefGoogle Scholar
  27. 27.
    Coyle P. Vascular patterns of the rat hippocampal formation. Exp Neurol. 1976;52(3):447–58.PubMedCrossRefGoogle Scholar
  28. 28.
    Shah AA, Treit D. Excitotoxic lesions of the medial prefrontal cortex attenuate fear responses in the elevated-plus maze, social interaction and shock probe burying tests. Brain Res. 2003;969(1–2):183–94.PubMedCrossRefGoogle Scholar
  29. 29.
    Bertoglio LJ, Joca SR, Guimaraes FS. Further evidence that anxiety and memory are regionally dissociated within the hippocampus. Behav Brain Res. 2006;175(1):183–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Morris PG, Wilson JT, Dunn L. Anxiety and depression after spontaneous subarachnoid hemorrhage. Neurosurgery. 2004;54(1):47–52 (discussion 52–4).PubMedCrossRefGoogle Scholar
  31. 31.
    Visser-Meily JM, Rhebergen ML, Rinkel GJ, van Zandvoort MJ, Post MW. Long-term health-related quality of life after aneurysmal subarachnoid hemorrhage: relationship with psychological symptoms and personality characteristics. Stroke. 2009;40(4):1526–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Fontanella M, Perozzo P, Ursone R, Garbossa D, Bergui M. Neuropsychological assessment after microsurgical clipping or endovascular treatment for anterior communicating artery aneurysm. Acta Neurochir (Wien). 2003;145(10):867–72 (discussion 72).CrossRefGoogle Scholar
  33. 33.
    von Vogelsang AC, Forsberg C, Svensson M, Wengstrom Y. Patients experience high levels of anxiety 2 years following aneurysmal subarachnoid hemorrhage. World Neurosurg. 2015;83(6):1090–7.CrossRefGoogle Scholar
  34. 34.
    Ronne-Engstrom E, Enblad P, Lundstrom E. Outcome after spontaneous subarachnoid hemorrhage measured with the EQ-5D. Stroke. 2011;42(11):3284–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Al-Khindi T, Macdonald RL, Schweizer TA. Decision-making deficits persist after aneurysmal subarachnoid hemorrhage. Neuropsychology. 2014;28(1):68–74.PubMedCrossRefGoogle Scholar
  36. 36.
    Escartin G, Junque C, Juncadella M, Gabarros A, de Miquel MA, Rubio F. Decision-making impairment on the Iowa Gambling Task after endovascular coiling or neurosurgical clipping for ruptured anterior communicating artery aneurysm. Neuropsychology. 2012;26(2):172–80.PubMedCrossRefGoogle Scholar
  37. 37.
    Mavaddat N, Kirkpatrick PJ, Rogers RD, Sahakian BJ. Deficits in decision-making in patients with aneurysms of the anterior communicating artery. Brain. 2000;123(Pt 10):2109–17.PubMedCrossRefGoogle Scholar
  38. 38.
    de Bruin JP, Sanchez-Santed F, Heinsbroek RP, Donker A, Postmes P. A behavioural analysis of rats with damage to the medial prefrontal cortex using the Morris water maze: evidence for behavioural flexibility, but not for impaired spatial navigation. Brain Res. 1994;652(2):323–33.PubMedCrossRefGoogle Scholar
  39. 39.
    Compton DM, Griffith HR, McDaniel WF, Foster RA, Davis BK. The flexible use of multiple cue relationships in spatial navigation: a comparison of water maze performance following hippocampal, medial septal, prefrontal cortex, or posterior parietal cortex lesions. Neurobiol Learn Mem. 1997;68(2):117–32.PubMedCrossRefGoogle Scholar
  40. 40.
    Jo YS, Park EH, Kim IH, Park SK, Kim H, Kim HT, et al. The medial prefrontal cortex is involved in spatial memory retrieval under partial-cue conditions. J Neurosci. 2007;27(49):13567–78.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Toshihiro Sasaki
    • 1
  • Ulrike Hoffmann
    • 1
  • Motomu Kobayashi
    • 1
  • Huaxin Sheng
    • 1
  • Abdelkader Ennaceur
    • 2
  • Frederick W. Lombard
    • 1
  • David S. Warner
    • 1
    Email author
  1. 1.Multidisciplinary Neuroprotection Laboratories, Department of AnesthesiologyDuke University Medical CenterDurhamUSA
  2. 2.Department of PharmacyUniversity of SunderlandSunderlandUK

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