Skip to main content
Top
Published in:

12-07-2022 | Intracranial Hypertension | Original Article

Sustained ICP Elevation Is a Driver of Spatial Memory Deficits After Intraventricular Hemorrhage and Leads to Activation of Distinct Microglial Signaling Pathways

Authors: Chloe H. Puglisi, Bradley P. Ander, Catherine Peterson, Janet A. Keiter, Heather Hull, Cameron W. Hawk, Venina S. Kalistratova, Ali Izadi, Gene G. Gurkoff, Frank R. Sharp, Ben Waldau

Published in: Translational Stroke Research | Issue 4/2023

Login to get access

Abstract

The mechanisms of cognitive decline after intraventricular hemorrhage (IVH) in some patients continue to be poorly understood. Multiple rodent models of intraventricular or subarachnoid hemorrhage have only shown mild or even no cognitive impairment on subsequent behavioral testing. In this study, we show that intraventricular hemorrhage only leads to a significant spatial memory deficit in the Morris water maze if it occurs in the setting of an elevated intracranial pressure (ICP). Histopathological analysis of these IVH + ICP animals did not show evidence of neuronal degeneration in the hippocampal formation after 2 weeks but instead showed significant microglial activation measured by lacunarity and fractal dimensions. RNA sequencing of the hippocampus showed distinct enrichment of genes in the IVH + ICP group but not in IVH alone having activated microglial signaling pathways. The most significantly activated signaling pathway was the classical complement pathway, which is used by microglia to remove synapses, followed by activation of the Fc receptor and DAP12 pathways. Thus, our study lays the groundwork for identifying signaling pathways that could be targeted to ameliorate behavioral deficits after IVH.
Appendix
Available only for authorised users
Literature
1.
go back to reference Wiggins WS, Moody DM, Toole JF, Laster DW, Ball MR. Clinical and computerized tomographic study of hypertensive intracerebral hemorrhage. Arch Neurol. 1978;35:832–3.CrossRefPubMed Wiggins WS, Moody DM, Toole JF, Laster DW, Ball MR. Clinical and computerized tomographic study of hypertensive intracerebral hemorrhage. Arch Neurol. 1978;35:832–3.CrossRefPubMed
2.
go back to reference Angelopoulos M, Gupta SR, Azat Kia B. Primary intraventricular hemorrhage in adults: clinical features, risk factors, and outcome. Surg Neurol. 1995;44:433–6 (discussion 437).CrossRefPubMed Angelopoulos M, Gupta SR, Azat Kia B. Primary intraventricular hemorrhage in adults: clinical features, risk factors, and outcome. Surg Neurol. 1995;44:433–6 (discussion 437).CrossRefPubMed
3.
go back to reference Steiner T, Diringer MN, Schneider D, Mayer SA, Begtrup K, Broderick J, et al. Dynamics of intraventricular hemorrhage in patients with spontaneous intracerebral hemorrhage: risk factors, clinical impact, and effect of hemostatic therapy with recombinant activated factor VII. Neurosurgery. 2006;59:767–73 (discussion 773-4).CrossRef Steiner T, Diringer MN, Schneider D, Mayer SA, Begtrup K, Broderick J, et al. Dynamics of intraventricular hemorrhage in patients with spontaneous intracerebral hemorrhage: risk factors, clinical impact, and effect of hemostatic therapy with recombinant activated factor VII. Neurosurgery. 2006;59:767–73 (discussion 773-4).CrossRef
4.
5.
go back to reference Gaberel T, Magheru C, Emery E. Management of non-traumatic intraventricular hemorrhage. Neurosurg Rev. 2012;35:485–94 (discussion 494-5).CrossRefPubMed Gaberel T, Magheru C, Emery E. Management of non-traumatic intraventricular hemorrhage. Neurosurg Rev. 2012;35:485–94 (discussion 494-5).CrossRefPubMed
6.
go back to reference Dodel R, Winter Y, Ringel F, Spottke A, Gharevi N, Müller I, et al. Cost of illness in subarachnoid hemorrhage: a German longitudinal study. Stroke. 2010;41:2918–23.CrossRefPubMed Dodel R, Winter Y, Ringel F, Spottke A, Gharevi N, Müller I, et al. Cost of illness in subarachnoid hemorrhage: a German longitudinal study. Stroke. 2010;41:2918–23.CrossRefPubMed
7.
go back to reference Kreiter KT, Copeland D, Bernardini GL, Bates JE, Peery S, Claassen J, et al. Predictors of cognitive dysfunction after subarachnoid hemorrhage. Stroke Am Heart Assoc. 2002;33:200–9. Kreiter KT, Copeland D, Bernardini GL, Bates JE, Peery S, Claassen J, et al. Predictors of cognitive dysfunction after subarachnoid hemorrhage. Stroke Am Heart Assoc. 2002;33:200–9.
8.
go back to reference Al-Khindi T, Macdonald RL, Schweizer TA. Cognitive and functional outcome after aneurysmal subarachnoid hemorrhage. Stroke. 2010;41:e519–36.CrossRefPubMed Al-Khindi T, Macdonald RL, Schweizer TA. Cognitive and functional outcome after aneurysmal subarachnoid hemorrhage. Stroke. 2010;41:e519–36.CrossRefPubMed
9.
go back to reference Tuhrim S, Horowitz DR, Sacher M, Godbold JH. Volume of ventricular blood is an important determinant of outcome in supratentorial intracerebral hemorrhage. Crit Care Med. 1999;27:617–21.CrossRefPubMed Tuhrim S, Horowitz DR, Sacher M, Godbold JH. Volume of ventricular blood is an important determinant of outcome in supratentorial intracerebral hemorrhage. Crit Care Med. 1999;27:617–21.CrossRefPubMed
10.
go back to reference Garton T, Hua Y, Xiang J, Xi G, Keep RF. Challenges for intraventricular hemorrhage research and emerging therapeutic targets. Expert Opin Ther Targets. 2017;21:1111–22.CrossRefPubMedCentral Garton T, Hua Y, Xiang J, Xi G, Keep RF. Challenges for intraventricular hemorrhage research and emerging therapeutic targets. Expert Opin Ther Targets. 2017;21:1111–22.CrossRefPubMedCentral
11.
go back to reference Mracsko E, Veltkamp R. Neuroinflammation after intracerebral hemorrhage. Front Cell Neurosci. 2014;8:388.CrossRefPubMed Mracsko E, Veltkamp R. Neuroinflammation after intracerebral hemorrhage. Front Cell Neurosci. 2014;8:388.CrossRefPubMed
12.
go back to reference Kamal K, Keiter JA, Binyamin TR, de la Cruz Dapula JN, Vergara AR, Hawk CW, et al. Mechanical injury and blood are drivers of spatial memory deficits after rapid intraventricular hemorrhage. Neurobiol Dis. 2020;145:105084.CrossRefPubMedPubMedCentral Kamal K, Keiter JA, Binyamin TR, de la Cruz Dapula JN, Vergara AR, Hawk CW, et al. Mechanical injury and blood are drivers of spatial memory deficits after rapid intraventricular hemorrhage. Neurobiol Dis. 2020;145:105084.CrossRefPubMedPubMedCentral
14.
go back to reference 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 [Internet]. 2014;34. Available from: https://doi.org/10.1038/jcbfm.2014.108 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 [Internet]. 2014;34. Available from: https://​doi.​org/​10.​1038/​jcbfm.​2014.​108
16.
go back to reference Garthe A, Behr J, Kempermann G. Adult-generated hippocampal neurons allow the flexible use of spatially precise learning strategies. PLoS ONE. 2009;4:e5464.CrossRefPubMedPubMedCentral Garthe A, Behr J, Kempermann G. Adult-generated hippocampal neurons allow the flexible use of spatially precise learning strategies. PLoS ONE. 2009;4:e5464.CrossRefPubMedPubMedCentral
18.
go back to reference Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.CrossRefPubMed Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.CrossRefPubMed
19.
go back to reference Liao Y, Wang J, Jaehnig EJ, Shi Z, Zhang B. WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs. Nucleic Acids Res. 2019;47:W199-205.CrossRefPubMedPubMedCentral Liao Y, Wang J, Jaehnig EJ, Shi Z, Zhang B. WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs. Nucleic Acids Res. 2019;47:W199-205.CrossRefPubMedPubMedCentral
20.
go back to reference Noh J-E, Oh S-H, Park I-H, Song J. Intracerebral transplants of GMP-grade human umbilical cord-derived mesenchymal stromal cells effectively treat subacute-phase ischemic stroke in a rodent model. Front Cell Neurosci. 2020;14:546659.CrossRefPubMedPubMedCentral Noh J-E, Oh S-H, Park I-H, Song J. Intracerebral transplants of GMP-grade human umbilical cord-derived mesenchymal stromal cells effectively treat subacute-phase ischemic stroke in a rodent model. Front Cell Neurosci. 2020;14:546659.CrossRefPubMedPubMedCentral
21.
go back to reference Yousef H, Czupalla CJ, Lee D, Chen MB, Burke AN, Zera KA, et al. Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1. Nat Med. 2019;25:988–1000.CrossRefPubMedPubMedCentral Yousef H, Czupalla CJ, Lee D, Chen MB, Burke AN, Zera KA, et al. Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1. Nat Med. 2019;25:988–1000.CrossRefPubMedPubMedCentral
22.
go back to reference Wang C, Yue H, Hu Z, Shen Y, Ma J, Li J, et al. Microglia mediate forgetting via complement-dependent synaptic elimination. Science. 2020;367:688–94.CrossRefPubMed Wang C, Yue H, Hu Z, Shen Y, Ma J, Li J, et al. Microglia mediate forgetting via complement-dependent synaptic elimination. Science. 2020;367:688–94.CrossRefPubMed
23.
go back to reference Hwang IK, Park JH, Lee T-K, Kim DW, Yoo K-Y, Ahn JH, et al. CD74-immunoreactive activated M1 microglia are shown late in the gerbil hippocampal CA1 region following transient cerebral ischemia. Mol Med Rep. 2017;15:4148–54.CrossRefPubMedPubMedCentral Hwang IK, Park JH, Lee T-K, Kim DW, Yoo K-Y, Ahn JH, et al. CD74-immunoreactive activated M1 microglia are shown late in the gerbil hippocampal CA1 region following transient cerebral ischemia. Mol Med Rep. 2017;15:4148–54.CrossRefPubMedPubMedCentral
24.
go back to reference He J-H, Liu R-P, Peng Y-M, Guo Q, Zhu L-B, Lian Y-Z, et al. Differential and paradoxical roles of new-generation antidepressants in primary astrocytic inflammation. J Neuroinflammation. 2021;18:47.CrossRefPubMedPubMedCentral He J-H, Liu R-P, Peng Y-M, Guo Q, Zhu L-B, Lian Y-Z, et al. Differential and paradoxical roles of new-generation antidepressants in primary astrocytic inflammation. J Neuroinflammation. 2021;18:47.CrossRefPubMedPubMedCentral
25.
go back to reference Virtanen P, Gommers R, Oliphant TE, Haberland M, Reddy T, Cournapeau D, et al. SciPy 10: fundamental algorithms for scientific computing in Python. Nat Methods. 2020;17:261–72.CrossRefPubMedPubMedCentral Virtanen P, Gommers R, Oliphant TE, Haberland M, Reddy T, Cournapeau D, et al. SciPy 10: fundamental algorithms for scientific computing in Python. Nat Methods. 2020;17:261–72.CrossRefPubMedPubMedCentral
26.
27.
28.
go back to reference Sanchez B, Delemos CD, Sandhu KS, Peterson C, Cord BJ, Gurkoff GG, et al. Aneurysmal subarachnoid hemorrhage survivors show long-term deficits in spatial reference memory in a pilot study of a virtual water maze paradigm. Clin Neurol Neurosurg. 2021;207:106788.CrossRefPubMed Sanchez B, Delemos CD, Sandhu KS, Peterson C, Cord BJ, Gurkoff GG, et al. Aneurysmal subarachnoid hemorrhage survivors show long-term deficits in spatial reference memory in a pilot study of a virtual water maze paradigm. Clin Neurol Neurosurg. 2021;207:106788.CrossRefPubMed
29.
go back to reference Mangano FT, McAllister JP 2nd, Jones HC, Johnson MJ, Kriebel RM. The microglial response to progressive hydrocephalus in a model of inherited aqueductal stenosis. Neurol Res. 1998;20:697–704.CrossRefPubMed Mangano FT, McAllister JP 2nd, Jones HC, Johnson MJ, Kriebel RM. The microglial response to progressive hydrocephalus in a model of inherited aqueductal stenosis. Neurol Res. 1998;20:697–704.CrossRefPubMed
30.
go back to reference Wu K-Y, Tang F-L, Lee D, Zhao Y, Song H, Zhu X-J, et al. Ependymal Vps35 promotes ependymal cell differentiation and survival, suppresses microglial activation, and prevents neonatal hydrocephalus. J Neurosci Soc Neurosci. 2020;40:3862–79.CrossRef Wu K-Y, Tang F-L, Lee D, Zhao Y, Song H, Zhu X-J, et al. Ependymal Vps35 promotes ependymal cell differentiation and survival, suppresses microglial activation, and prevents neonatal hydrocephalus. J Neurosci Soc Neurosci. 2020;40:3862–79.CrossRef
31.
go back to reference Fernández-Arjona MDM, León-Rodríguez A, López-Ávalos MD, Grondona JM. Microglia activated by microbial neuraminidase contributes to ependymal cell death. Fluids Barriers CNS. 2021;18:15.CrossRefPubMedPubMedCentral Fernández-Arjona MDM, León-Rodríguez A, López-Ávalos MD, Grondona JM. Microglia activated by microbial neuraminidase contributes to ependymal cell death. Fluids Barriers CNS. 2021;18:15.CrossRefPubMedPubMedCentral
32.
go back to reference Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, et al. The classical complement cascade mediates CNS synapse elimination. Cell. 2007;131:1164–78.CrossRefPubMed Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, et al. The classical complement cascade mediates CNS synapse elimination. Cell. 2007;131:1164–78.CrossRefPubMed
33.
go back to reference Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012;74:691–705.CrossRefPubMedPubMedCentral Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012;74:691–705.CrossRefPubMedPubMedCentral
36.
go back to reference Lin Y, Pan Y, Wang M, Huang X, Yin Y, Wang Y, et al. Blood-brain barrier permeability is positively correlated with cerebral microvascular perfusion in the early fluid percussion-injured brain of the rat. Lab Invest. 2012;92:1623–34.CrossRefPubMed Lin Y, Pan Y, Wang M, Huang X, Yin Y, Wang Y, et al. Blood-brain barrier permeability is positively correlated with cerebral microvascular perfusion in the early fluid percussion-injured brain of the rat. Lab Invest. 2012;92:1623–34.CrossRefPubMed
38.
go back to reference Fu R, Shen Q, Xu P, Luo JJ, Tang Y. Phagocytosis of microglia in the central nervous system diseases. Mol Neurobiol. 2014;49:1422–34.CrossRefPubMed Fu R, Shen Q, Xu P, Luo JJ, Tang Y. Phagocytosis of microglia in the central nervous system diseases. Mol Neurobiol. 2014;49:1422–34.CrossRefPubMed
39.
go back to reference Jairaman A, McQuade A, Granzotto A, Kang YJ, Chadarevian JP, Gandhi S, et al. TREM2 regulates purinergic receptor-mediated calcium signaling and motility in human iPSC-derived microglia. Elife [Internet]. 2022;11. Available from: https://doi.org/10.7554/eLife.73021 Jairaman A, McQuade A, Granzotto A, Kang YJ, Chadarevian JP, Gandhi S, et al. TREM2 regulates purinergic receptor-mediated calcium signaling and motility in human iPSC-derived microglia. Elife [Internet]. 2022;11. Available from: https://​doi.​org/​10.​7554/​eLife.​73021
40.
go back to reference Buerke M, Prufer D, Dahm M, Oelert H, Meyer J, Darius H. Blocking of classical complement pathway inhibits endothelial adhesion molecule expression and preserves ischemic myocardium from reperfusion injury1. JPET. 1998;286:429–38. Buerke M, Prufer D, Dahm M, Oelert H, Meyer J, Darius H. Blocking of classical complement pathway inhibits endothelial adhesion molecule expression and preserves ischemic myocardium from reperfusion injury1. JPET. 1998;286:429–38.
41.
go back to reference D’Ambrosio AL, Pinsky DJ, Connolly ES. The role of the complement cascade in ischemia/reperfusion injury: implications for neuroprotection. Mol Med. 2001;7:367–82.CrossRefPubMedPubMedCentral D’Ambrosio AL, Pinsky DJ, Connolly ES. The role of the complement cascade in ischemia/reperfusion injury: implications for neuroprotection. Mol Med. 2001;7:367–82.CrossRefPubMedPubMedCentral
42.
go back to reference Ducruet AF, Zacharia BE, Sosunov SA, Gigante PR, Yeh ML, Gorski JW, et al. Complement inhibition promotes endogenous neurogenesis and sustained anti-inflammatory neuroprotection following reperfused stroke. PLoS ONE. 2012;7:e38664.CrossRefPubMedPubMedCentral Ducruet AF, Zacharia BE, Sosunov SA, Gigante PR, Yeh ML, Gorski JW, et al. Complement inhibition promotes endogenous neurogenesis and sustained anti-inflammatory neuroprotection following reperfused stroke. PLoS ONE. 2012;7:e38664.CrossRefPubMedPubMedCentral
43.
go back to reference Bayry J, Misra N, Latry V, Prost F, Delignat S, Lacroix-Desmazes S, et al. Mechanisms of action of intravenous immunoglobulin in autoimmune and inflammatory diseases. Transfus Clin Biol. 2003;10:165–9.CrossRefPubMed Bayry J, Misra N, Latry V, Prost F, Delignat S, Lacroix-Desmazes S, et al. Mechanisms of action of intravenous immunoglobulin in autoimmune and inflammatory diseases. Transfus Clin Biol. 2003;10:165–9.CrossRefPubMed
44.
45.
go back to reference Deczkowska A, Weiner A, Amit I. The physiology, pathology, and potential therapeutic applications of the TREM2 signaling pathway. Cell. 2020;181:1207–17.CrossRefPubMed Deczkowska A, Weiner A, Amit I. The physiology, pathology, and potential therapeutic applications of the TREM2 signaling pathway. Cell. 2020;181:1207–17.CrossRefPubMed
Metadata
Title
Sustained ICP Elevation Is a Driver of Spatial Memory Deficits After Intraventricular Hemorrhage and Leads to Activation of Distinct Microglial Signaling Pathways
Authors
Chloe H. Puglisi
Bradley P. Ander
Catherine Peterson
Janet A. Keiter
Heather Hull
Cameron W. Hawk
Venina S. Kalistratova
Ali Izadi
Gene G. Gurkoff
Frank R. Sharp
Ben Waldau
Publication date
12-07-2022
Publisher
Springer US
Published in
Translational Stroke Research / Issue 4/2023
Print ISSN: 1868-4483
Electronic ISSN: 1868-601X
DOI
https://doi.org/10.1007/s12975-022-01061-0