Animal models of neurological deficits: how relevant is the rat?

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Abstract

Animal models of neurological deficits are essential for the assessment of new therapeutic options. It has been suggested that rats are not as appropriate as primates for the symptomatic modelling of disease, but a large body of data argues against this view. Comparative analyses of movements in rats and primates show homology of many motor patterns across species. Advances have been made in identifying rat equivalents of akinesia, tremor, postural deficits and dyskinesia, which are relevant to Parkinson's disease. Rat models of hemiplegia, neglect and tactile extinction are useful in assessing the outcome of ischaemic or traumatic brain injury, and in monitoring the effects of therapeutic interventions. Studies in rodents that emphasize careful behavioural analysis should continue to be developed as effective and inexpensive models that complement studies in primates.

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References

  1. 1

    Iwaniuk, A. N. & Whishaw, I. Q. On the origin of skilled forelimb movements. Trends Neurosci. 23, 372–376 (2000).

  2. 2

    Metz, G. A., Farr, T., Ballermann, M. & Whishaw, I. Q. Chronic levodopa therapy does not improve skilled reach accuracy or reach range on a pasta matrix reaching task in 6-OHDA dopamine-depleted (hemi-Parkinson analogue) rats. Eur. J. Neurosci. 14, 27–37 (2001).

  3. 3

    Whishaw, I. Q. et al. Impairment of pronation, supination, and body co-ordination in reach-to-grasp tasks in human Parkinson's disease (PD) reveals homology to deficits in animal models. Behav. Brain Res. (in the press).

  4. 4

    Rouiller, E. M., Liang, F. Y., Moret, V. & Wiesendanger, M. Trajectory of redirected corticospinal axons after unilateral lesion of the sensorimotor cortex in neonatal rat; a Phaseolus vulgaris-leucoagglutinin (PHA-L) tracing study. Exp. Neurol. 114, 53–65 (1991).

  5. 5

    Valverde, F. The pyramidal tract in rodents. A study of its relationship with the posterior column nuclei, dorsolateral reticular formation of the medulla oblongata, and cervical spinal cord. Z. Zellforsch. Mikrosk. Anat. 71, 298–363 (1996).

  6. 6

    Nudo, R. J. & Masterton, R. B. Descending pathways to the spinal cord, III. Sites of origin of the corticospinal tract. J. Comp. Neurol. 296, 559–583 (1990).

  7. 7

    Zilles, K. in The Cerebral Cortex of the Rat (eds Kolb, B. & Tees, R. C.) 77–112 (MIT Press, Cambridge, Massachusetts, 1990).

  8. 8

    Nudo, R. J. & Masterton, R. B. Descending pathways to the spinal cord, IV. Some factors related to the amount of cortex devoted to the corticospinal tract. J. Comp. Neurol. 296, 584–597 (1990).

  9. 9

    Passingham, R. E., Myers, C., Rawlins, N., Lightfoot, V. & Fearn, S. Premotor cortex in the rat. Behav. Neurosci. 102, 101–109 (1988).

  10. 10

    Graybiel, A. M. Building action repertoires: memory and learning functions of the basal ganglia. Curr. Opin. Neurobiol. 5, 733–741 (1995).

  11. 11

    Redgrave, P., Prescott, T. J. & Gurney, K. The basal ganglia: a vertebrate solution to the selection problem? Neuroscience 89, 1009–1023 (1999).

  12. 12

    Dirnagl, U., Iadecola, C. & Moskowitz, M. A. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 22, 391–397 (1999).

  13. 13

    Boyce, S., Rupniak, N. M. J., Steventon, M. J. & Iversen, S. D. Characterization of dyskinesias induced by l-DOPA in MPTP-treated squirrel monkeys. Psychopharmacology 102, 21–27 (1990).

  14. 14

    Gomez-Mancilla, B. & Bedard, P. J. Effect of nondopaminergic drugs on l-DOPA-induced dyskinesias in MPTP-treated monkeys. Clin. Neuropharmacol. 16, 418–427 (1993).

  15. 15

    Langston, J. W., Quik, M., Petzinger, G., Jakowec, M. & Di Monte, D. A. Investigating levodopa-induced dyskinesias in the parkinsonian primate. Ann. Neurol. 47, S79–S89 (2000).

  16. 16

    Löschmann, P. A. et al. Motor activity following the administration of selective D-1 and D-2 dopaminergic drugs to MPTP-treated common marmosets. Psychopharmacology 109, 49–56 (1992).

  17. 17

    Pearce, R. K., Banerji, T., Jenner, P. & Marsden, C. D. De novo administration of ropinirole and bromocriptine induces less dyskinesia than l-DOPA in the MPTP-treated marmoset. Mov. Disord. 13, 234–241 (1998).

  18. 18

    Schneider, J. S. Levodopa-induced dyskinesias in parkinsonian monkeys: relationship to extent of nigrostriatal damage. Pharmacol. Biochem. Behav. 34, 193–196 (1989).

  19. 19

    Salamone, J. D. et al. Tremulous jaw movements in rats: a model of parkinsonian tremor. Prog. Neurobiol. 56, 591–611 (1998).

  20. 20

    Staal, R. G., Hogan, K. A., Liang, C. L., German, D. C. & Sonsalla, P. K. In vitro studies of striatal vesicles containing the vesicular monoamine transporter (VMAT2): rat versus mouse differences in sequestration of 1-methyl-4-phenylpyridinium. J. Pharmacol. Exp. Ther. 293, 329–335 (2000).

  21. 21

    Sundstrom, E. & Samuelsson, E. B. Comparison of key steps in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in rodents. Pharmacol. Toxicol. 81, 226–231 (1997).

  22. 22

    Ungerstedt, U. 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur. J. Pharmacol. 5, 107–110 (1968).

  23. 23

    Schallert, T. & Wilcox, R. E. in Neuromethods (Series 1: Neurochemistry), General Neurochemical Techniques (eds Boulton, A. A. & Baker, G. B.) 343–387 (Humana, Clifton, New Jersey, 1985).

  24. 24

    Kirik, D., Rosenblad, C. & Björklund, A. Characterization of behavioral and neurodegenerative changes following partial lesions of the nigrostriatal dopamine system induced by intrastriatal 6-hydroxydopamine in the rat. Exp. Neurol. 152, 259–277 (1998).

  25. 25

    Sauer, H. & Oertel, W. H. Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: a combined retrograde tracing and immunocytochemical study in the rat. Neuroscience 59, 401–415 (1994).

  26. 26

    Wolfarth, S., Konieczny, J., Smialowska, M., Schulze, G. & Ossowska, K. Influence of 6-hydroxydopamine lesion of the dopaminergic nigrostriatal pathway on the muscle tone and electromyographic activity measured during passive movements. Neuroscience 74, 985–996 (1996).

  27. 27

    Rodter, A., Winkler, C., Samii, M. & Nikkhah, G. Complex sensorimotor behavioral changes after terminal striatal 6-OHDA lesion and transplantation of dopaminergic embryonic micrografts. Cell Transplant. 9, 197–214 (2000).

  28. 28

    Schallert, T., Whishaw, I. Q., Ramirez, V. D. & Teitelbaum, P. Compulsive abnormal walking caused by anticholinergics in akinetic, 6-hydroxydopamine-treated rats. Science 199, 1461–1463 (1978).

  29. 29

    Marshall, J. F., Richardson, J. S. & Teitelbaum, P. Nigrostriatal bundle damage and the lateral hypothalamic syndrome. J. Comp. Physiol. Psychol. 87, 808–830 (1974).

  30. 30

    Schallert, T., De Ryck, M., Whishaw, I. Q., Ramirez, V. D. & Teitelbaum, P. Excessive bracing reactions and their control by atropine and l–DOPA in an animal analog of parkinsonism. Exp. Neurol. 64, 33–43 (1979).

  31. 31

    Berardelli, A., Rothwell, J. C., Thompson, P. D. & Hallett, M. Pathophysiology of bradykinesia in Parkinson's disease. Brain 124, 2131–2146 (2001).

  32. 32

    Buonamici, M., Maj, R., Pagani, F., Rossi, A. C. & Khazan, N. Tremor at rest episodes in unilaterally 6-OHDA-induced substantia nigra lesioned rats: EEG–EMG and behavior. Neuropharmacology 25, 323–325 (1986).

  33. 33

    Lindner, M. D. et al. Incomplete nigrostriatal dopaminergic cell loss and partial reductions in striatal dopamine produce akinesia, rigidity, tremor and cognitive deficits in middle-aged rats. Behav. Brain Res. 102, 1–16 (1999).

  34. 34

    Schallert, T., Petrie, B. F. & Whishaw, I. Q. Neonatal dopamine depletion: spared and unspared sensorimotor and attentional disorders and effects of further depletion in adulthood. Psychobiology 17, 386–396 (1989).

  35. 35

    Schwarting, R. K. W. & Huston, J. P. The unilateral 6-hydroxydopamine lesion model in behavioural brain research. Analysis of functional deficits, recovery and treatments. Prog. Neurobiol. 50, 275–331 (1996).

  36. 36

    Annett, L. E., Rogers, D. C., Hernandez, T. D. & Dunnett, S. B. Behavioural analysis of unilateral monoamine depletion in the marmoset. Brain 115, 825–856 (1992).

  37. 37

    Dunnett, S. B. & Robbins, T. W. The functional role of mesotelencephalic dopamine systems. Biol. Rev. Camb. Philos. Soc. 67, 491–518 (1992).

  38. 38

    Ungerstedt, U. 6-hydroxydopamine-induced degeneration of the nigrostriatal dopamine pathway: the turning syndrome. Pharmacol Ther 2, 37–40 (1976). | PubMed |

  39. 39

    Lundblad, M. et al. Pharmacological validation of behavioural measures of dyskinesia and akinesia in a rat model of Parkinson's disease. Eur. J. Neurosci. 15, 120–132 (2002).

  40. 40

    Metz, G. A. & Whishaw, I. Q. Drug-induced rotation in unilateral dopamine-depleted rats is not correlated with end-point or qualitative measures of forelimb or hindlimb motor performance. Neuroscience 111, 325–336 (2002).

  41. 41

    Schallert, T., Norton, D. & Jones, T. A. A clinically relevant unilateral model of Parkinsonian akinesia. J. Neural Transplant. Plast. 3, 332–333 (1992).

  42. 42

    Schallert, T. & Tillerson, J. L. in Central Nervous System Diseases: Innovative Models of CNS Diseases from Molecule to Therapy (eds Emerich, D. F., Dean III, R. L. & Sanberg, P. R.) 131–151 (Humana, Totowa, New Jersey, 2000).

  43. 43

    Barker, R. & Dunnett, S. B. Ibotenic acid lesions of the striatum reduce drug-induced rotation in the 6-hydroxydopamine-lesioned rat. Exp. Brain. Res. 101, 365–374 (1994).

  44. 44

    Isacson, O. Behavioral effects and gene delivery in a rat model of Parkinson's disease. Science 269, 856–857 (1995).

  45. 45

    Schallert, T., Upchurch, M., Wilcox, R. E. & Vaughn, D. M. Posture-independent sensorimotor analysis of interhemispheric receptor asymmetries in neostriatum. Pharmacol. Biochem. Behav. 18, 753–759 (1983).

  46. 46

    Miklyaeva, E. I., Martens, D. J. & Whishaw, I. Q. Impairments and compensatory adjustments in spontaneous movement after unilateral dopamine depletion in rats. Brain Res. 681, 23–40 (1995).

  47. 47

    Carli, M., Evenden, J. L. & Robbins, T. W. Depletion of unilateral striatal dopamine impairs initiation of contralateral actions and not sensory attention. Nature 313, 679–682 (1985).

  48. 48

    Spirduso, W. W. et al. Reactive capacity: a sensitive behavioral marker of movement initiation and nigrostriatal dopamine function. Brain Res. 335, 45–54 (1985).

  49. 49

    Montoya, C. P., Campbell-Hope, L. J., Pemberton, K. D. & Dunnett, S. B. The 'staircase test': a measure of independent forelimb reaching and grasping abilities in rats. J. Neurosci. Methods 36, 219–228 (1991).

  50. 50

    Nutt, J. G. Levodopa-induced dyskinesia: review, observations and speculations. Neurology 40, 340–345 (1990).

  51. 51

    Clarke, C. E., Boyce, S., Robertson, R. G., Sambrook, M. A. & Crossman, A. R. Drug-induced dyskinesia in primates rendered hemiparkinsonian by intracarotid administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). J. Neurol. Sci. 90, 307–314 (1989).

  52. 52

    Brotchie, J. M. & Fox, S. H. Quantitative assessment of dyskinesias in subhuman primates. Mov. Disord. 14, 40–47 (1999).

  53. 53

    Hagell, P. & Widner, H. Clinical rating of dyskinesias in Parkinson's disease: use and reliability of a new rating scale. Mov. Disord. 14, 448–455 (1999).

  54. 54

    Cenci, M. A., Lee, C. S. & Björklund, A. l-DOPA-induced dyskinesia in the rat is associated with striatal overexpression of prodynorphin- and glutamic acid decarboxylase mRNA. Eur. J. Neurosci. 10, 2694–2706 (1998).

  55. 55

    Lee, C. S., Cenci, M. A., Schulzer, M. & Bjorklund, A. Embryonic ventral mesencephalic grafts improve levodopa-induced dyskinesia in a rat model of Parkinson's disease. Brain 123, 1365–1379 (2000).

  56. 56

    Winkler, C., Kirik, D., Björklund, A. & Cenci, M. A. l-DOPA-induced dyskinesia in the intrastriatal 6-hydroxydopamine lesion model of Parkinson's disease: relation to motor and cellular parameters of nigrostriatal function. Neurobiol. Dis. (in the press).

  57. 57

    Brotchie, J. M., Henry, B., Hille, C. J. & Crossman, A. R. in Advances in Neurology. Dystonia 3 (eds Fahn, S., Marsden, C. D. & DeLong, M. R.) 41–52 (Lippincott–Raven, Philadelphia, Pennsylvania, 1998).

  58. 58

    Andersson, M., Hilbertson, A. & Cenci, M. A. Striatal fosB expression is causally linked with l-DOPA-induced abnormal involuntary movements and the associated upregulation of striatal prodynorphin mRNA in a rat model of Parkinson's disease. Neurobiol. Dis. 6, 461–474 (1999).

  59. 59

    Doucet, J.-P. et al. Chronic alterations in dopaminergic neurotransmission produce a persistent elevation of Δ-FosB-like proteins in both the rodent and primate striatum. Eur. J. Neurosci. 8, 365–381 (1996).

  60. 60

    Johansson, P. A., Andersson, M., Andersson, K. E. & Cenci, M. A. Alterations in cortical and basal ganglia levels of opioid receptor binding in a rat model of l-DOPA-induced dyskinesia. Neurobiol. Dis. 8, 220–239 (2001).

  61. 61

    Piccini, P., Weeks, R. A. & Brooks, D. J. Alterations in opioid receptor binding in Parkinson's disease patients with levodopa-induced dyskinesias. Ann. Neurol. 42, 720–726 (1997).

  62. 62

    Kanda, T. et al. Adenosine A2A antagonist: a novel antiparkinsonian agent that does not provoke dyskinesia in parkinsonian monkeys. Ann. Neurol. 43, 507–513 (1998).

  63. 63

    Bezard, E., Brotchie, J. M. & Gross, C. E. Pathophysiology of levodopa-induced dyskinesia: potential for new therapies. Nature Rev. Neurosci. 2, 577–588 (2001).

  64. 64

    Chase, T. N. Levodopa therapy: consequences of the nonphysiologic replacement of dopamine. Neurology 50, S17–S25 (1998).

  65. 65

    Andersson, M., Konradi, C. & Cenci, M. A. CREB is required for dopamine-dependent gene expression in the intact but not the dopamine-denervated striatum. J. Neurosci. 21, 9930–9943 (2001).

  66. 66

    Creese, I. & Iversen, S. D. Blockage of amphetamine induced motor stimulation and stereotypy in the adult rat following neonatal treatment with 6-hydroxydopamine. Brain Res. 55, 369–382 (1973).

  67. 67

    McLean, P. D. Effects of lesions of globus pallidus on species-typical display behavior of squirrel monkeys. Brain Res. 149, 175–196 (1978).

  68. 68

    Alonso de Lecinana, M., Diez-Tejedor, E., Carceller, F. & Roda, J. M. Cerebral ischemia: from animal studies to clinical practice. Should the methods be reviewed? Cerebrovasc. Dis. 11, 20–30 (2001).

  69. 69

    Fuxe, K. et al. Endothelin-1 induced lesions of the frontoparietal cortex of the rat. A possible model of focal cortical ischemia. Neuroreport 8, 2623–2629 (1997).

  70. 70

    Ginsberg, M. D. & Busto, R. in Cerebrovascular Diseases. Pathophysiology, Diagnosis, and Management (eds Ginsberg, M. D. & Bogousslavsky, J.) 14–35 (1998).

  71. 71

    Kline, A. E. & Dixon, C. E. in Head Trauma: Basic, Preclinical and Clinical Directions (eds Miller, L. P., Hayes, R. L. & Newcomb, J. K.) 65–84 (John Wiley & Sons, New York, 2001).

  72. 72

    Koehler, R. C. in Cerebrovascular Diseases. Pathophysiology, Diagnosis, and Management (eds Ginsberg, M. D. & Bogousslavsky, J.) 36–51 (Blackwell Science, Boston, Massachusetts, 1998).

  73. 73

    Corbett, D. & Nurse, S. The problem of assessing effective neuroprotection in experimental cerebral ischemia. Prog. Neurobiol. 54, 531–548 (1998).

  74. 74

    DeVries, A. C., Nelson, R. J., Traystman, R. J. & Hurn, P. D. Cognitive and behavioral assessment in experimental stroke research: will it prove useful? Neurosci. Biobehav. Rev. 25, 325–342 (2001).

  75. 75

    Schallert, T., Leasure, J. L. & Kolb, B. Experience-associated structural events, subependymal cellular proliferative activity, and functional recovery after injury to the central nervous system. J. Cereb. Blood Flow Metab. 20, 1513–1528 (2000).

  76. 76

    Kolb, B. & Whishaw, I. Q. Earlier is not always better: behavioral dysfunction and abnormal cerebral morphogenesis following neonatal cortical lesions in the rat. Behav. Brain Res. 17, 25–43 (1985).

  77. 77

    Schallert, T., Fleming, S. M., Leasure, J. L., Tillerson, J. L. & Bland, S. T. CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury. Neuropharmacology 39, 777–787 (2000).

  78. 78

    Lees, K. R. & Diener, H.-C. in Cerebral Blood Flow and Metabolism (eds Edvinsson, L. & Krause, D. N.) 452–456 (Lippincott, Williams & Wilkins, Philadelphia, Pennsylvania, 2002).

  79. 79

    Li, Z. et al. A test for detecting long-term sensorimotor dysfunction in the mouse after focal cerebral ischemia. J. Neurosci. Methods (in the press).

  80. 80

    Schallert, T., Fleming, S. & Bland, S. T. in Pharmacology of Cerebral Ischemia (eds Krieglstein, J. & Klumpp, S.) 329–344 (Medpharm Scientific, Stuttgart, 2000).

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Acknowledgements

We wish to thank M. Woodlee and P. Whishaw for their help, and P. Hagell, M.-L. Smith and P. Mohapel for critical discussions.

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Correspondence to M. Angela Cenci.

Supplementary information

Movie 1 | Skilled limb movements in an intact ratA control rat reaches for a food pellet using normal movements. A detailed analysis of its skilled limb movements reveals very similar motor components in humans and in rats. (MOV 772 kb)

Movie 2 | Tremor at restOccasional resting tremor has been observed in the wrist and the paw of rats that have been lesioned with 6-hydroxydopamine (6-OHDA). Tremor occurs when the forelimb is not being used for movement or postural support in the home cage. (MOV 196 kb)

Movie 3 | Akinesia in a rat model of Parkinson’s disease Severe unilateral loss of nigrostriatal dopamine terminals in a rat 1.6 years after the infusion of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle in the right hemisphere. The rat shows deficits in movement initiation (spontaneous stepping) with its left, but not its right, forelimb. In this test, the experimenter does not impose weight shifting; rather, the rat is allowed to initiate stepping on its own. Note that normal rats use primarily their forelimbs, rather than their hindlimbs, to initiate walking. (MOV 400 kb)

Movie 4 | The cylinder testThe cylinder test: Limb-use asymmetry caused by unilateral loss of nigrostriatal dopamine after infusion of 6-hydroxydopamine (6-OHDA) into the nigrostriatal projections of the left hemisphere. The rat shows a preference for the left forelimb when initiating weight-shifting movements during vertical/lateral exploration. Use of the right forelimb is impaired; it is not used independently for weight shifts, support or stepping movements on the walls of the cylinder. The level of dopamine-terminal loss is correlated with percentage preferential use of the non-impaired forelimb. (MOV 776 kb)

Movie 5 | Skilled limb movements in a 6-OHDA-lesioned ratRats with unilateral 6-hydroxydopamine (6-OHDA) lesions show abnormalities in both quantitative and qualitative aspects of reach-to-grasp movements on the side contralateral to dopamine depletion. When approaching a target, the impaired limb makes fragmented rather than concurrent movements, and shows incomplete pronation on the substrate. The deficits are partially compensated for using whole-body movements. (MOV 861 kb)

Movie 6 | Minimal dyskinesiaWhen treated with 3,4-dihydroxyphenylalanine (l-DOPA), rats with unilateral 6-hydroxydopamine (6-OHDA) lesions can show abnormal involuntary movements (AIMs), which mainly affect the forelimb contralateral to the lesion, the trunk and the orofacial musculature. These abnormal involuntary movements can be quantified on the basis of their topographical distribution, amplitude and duration; that is, using the same criteria that are used in the clinic. This sequence of movies shows rats with l-DOPA-induced AIMs of increasing amplitude and severity. (MOV 921 kb)

Movie 7 | Noticeable dyskinesia (MOV 951 kb)

Movie 8 | Moderate dyskinesia (MOV 966 kb)

Movie 9| Severe dyskinesia (MOV 1363 kb)

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DATABASES

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amantadine

bromocriptine

clozapine

l-DOPA

OMIM

Parkinson's disease

FURTHER INFORMATION

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Parkinson disease

stroke

traumatic central nervous system injury

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Cenci, M., Whishaw, I. & Schallert, T. Animal models of neurological deficits: how relevant is the rat?. Nat Rev Neurosci 3, 574–579 (2002) doi:10.1038/nrn877

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