R Brian Roome1, Robert F Bartlett1, Matthew Jeffers2, Jieying Xiong1, Dale Corbett3, Jacqueline L Vanderluit4. 1. BioMedical Sciences, Faculty of Medicine Memorial University of Newfoundland, 300 Prince Phillip Dr., St. John's, NL A1B 3V6, Canada; Heart and Stroke Foundation of Canada, Canadian Partnership for Stroke Recovery, Canada. 2. BioMedical Sciences, Faculty of Medicine Memorial University of Newfoundland, 300 Prince Phillip Dr., St. John's, NL A1B 3V6, Canada; Heart and Stroke Foundation of Canada, Canadian Partnership for Stroke Recovery, Canada; Department Cellular & Molecular Medicine, University of Ottawa, 451 Smyth Rd, Ottawa, ON K1H 8M5, Canada. 3. BioMedical Sciences, Faculty of Medicine Memorial University of Newfoundland, 300 Prince Phillip Dr., St. John's, NL A1B 3V6, Canada; Heart and Stroke Foundation of Canada, Canadian Partnership for Stroke Recovery, Canada; Department Cellular & Molecular Medicine, University of Ottawa, 451 Smyth Rd, Ottawa, ON K1H 8M5, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada. 4. BioMedical Sciences, Faculty of Medicine Memorial University of Newfoundland, 300 Prince Phillip Dr., St. John's, NL A1B 3V6, Canada; Heart and Stroke Foundation of Canada, Canadian Partnership for Stroke Recovery, Canada. Electronic address: j.vanderluit@mun.ca.
Abstract
BACKGROUND: Despite the availability of numerous transgenic mouse lines to study the role of individual genes in promoting neural repair following stroke, few studies have availed of this technology, primarily due to the lack of a reproducible ischemic injury model in the mouse. Intracortical injections of Endothelin-1 (ET1) a potent vasoconstrictive agent, reliably produces focal infarcts with concomitant behavioral deficits in rats. In contrast, ET1 infarcts in mice are significantly smaller and do not generate consistent behavioral deficits. NEW METHOD: We have modified the ET1 ischemia model to target the anterior forelimb motor cortex (aFMC) and show that this generates a reproducible focal ischemic injury in mice with consistent behavioral deficits. Furthermore, we have developed a novel analysis of the cylinder test by quantifying paw-dragging behavior. RESULTS: ET1 injections which damage deep layer neurons in the aFMC generate reproducible deficits on the staircase test. Cylinder test analysis showed no forelimb asymmetry post-injection; however, we observed a novel paw-dragging behavior in mice which is a positive sign of damage to the FMC. COMPARISON WITH EXISTING METHODS: Previous ET1 studies have demonstrated inconsistent behavioral deficits; however, targeting ET1 injections to the aFMC reliably results in staircase deficits. We show that analysis of paw-dragging behavior in the cylinder test is a more sensitive measure of damage to the FMC than the classical forelimb asymmetry analysis. CONCLUSIONS: We have developed a focal ischemic injury model in the mouse that results in reproducible behavioral deficits and can be used to test future regenerative therapies.
BACKGROUND: Despite the availability of numerous transgenic mouse lines to study the role of individual genes in promoting neural repair following stroke, few studies have availed of this technology, primarily due to the lack of a reproducible ischemic injury model in the mouse. Intracortical injections of Endothelin-1 (ET1) a potent vasoconstrictive agent, reliably produces focal infarcts with concomitant behavioral deficits in rats. In contrast, ET1infarcts in mice are significantly smaller and do not generate consistent behavioral deficits. NEW METHOD: We have modified the ET1ischemia model to target the anterior forelimb motor cortex (aFMC) and show that this generates a reproducible focal ischemic injury in mice with consistent behavioral deficits. Furthermore, we have developed a novel analysis of the cylinder test by quantifying paw-dragging behavior. RESULTS:ET1 injections which damage deep layer neurons in the aFMC generate reproducible deficits on the staircase test. Cylinder test analysis showed no forelimb asymmetry post-injection; however, we observed a novel paw-dragging behavior in mice which is a positive sign of damage to the FMC. COMPARISON WITH EXISTING METHODS: Previous ET1 studies have demonstrated inconsistent behavioral deficits; however, targeting ET1 injections to the aFMC reliably results in staircase deficits. We show that analysis of paw-dragging behavior in the cylinder test is a more sensitive measure of damage to the FMC than the classical forelimb asymmetry analysis. CONCLUSIONS: We have developed a focal ischemic injury model in the mouse that results in reproducible behavioral deficits and can be used to test future regenerative therapies.
Authors: Matthew A Edwardson; Ximing Wang; Brent Liu; Li Ding; Christianne J Lane; Caron Park; Monica A Nelsen; Theresa A Jones; Steven L Wolf; Carolee J Winstein; Alexander W Dromerick Journal: Neurorehabil Neural Repair Date: 2017-01-01 Impact factor: 3.919