Summary
Select functional outcome tests commonly used for evaluating sensorimotor and cognitive capacity in rodents with focal intracerebral ischemic or hemorrhagic injury are described, along with upgrades and issues of concern for translational research. An emphasis is placed on careful quantitative and qualitative assessment of acute and long-term behavioral deficits, and on avoidance of frequent pitfalls. Methods for detecting different degrees of injury and treatment-related improvements are included. Determining the true potential of an intervention requires a set of behavioral analyses that can monitor compensatory learning. In a number of preclinical outcome tests, animals can develop remarkably effective “tricks” that are difficult to detect but frequently lead to dramatic improvements in performance, particularly with repeated practice. However, some interventions may facilitate learning without promoting brain repair, but these may not translate into a meaningful level of benefit in the clinic. Additionally, it is important to determine whether there are any preinjury functional asymmetries in order to accurately assess damage-related changes in behavior. This is illustrated by the fact that some animals have chronic endogenous asymmetries and that others, albeit infrequently, can sustain a spontaneous cerebral stroke, without any experimental induction, that can lead to chronic deficits as reflected by behavioral, imaging, and histological analyses. Finally, a useful new modification of the water maze that involves moving the platform from trial to trial within the target quadrant is reviewed, and its advantages over the standard version are discussed.
Article PDF
Similar content being viewed by others
References
Benton AL. Jacque Loeb and the method of double stimulation. J Hist Med Allied Sci 1952; 11: 47–53.
Benton AL, Levin HS. An experimental study of ‘obscuration’. Neurology 1972;22: 1176–1181.
Schallert T, Whishaw IQ. Bilateral cutaneous stimulation of the somatosensory system in hemidecorticate rats. Behav Neurosci 1984;98: 518–540.
Schallert T, Whishaw IQ. Neonatal hemidecortication and bilateral cutaneous stimulation in rats. Devel Psychobiol 1985;18: 501–514.
Schallert T, Upchurch M, Lobaugh N, et al. Tactile extinction: distinguishing between sensorimotor and motor asymmetries in rats with unilateral nigrostriatal damage. Pharmacol Biochem Behav 1982;16: 455–462.
Schallert T, Upchurch M, Wilcox RE, Vaughn DM. Posture-independent sensorimotor analysis of inter-hemispheric receptor asymmetries in neostriatum. Pharmacol Biochem Behav 1983;18: 753–759.
Schallert T, Fleming SM, Leasure JL, Tillerson JL, Bland ST. CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, Parkinsonism, and spinal cord injury. Neuropharmacology 2000;39: 777–787.
Fleming SM, Delville Y, Schallert T. An intermittent, controlled-rate slow progressive degeneration model of Parkinson’s disease: antiparkinson effects of Sinemet and protective effects of methyl-phenidate. Behav Brain Res 2005;156: 201–213.
Markgraf CG, Green EJ, Hurwitz BE, et al. Sensorimotor and cognitive consequences of middle cerebral artery occlusion in rats. Brain Res 1992;575: 238–246.
Barth TM, Jones TA, Schallert T. Functional subdivisions of the rat somatic sensorimotor cortex. Behav Brain Res 1990;39: 73–95.
Schallert T, Hernandez TD, Barth TM. Recovery of function after brain damage: severe and chronic disruption by diazepam. Brain Res 1986;379: 104–111.
Hernandez TD, Schallert T. Seizures and recovery from experimental brain damage. Exp Neurol 1988;102: 318–324.
Hua Y, Schallert T, Keep RF, Wu J, Hoff JT, Xi G. Behavioral tests after intracerebral hemorrhage in the rat. Stroke 2002;33: 2478–2484.
Karhunen H, Virtanen T, Schallert T, Sivenius J, Jolkkonen J. Forelimb use after focal cerebral ischemia in rats treated with an alpha 2-adrenoceptor antagonist. Pharmacol Biochem Behav 2003; 74: 663–669.
Maclellan CL, Grams J, Adams K, Colbourne F. Combined use of a cytoprotectant and rehabilitation therapy after severe intracerebral hemorrhage in rats. Brain Res 2005;1063: 40–47.
Roof RL, Schielke GP, Ren X, Hall ED. A comparison of longterm functional outcome after 2 middle cerebral artery occlusion models in rats. Stroke 2001;32: 2648–2657.
Nakamura T, Xi G, Hua Y, Schallert T, Hoff JT, Keep RF. Intracerebral hemorrhage in mice: model characterization and application for genetically modified mice. J Cereb Blood Flow Metab 2004;24: 487–494.
Wu J, Hua Y, Keep RF, Schallert T, Hoff JT, Xi G. Oxidative brain injury from extravasated erythrocytes after intracerebral hemorrhage. Brain Res 2002;953: 45–52.
Li X, Blizzard KK, Zeng Z, DeVries AC, Hum PD, McCullough LD. Chronic behavioral testing after focal ischemia in the mouse: functional recovery and the effects of gender. Exp Neurol 2004; 187: 94–104.
Hua Y, Wu JM, Pecina S, et al. Ischemic preconditioning procedure induces behavioral deficits in the absence of brain injury? Neurolog Res 2005;27: 261–267.
Schallert T, Kozlowski DA, Humm JL, Cocke RR. Use-dependent structural events in recovery of function. Adv Neurol 1997;73: 229–238.
Tillerson JL, Cohen AD, Philhower J, Miller GW, Zigmond MJ, Schallert T. Forced limb-use effects on the behavioral and neurochemical effects of 6-hydroxydopamine. J Neurosci 2001;21: 4427–4435.
Tillerson JL, Cohen AD, Caudle WM, Zigmond MJ, Schallert T, Miller GW. Forced nonuse in unilateral parkinsonian rats exacerbates injury. J Neurosci 2002;22: 6790–6799.
Schallert T, Tillerson JL. Intervention strategies for degeneration of dopamine neurons in parkinsonism: optimizing behavioral assessment of outcome. In: Emerich DF, Dean RLI, Sanberg PR, eds. CNS diseases: innovate models of CNS diseases from molecule to therapy. Totowa, New Jersey: Humana Press; 2000: 131–151.
Woodlee MT, Asseo-Garcia AM, Zhao X, Liu SJ, Jones TA, Schallert T. Testing forelimb placing “across the midline” reveals distinct, lesion-dependent patterns of recovery in rats. Exp Neurol 2005;191: 310–317.
Schallert T, Woodlee MT. Brain-dependent movements and cerebral-spinal connections: Key targets of cellular and behavioral enrichment in CNS injury models. J Rehabil Res Dev 2003;40: S9-S17.
Wolgin DL, Kehoe P. Cortical KC1 reinstates forelimb placing following damage to the internal capsule. Physiol Behav 1983;31: 197–202.
Jones TA, Schallert T. Overgrowth and pruning of dendrites in adult rats recovering from neocortical damage. Brain Res 1992; 581: 156–160.
Jones TA, Schallert T. Use-dependent growth of pyramidal neurons after neocortex damage. J Neurosci 1994;14: 2140–2152.
Schallert T, Leasure JL, Kolb B. Experience-associated structural events, subependymal proliferation activity, and functional recovery after injury to the central nervous system: a review. J Cereb Blood Flow Metab 2000;20: 1513–1528.
Chu CJ, Jones TA. Experience-dependent structural plasticity in cortex heterotopic to focal cortical damage. Exp Neurol 2002; 1666: 403–414.
Luke LM, Allred RP, Jones TA. Unilateral ischemic sensorimotor cortical damage induces contralesional synaptogenesis and enhances skilled forelimb reaching with the ipsilateral forelimb in adult male rats. Synapse 2004;54: 187–199.
Zhang L, Schallert T, Zhang ZG, et al. A test for detecting longterm sensorimotor dysfunction in the mouse after focal cerebral ischemia. J Neurosci Methods 2002;117: 207–214.
Schallert T, Woodlee MT, Fleming SM. Disentangling multiple types of recovery from brain injury. In: Krieglstein J, Klumpp S, eds. Pharmacology of cerebral ischemia. Stuttgart: Medpharm Scientific Publishers; 2002: 201–216.
Bliss T, Kelly S, Ankur S, et al. Transplantation of hNT neurons into the ischemic cortex: cell survival and effect on sensorimotor behavior. J Neurosci Res 2006;83: 1004–1014.
Barth TM, Grant ML, Schallert T. Effects of MK-801 on recovery from sensorimotor cortex lesions. Stroke 1990;21: 153–157.
Morris RGM. Spatial localization does not require the presence of local cues. Learn Motiv 1981;12: 239–260.
Choi SH, Woodlee MT, Hong JJ, Schallert T. A simple modification of the water maze test to enhance daily detection of spatial memory in rats and mice. J Neurosci Methods 2006;156: 182–193.
Morris RGM, Garrud P, Rawlins HN. Place navigation impaired in rats with hippocampal lesions. Nature 1982;297: 681–683.
Sutherland RJ, Kolb B, Whishaw IQ. Spatial mapping: definitive disruption by hippocampal or medial frontal cortical damage in the rat. Neurosci Lett 1982;31: 271–276.
Russell JC, Towns DR, Anderson SH, Clout MN. Intercepting the first rat ashore. Nature 2005;437: 1107.
Whishaw IQ, Schallert T. Hippocampal RSA (theta), apnea, bradycardia and effects of atropine during underwater swimming in the rat. Electroencephalogr Clin Neurophysiol 1977;42: 389–396.
D’Hooge R, De Deyn PP. Applications of the Morris water maze in the study of learning and memory. Brain Res Rev 2001;36: 60–90.
Day LB, Schallert T. Anticholinergic effects on acquisition of place learning in the Morris water task: spatial mapping deficit or inability to inhibit nonplace strategies? Behav Neurosci 1996;110: 998–1005.
Day LB, Weisand M, Sutherland RJ, Schallert T. The hippocampus is not necessary for a place response but may be necessary for pliancy. Behav Neurosci 1999;113: 914–924.
Whishaw IQ, Cassel JC, Jarrad LE. Rats with fimbria-fornix lesions display a place response in a swimming pool: a dissociation between getting there and knowing where. J Neurosci 1995;15: 5779–5788.
Kimble DP. Hippocampus and internal inhibition. Psychol Bull 1968;70: 285–295.
Karhunen H, Pitkanen A, Virtanen T, et al. Long-term functional consequences of transient occlusion of the middle cerebral artery in rats: a 1-year follow-up of the development of epileptogenesis and memory impairment in relation to sensorimotor deficits. Epilepsy Res 2003;54: 1–10.
Hodges H. Maze procedures: the radial-arm and water maze compared. Brain Res Cogn Brain Res 1996;3–4: 167–181.
Gerlai R, Roder J. Spatial and nonspatial learning in mice: effects of S100 beta overexpression and age. Neurobiol Learn Mem 1996; 66: 143–154.
Lindner MD, Schallert T. Aging and atropine effects on spatial navigation in the Morris water task. Behav Neurosci 1988;102: 621–634.
Buresova O, Krekule I, Zahalka A, Bures J. On-demand platform improves accuracy of the Morris water maze procedure. J Neurosci Methods 1985;15: 63–72.
Spooner RI, Thomson A, Hall J, Morris RG, Salter SH. The Atlantis platform: a new design and further developments of Buresova’s on-demand platform for the water maze. Learn Mem 1994;1: 203–211.
Whishaw IQ. Lateralization and reaching skill related: results and implications from a large sample of Long-Evans rats. Behav Brain Res 1992;52: 45–48.
Montoya CP, Campbell-Hope LJ, Pemberton KD, Dunnett SB. The “staircase test”: a measure of independent forelimb reaching and grasping abilities in rats. J Neurosci Methods 1991;36: 219–228.
Adkins-Muir DL, Jones TA. Cortical electrical stimulation combined with rehabilitative training: enhanced functional recovery and dendritic plasticity following focal cortical ischemia in rats. Neurol Res 2003;25: 780–788.
Cenci MA, Whishaw IQ, Schallert T. Animal models of neurological deficits: how relevant is the rat? Nat Rev Neurosci 2002;3: 574–579.
Whishaw IQ, Schallert T, Kolb B. An analysis of feeding and sensorimotor abilities of rats after decortication. J Comp Physiol Psychol 1981;95: 85–103.
Stoltz S, Humm JL, Schallert T. Cortical injury impairs contralateral forelimb immobility during swimming: a simple test for loss of inhibitory motor control. Behav Brain Res 1999;106: 127–132.
Kolb B, Tomie JA. Recovery from early cortical damage in rats. IV. Effects of hemidecortication at 1, 5, or 10 days of age on cerebral anatomy and behavior. Behav Brain Res 1988;28: 259–274.
Felt BT, Schallert T, Shao J, Liu Y, Li X, Barks JD. Early appearance of functional deficits after neonatal excitotoxic and hypoxicischemic injury: fragile recovery after development and role of the NMDA receptor. Dev Neurosci 2002;24: 418–425.
Kleim, JA, Jones TA, Schallert T. Motor enrichment and the induction of plasticity before and after brain injury. Neurochem Res 2003;28: 1757–1769.
Risedal A, Zeng J, Johansson BB. Early training may exacerbate brain damage after focal brain ischemia in the rat. J Cereb Blood Flow Metab 1999;19: 997–1003.
DeBow SB, McKenna JE, Kolb B, et al. Immediate constraint-induced movement therapy causes local hyperthermia and exacerbates cerebral injury in rats. Can J Physiol Pharmacol 2004;82: 231–237.
Bland ST, Schallert T, Strong R, Aronowski J, Grotta JC, Feeney DM. Early exclusive use of the affected forelimb after moderate transient focal ischemia in rats: functional and anatomic outcome. Stroke 2000;31: 1144–1152.
Schallert T, Fleming SM, Woodlee MT. Should the injured and intact hemispheres be treated differently during the early phases of physical restorative therapy in experimental stroke or parkinsonism? Phys Med Rehab Clin 2003;14: 1–20.
Schallert T, Lindner MD. Rescuing neurons from trans-synaptic degeneration after brain damage: helpful, harmful, or neutral in recovery of function. Can J Psychol 1990;44: 276–292.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Schallert, T. Behavioral tests for preclinical intervention assessment. NeuroRX 3, 497–504 (2006). https://doi.org/10.1016/j.nurx.2006.08.001
Published:
Issue Date:
DOI: https://doi.org/10.1016/j.nurx.2006.08.001