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

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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.

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Data Availability

The datasets generated during the RNAseq analysis are available in Online Resource 4a-e and archived in the Zenodo repository (https://doi.org/10.5281/zenodo.6395261).

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Acknowledgements

We would like to thank Mr. James Graham from the UC Davis Nutrition Department for conducting corticosterone analyses. We would like to thank Dr. Douglas Rowland for his support for the MR imaging. RNA libraries were prepared and sequenced by the skilled team at the UC Davis Genomics Shared Resource. Finally, we would like to thank Ms. Angelica Michelle Bachman and Dr. Melissa Bauman from the Rodent Behavior Core at UC Davis.

Funding

This work was supported by the National Institutes of Neurological Disorder and Stroke grants K08NS105914 (BW) and R01NS106950 (BPA, FRS). Dr. Rowland is supported by the Chan Zuckerberg Initiative Donor-Advised Fund (2019–198156) of the Silicon Valley Community Foundation. The skilled team at the UC Davis Genomics Shared Resource is funded by a UC Davis Comprehensive Cancer Center Support Grant awarded by the National Cancer Institute (NCI P30CA093373). Dr. Melissa Bauman from the Rodent Behavior Core at UC Davis is supported by a MIND Institute Intellectual and Developmental Disabilities Research Center grant (P50HD103526).

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Authors and Affiliations

  1. Department of Neurological Surgery, University of California at Davis Medical Center, 4860 Y Street, ACC 3740, Sacramento, CA, 95817, USA

    Chloe H. Puglisi, Catherine Peterson, Janet A. Keiter, Cameron W. Hawk, Venina S. Kalistratova, Ali Izadi, Gene G. Gurkoff & Ben Waldau

  2. Department of Neurology, University of California at Davis Medical Center, 4860 Y Street, ACC 3700, Sacramento, CA, 95817, USA

    Bradley P. Ander, Heather Hull & Frank R. Sharp

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  1. Chloe H. Puglisi
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Contributions

Conceptualization: Ben Waldau, Frank Sharp; methodology: Catherine Peterson, Chloe Puglisi, Heather Hull, Cameron Hawk, Venina Kalistratova; formal analysis and investigation: Chloe Puglisi, Bradley Ander, Janet Keiter, Catherine Peterson, Ali Izadi, Gene Gurkoff, Ben Waldau; writing—original draft preparation: Chloe Puglisi, Bradley Ander, Janet Keiter; writing—review and editing: Ben Waldau, Frank Sharp, Chloe Puglisi, Bradley Ander; funding acquisition: Ben Waldau, Frank Sharp, Bradley Ander; supervision: Ben Waldau, Frank Sharp.

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Correspondence to Ben Waldau.

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Ethical Approval

This study was approved by the University of California at Davis Institutional Animal Care and Use Committee. The welfare of animals was monitored by a veterinarian.

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The authors declare no competing interests.

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Puglisi, C.H., Ander, B.P., Peterson, C. et al. Sustained ICP Elevation Is a Driver of Spatial Memory Deficits After Intraventricular Hemorrhage and Leads to Activation of Distinct Microglial Signaling Pathways. Transl. Stroke Res. 14, 572–588 (2023). https://doi.org/10.1007/s12975-022-01061-0

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