Regular Article Assessing behavioural function following a pyramidotomy lesion of the corticospinal tract in adult mice Michelle L. Starkey a , Andrew W. Barritt a , Ping K. Yip a , Meirion Davies a , Frank P.T. Hamers b , Stephen B. McMahon a , Elizabeth J. Bradbury a, * a Neurorestoration Group, CARD Wolfson Wing, Hodgkin Building, King’s College London, Guy’s Campus, London Bridge, London SE1 IUL, UK b Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, The Netherlands Received 24 January 2005; revised 27 May 2005; accepted 27 June 2005 Available online 26 July 2005 Abstract We have developed a pyramidotomy model in mice to lesion the corticospinal tract at the level of the brainstem pyramidal tract, and evaluated the resultant impairments in motor function in a series of behavioural tests. Adult C57BL/6 mice received a unilateral pyramidotomy and a control group of mice underwent sham surgery. We studied the effects of this lesion on forepaw function using five behavioural paradigms, some of which have been widely used in rat studies but have not been fully explored in mice. The tests used were: a rearing test, which assesses forepaw use for weight support during spontaneous vertical exploration of a cylinder; a grid walking test, which assesses the ability to accurately place the forepaws during exploration of an elevated grid; a tape-removal test, which measures both sensory and motor function of the forepaw; a CatWalk automated gait analysis, which provides a number of quantitative measures including stride length and stride width during locomotion; and a staircase reaching task, which assesses skilled independent forepaw use. All tests revealed lesion effects on forepaw function with the tape removal, grid walking, rearing and CatWalk tests demonstrating robust effects throughout the testing period. The development of a pyramidotomy lesion model in mice, together with behavioural tests which can reliably measure functional impairments, will provide a valuable tool for assessing therapeutic strategies to promote regeneration and plasticity. D 2005 Elsevier Inc. All rights reserved. Keywords: Pyramidotomy; Corticospinal tract (CST); Pyramidal tract; Unilateral lesion; Mice; Regeneration; Plasticity; Forepaw function Introduction Following injury to the adult mammalian central nervous system (CNS), axonal regeneration and plasticity is extremely limited. Most of the functional deficits resulting from injury to the spinal cord are caused by the interruption of descending and ascending axonal tracts, and the persistence of these deficits is due to their failure to regenerate (Schwab and Bartholdi, 1996; Houle and Tessler, 2003; Selzer, 2003). This failure is thought to be due to the combination of a limited inherent regenerative capacity of the axons (Schwab and Bartholdi, 1996; Neumann and Woolf, 1999); an insufficiency of trophic factors (Widenfalk et al., 2001; Jones et al., 2001) and the presence of growth inhibitory molecules, such as chondroitin sulphate proteo- glycans (Fawcett and Asher, 1999; Silver and Miller, 2004) and myelin-associated neurite growth inhibitors (Schwab, 2002; McGee and Strittmatter, 2003; Filbin, 2003). Although a number of recent studies have demonstrated a capacity for some spinal systems to spontaneously sprout in the adult (Raineteau and Schwab, 2001; Weidner et al., 2001; Bareyre et al., 2004), the fact is that there is limited functional recovery following CNS injury and there is a great potential for enhancing CNS plasticity with the aim of promoting functional improvements. One recent focus has been to study intact systems following CNS injury, with the aim of enhancing plasticity of spared fibres. A number of studies have investigated 0014-4886/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2005.06.017 * Corresponding author. Fax: +44 20 7848 6165. E-mail address: elizabeth.bradbury@kcl.ac.uk (E.J. Bradbury). Experimental Neurology 195 (2005) 524 – 539 www.elsevier.com/locate/yexnr