Degeneration of the nigral dopamine neurons after 6-hydroxydopamine injection into the rat striatum

Ichitani, Yukio; Okamura, Hitoshi; Matsumoto, Yoshitake; Nagatsu, Ikuko; Ibata, Yasuhiko

doi:10.1016/0006-8993(91)90481-a

Cited by 90 publications

(34 citation statements)

References 11 publications

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“…In adult animals, injection of 6-OHDA into striatum results in the death of dopaminergic neurons (Sauer and Oertel, 1994). In adult animals, however, direct injection of 6-OHDA into SN (Jeon et al, 1995) or injection into striatum (Ichitani et al, 1991(Ichitani et al, , 1994 does not appear to induce apoptotic cell death. Nevertheless, it remains possible that immature dopaminergic neurons respond differently to the toxin than mature neurons do, and they die with an apoptotic morphology.…”

Section: Discussionmentioning

confidence: 99%

“…In the former instance, it is possible, for example, that the apoptotic cell death is attributable to the loss of target-derived support, whereas the nonapoptotic death is attributable to the direct effect of retrogradely transported toxin (Ichitani et al, 1991(Ichitani et al, , 1994Sauer and Oertel, 1994). In the latter instance, it is possible that as the animal matures the morphology changes from an apoptotic to a nonapoptotic form, while the death mechanism remains that of programmed cell death.…”

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Early Developmental Destruction of Terminals in the Striatal Target Induces Apoptosis in Dopamine Neurons of the Substantia Nigra

et al. 1997

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Many developing neural systems with peripheral projections depend on their target for trophic support during a critical period of natural cell death. Much less is known about central systems. That dopaminergic neurons of the substantia nigra may depend on their target, the striatum, during development is suggested by the presence of a natural apoptotic cell death event in these neurons that can be augmented by an early developmental axon-sparing striatal injury. To further assess the target dependence of these neurons, we have used the selective neurotoxin 6-hydroxydopamine to lesion their terminals within the striatum during development, while sparing intrinsic striatal target neurons. This lesion results in an induction of apoptotic cell death in phenotypically defined dopaminergic neurons that appears on the third postlesion day and persists until the tenth. This inducibility of cell death is dependent on developmental age: it is most marked before postnatal day (PND) 14. As late as PND42, inducibility is still detectable but much less so. In addition, at day 42 the morphology of cell death changes and becomes nonapoptotic in some cells. We conclude that terminal injury during a critical period of postnatal development, like axon-sparing target injury, induces augmented apoptotic death in mesencephalic dopaminergic neurons. These results suggest that these neurons have a period of target dependence. Regulation of this dependence is likely to influence the mature adult number of dopaminergic neurons.

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Section: Discussionmentioning

confidence: 99%

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Early Developmental Destruction of Terminals in the Striatal Target Induces Apoptosis in Dopamine Neurons of the Substantia Nigra

et al. 1997

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“…As described previously (Berger et al, 1991;Ichitani et al, 1991), our 6-OHDA injections into the lateral striatum induced a partial retrograde degeneration of dopaminergic cell bodies in the lateral part of the substantia nigra, with a sparing of the mesolimbic dopaminergic pathway and a complete dopamine deafferentation of the lateral striatum (dorsal and ventral parts). Moreover, in our experimental conditions, the striatal DA depletion was not associated with a loss of efferent neurons.…”

Section: Discussionmentioning

confidence: 99%

Lesion to the Nigrostriatal Dopamine System Disrupts Stimulus-Response Habit Formation

Faure¹,

Haberland²,

Condé³

et al. 2005

J. Neurosci.

356

264

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Acquisition and performance of instrumental actions are assumed to require both action-outcome and stimulus-response (S-R) habit processes. Over the course of extended training, control over instrumental performance shifts from goal-directed action-outcome associations to S-R associations that progressively gain domination over behavior. Lesions of the lateral part of the dorsal striatum disrupt this process, and rats with lesions to the lateral striatum showed selective sensitivity to devaluation of the instrumental outcome (Yin et al., 2004), indicating that this area is necessary for habit formation. The present experiment further explored the basis of this dysfunction by examining the ability of rats subjected to bilateral 6-hydroxydopamine lesions of the nigrostriatal dopaminergic pathway to develop behavioral autonomy with overtraining. Rats were given extended training on two cued instrumental tasks associating a stimulus (a tone or a light) with an instrumental action (lever press or chain pull) and a food reward (pellets or sucrose). Both tasks were run daily in separate sessions. Overtraining was followed by a test of goal sensitivity by satiety-specific devaluation of the reward. In control animals, one action (lever press) was insensitive to reward devaluation, indicating that it became a habit, whereas the second action (chain pull) was still sensitive to goal devaluation. This result provides evidence that the development of habit learning may depend on the characteristics of the response. In dopamine-depleted rats, lever press and chain pull remained sensitive to reward devaluation, evidencing a role of striatal dopamine transmission in habit formation.

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“…To do so, we used a recent modification of the standard 6-OHDA lesion of the rat nigrostriatal projection (13)(14)(15). Unilateral 6-OHDA-lesioning of the dopaminergic terminals in the striatum rather than the medial forebrain bundle or the substantia nigra itself produces a delayed and progressive degeneration of ipsilateral nigral dopamine neurons with an onset 1 week after 6-OHDA injection (15).…”

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Glial cell line-derived neurotrophic factor but not transforming growth factor beta 3 prevents delayed degeneration of nigral dopaminergic neurons following striatal 6-hydroxydopamine lesion.

Sauer

Rosenblad

Björklund

1995

Proc. Natl. Acad. Sci. U.S.A.

348

195

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Glial cell line-derived neurotrophic factor (GDNF) and transforming growth factor j33 Parkinson disease is one of the most common neurological disorders of the elderly. It is characterized by a progressive degeneration of the dopaminergic neurons in the substantia nigra of the midbrain, leading to a loss of dopamine in the striatum, which constitutes the main projection field of these cells. Although therapeutically relevant augmentation of striatal dopamine can be achieved by drug therapy or intrastriatal transplantation of fetal dopaminergic neurons (1), there is at present no means by which the primary nigral degeneration can be halted. Neurotrophic factors capable of sustaining the survival of otherwise degenerating dopamine neurons are thus of considerable interest (2). GDNF was initially purified and cloned as a potent neurotrophic factor for cultured dopaminergic neurons of the developing substantia nigra (3), and it has been shown that the related transforming growth factors 32 and ,B3 (TGF-f32 and TGF-f33) exert a similar survival-promoting activity on this cell population in vitro (4-6). The expression patterns of GDNF, TGF-j32, and TGF-,B3 mRNAs in the developing rat striatum and substantia nigra further support the notion that one or several of these factors play important physiological roles for immature nigral dopamine neurons (4, 7-9). More recently, administration of GDNF to the basal ganglia has been shown to partially attenuate the disappearance of tyrosine hydroxylase (TH)-immunoreactive nigral neurons following surgical axotomy (10) and the acute toxic effects of systemic doses of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in adult mice (11) or of intracerebral 6-hydroxydopamine (6-OHDA) in rats (12).The aim of the present study was (i) to investigate whether GDNF would exert a protective effect in a model of delayed and progressive nigral cell death more closely related to the cell death seen in human Parkinson disease and (ii) to compare GDNF and the related TGF-f33 with respect to their capacity to counteract nigral dopamine cell degeneration in the adult rat brain.To do so, we used a recent modification of the standard 6-OHDA lesion of the rat nigrostriatal projection (13-15). Unilateral 6-OHDA-lesioning of the dopaminergic terminals in the striatum rather than the medial forebrain bundle or the substantia nigra itself produces a delayed and progressive degeneration of ipsilateral nigral dopamine neurons with an onset 1 week after 6-OHDA injection (15). One week prior to striatal 6-OHDA lesion, nigral cells were retrogradely labeled at the site of subsequent striatal toxin injection with the fluorescent retrograde tracer fluorogold. This allows a specific examination of those nigrostriatal neurons projecting to, or through, the focus of the 6-OHDA lesion. For within-animal controls, fluorogold injections were performed bilaterally, and only one of the labeled striata was subsequently lesioned with 6-OHDA. into both striata at sites 1 mm anterior to bregma and 3 mm later...

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Degeneration of the nigral dopamine neurons after 6-hydroxydopamine injection into the rat striatum

Cited by 90 publications

References 11 publications

Early Developmental Destruction of Terminals in the Striatal Target Induces Apoptosis in Dopamine Neurons of the Substantia Nigra

Early Developmental Destruction of Terminals in the Striatal Target Induces Apoptosis in Dopamine Neurons of the Substantia Nigra

Lesion to the Nigrostriatal Dopamine System Disrupts Stimulus-Response Habit Formation

Glial cell line-derived neurotrophic factor but not transforming growth factor beta 3 prevents delayed degeneration of nigral dopaminergic neurons following striatal 6-hydroxydopamine lesion.

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