RESTORATION OF COMPLEX SENSORIMOTOR BEHAVIOR AND SKILLED FORELIMB USE BY A MODIFIED NIGRAL CELL-SUSPENSION TRANSPLANTATION APPROACH IN THE RAT PARKINSON MODEL

被引:114
作者
NIKKHAH, G
DUAN, WM
KNAPPE, U
JODICKE, A
BJORKLUND, A
机构
[1] NORDSTADT HOSP, NEUROSURG CLIN, W-3000 HANNOVER, GERMANY
[2] UNIV LUND HOSP, DEPT NEUROL, RESTORAT NEUROL UNIT, S-22185 LUND, SWEDEN
关键词
D O I
10.1016/0306-4522(93)90559-X
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
While intrastriatal transplants of dopamie-rich ventral mesencephalic tissue are effective in reversing a variety of drug-induced behaviors in the rat Parkinson model, previous studies have failed to obtain significant graft-induced effects on deficits in certain aspects of complex sensorimotor behaviors. In the present study we have applied a modified cell suspension transplantation procedure, which allows more reproducible and consistent ventral mesencephalic transplants of large size, as well as more wide-spread distribution of the ventral mesencephalic tissue over multiple graft sites within the denervated caudate-putamen. Using this approach it has for the first time been possible to obtain significant amelioration of the lesion-induced deficits in skilled forelimb use and in the rats ability to switch from one behavior (eating) to another (orientation towards tactile stimuli), so-called disengage behavior. Rats with unilateral 6-hydroxydopamine lesions of the mesostriatal dopamine pathway received a total of 450,000 fetal ventral mesenoephalic cells, implanted either as two large deposits along a single injection tract (''Macro'' grafts), or as 18 small deposits along six injection tracts in the head of the denervated caudate-putamen (''Micro'' grafts) and the behavioral changes were studied up to three months after transplantation. On the drug-induced tests, both types of transplants reversed amphetamine- and D1-receptor agonist-induced turning, and produced a partial (50-75%) reduction in apomorphine-induced and D2-receptor agonist-induced turning. On the spontaneous sensorimotor tests, both types of grafts reversed the deficit in simple sensorimotor orientation. In addition, the Micro-grafted animals (which produced the most extensive reinnervation of the denervated striatum) showed a significant improvement in skilled forelimb use and in response latency in the disengage behavior test. Although the large sized Macro-grafted animals showed a similar trend, it did not reach significance. Moreover, the Micro grafts had a more pronounced effect on spontaneous turning behavior in a conditioned response test. The improvement in response latency in the disengage test was significantly correlated with the dopamine level in the nucleus accumbens, whereas the magnitude of the conditioned turning response was significantly correlated with the dopamine levels in the head of the caudate-putamen. The results show that intrastriatal nigral transplants, despite their ectopic placement, can ameliorate lesion-induced deficits also in more complex sensorimotor behaviors. This improved graft effect is likely to depend on both extensive dopaminergic reinnervation throughout the head of the caudate-putamen, as well as on closer integration of the grafted nigral tissue with the host striatal circuitry.
引用
收藏
页码:33 / 43
页数:11
相关论文
共 36 条
[11]   DOPAMINE-RICH GRAFTS AMELIORATE WHOLE-BODY MOTOR ASYMMETRY AND SENSORY NEGLECT BUT NOT INDEPENDENT LIMB USE IN RATS WITH 6-HYDROXYDOPAMINE LESIONS [J].
DUNNETT, SB ;
WHISHAW, IQ ;
ROGERS, DC ;
JONES, GH .
BRAIN RESEARCH, 1987, 415 (01) :63-78
[12]  
DUNNETT SB, 1983, ACTA PHYSIOL SCAND, P29
[13]  
DUNNETT SB, 1983, ACTA PHYSIOL SCAND, P39
[14]   EFFECTS OF DOPAMINE-RICH GRAFTS ON CONDITIONED ROTATION IN RATS WITH UNILATERAL 6-HYDROXYDOPAMINE LESIONS [J].
DUNNETT, SB ;
WHISHAW, IQ ;
JONES, GH ;
ISACSON, O .
NEUROSCIENCE LETTERS, 1986, 68 (01) :127-133
[15]   GRAFTS OF EMBRYONIC SUBSTANTIA NIGRA REINNERVATING THE VENTROLATERAL STRIATUM AMELIORATE SENSORIMOTOR IMPAIRMENTS AND AKINESIA IN RATS WITH 6-OHDA LESIONS OF THE NIGROSTRIATAL PATHWAY [J].
DUNNETT, SB ;
BJORKLUND, A ;
STENEVI, U ;
IVERSEN, SD .
BRAIN RESEARCH, 1981, 229 (01) :209-217
[16]   ELECTROPHYSIOLOGICAL CHARACTERISTICS OF CELLS WITHIN MESENCEPHALON SUSPENSION GRAFTS [J].
FISHER, LJ ;
YOUNG, SJ ;
TEPPER, JM ;
GROVES, PM ;
GAGE, FH .
NEUROSCIENCE, 1991, 40 (01) :109-122
[17]  
FREED WJ, 1991, RESTOR NEUROL NEUROS, V3, P109, DOI 10.3233/RNN-1991-3301
[18]   PHASIC VERSUS TONIC DOPAMINE RELEASE AND THE MODULATION OF DOPAMINE SYSTEM RESPONSIVITY - A HYPOTHESIS FOR THE ETIOLOGY OF SCHIZOPHRENIA [J].
GRACE, AA .
NEUROSCIENCE, 1991, 41 (01) :1-24
[19]  
HERMAN JP, 1989, RES PER ALZ, P21
[20]   ANATOMICAL AND BEHAVIORAL-COMPARISON OF UNILATERAL DOPAMINE-RICH GRAFTS IMPLANTED INTO THE STRIATUM OF NEONATAL AND ADULT-RATS [J].
HERMAN, JP ;
ABROUS, DN ;
LEMOAL, M .
NEUROSCIENCE, 1991, 40 (02) :465-475