Anatomical and behavioral comparison of unilateral dopamine-rich grafts implanted into the striatum of neonatal and adult rats

doi:10.1016/0306-4522(91)90134-A

Neuroscience

Volume 40, Issue 2, 1991, Pages 465-475

https://doi.org/10.1016/0306-4522(91)90134-A Get rights and content

Abstract

The anatomical and functional characteristics of dopamine neuron-rich grafts implanted into rat pups were compared with those of identical grafts implanted into adult hosts. The host nigrostriatal dopaminergic pathway was unilaterally destroyed by an intrahypothalamic injection of 6-hydroxydopamine. This was followed five days later by the implantation of a cellular suspension obtained from rat embryonic mesencephali. Identical operations were carried out on adult and infant (PD3) rats. The survival rate of implanted tyrosine hydroxylase-positive cells was lower in the neonates. On the other hand, in the neonate hosts, surviving immunoreactive cells migrated extensively throughout the host striatum coursing preferentially below the corpus callosum and towards the subependymal zone. The structural integrity of the host parenchyma was well maintained after the neonatal implantation, in contrast to that observed in the adults. Despite a difference in the cell survival rate, there was no major difference in reinnervation density between the two types of host.

The functional capacities of the implants were evaluated by measuring the rotational responses of the animals to dopaminergic agonists. The implants compensated the lesion-induced contralateral rotational response to the mixed agonist apomorphine and the D₁ agonist SCH-38393 in both neonates and adults. However, the response to the D₂ agonist LY-171555 was not significantly attenuated by the implant. The ipsilateral rotational response to amphetamine observed in the lesioned animals was also compensated and even reversed by the graft.

It is concluded that with respect to rotational behavior, similar functional benefits were observed following adult stage or neonatal implantation, despite differences in their anatomical development.

References (48)

AbrousN. et al.
Behavioral effects of intracerebral dopaminergic grafts after neonatal destruction of the mesencephalic dopaminergic system
Prog. Brain Res.
(1990)
BaulacM. et al.
Transplantation of oligodendrocytes in the newborn mouse brain: extension of myelination by transplanted cells. Anatomical study
Brain Res.
(1987)
Bjo¨rklundA. et al.
Reconstruction of the nigrostriatal dopamine pathway by intracerebral nigral transplants
Brain Res.
(1979)
BrundinP. et al.
Survival, growth and function of dopaminergic neurons grafted to the brain
CarderR.K. et al.
Amphetamine- and stress-induced turning after nigral transplants in neonatally dopamine-depleted rats
Devl Brain Res.
(1987)
DemierreB. et al.
Embryonic motoneurons grafted into the adult CNS can differentiate and migrate
Brain Res.
(1990)
GoutO. et al.
Remyelination by transplanted oligodendrocytes of a demyelinated lesion in the spinal cord of the adult shiverer mouse
Neurosci. Lett.
(1988)
HermanJ.P. et al.
Distorted development of intracerebral grafts: long-term maintenance of tyrosine hydroxylase-containing neurons in grafts of cortical tissue
Devl Brain Res.
(1988)
HermanJ.P. et al.
Reinnervation of the nucleus accumbens and frontal cortex of the rat by dopaminergic grafts and effects on hoarding behavior
Brain Res.
(1986)
LindsayR.M. et al.
An autoradiographic study of neuronal development, vascularization and glial cell migration from hippocampal transplants labelled in intermediate expiant culture
Neuroscience
(1984)

RogersD.C. et al.

Neonatal dopamine-rich grafts and 6-OHDA lesions independently provide partial protection from the adult nigrostriatal lesion syndrome

Behav. Brain Res.

(1989)

SieradzanK. et al.

Replacement of missing motoneurons by embryonic grafts in the rat spinal cord

Neuroscience

(1989)

Snyder-KellerA.M. et al.

Development of dopamine innervation and turning behavior in dopamine-depleted infant rats receiving unilateral nigral transplants

Neuroscience

(1989)

SoteloC. et al.

Reconstruction of the defective cerebellar circuitry in adult Purkinje cell degeneration mutant mice by Purkinje cell replacement through transplantation of solid embryonic implants

Neuroscience

(1987)

WhittemoreS.R. et al.

Neurotrophic factors for mammalian brain neurons: injury induction in neonatal, adult and aged rat brain

Devl Brain Res.

(1985)

AbercrombieM.

Estimation of nuclear population from microtome sections

Anat. Rec.

(1946)

AbrousN. et al.

Development of intracerebral dopaminergic grafts: a combined immunohistochemical and autoradiographic study of its time course and environ mental influences

J. comp. Neurol.

(1988)

AltmanJ. et al.

Development of brain stem in the rat. V. Thymidine-radioautoradiographic study of the time of origin of neurons in the midbrain tegmentum

J. comp. Neurol.

(1981)

BondareffW. et al.

Distribution of the extracellular space during postnatal maturation of rat cerebral cortex

Anat. Rec.

(1968)

Del CerroM.P. et al.

Evolution of the extracellular space in immature neurons

Experientia

(1968)

DunnettS.B. et al.

Intracerebral grafting of neuronal cell suspensions. V. Behavioural recovery in rats with bilateral 6-OHDA lesions following implantation of nigral cell suspensions

Acta physiol. scand., Suppl.

(1983)

ForniC. et al.

Time-course of recovery of dopamine neuron activity during reinnervation of the denervated striatum by fetal mesencephalic grafts as assessed by in vivo voltammetry

Expl Brain Res.

(1989)

GoldbergW.J. et al.

Transplant-derived astrocytes migrate into host lumbar and cervical spinal cord after implantation of E14 fetal cerebral cortex into adult thoracic spinal cord

J. Neurosci. Res.

(1987)

HanawayJ. et al.

Histogenesis of the substantia nigra, ventral tegmental area of Tsai and interpeduncular nucleus: an autoradiographic study of the mesencephalon in the rat

J. comp. Neurol.

(1971)

Cited by (35)

Survival of iPSC-derived grafts within the striatum of immunodeficient mice: Importance of developmental stage of both transplant and host recipient
2017, Experimental Neurology
Citation Excerpt :
Further studies evaluating intermediate ages between neonates and aged adults could define any potential contribution of aging to transplantation efficiency. iPSC-derived cell survival, and to a lesser degree migration, is higher in neonatal recipients than adults, which is supported in other studies on fetal-derived cellular transplantation (Hallas et al., 1980, Herman et al., 1991, Du et al., 1993, Gopinath et al., 1996, McLoon and Lund, 1984, Nieto-Sampedro et al., 1982, Nieto-Sampedro et al., 1984, Nikkhah et al., 1995, Oblinger et al., 1980, Rioux et al., 1991, Rogers and Dunnett, 1989). This has been previously attributed to the expression of various growth factors in the developing brain.
Degeneration of the striatum can occur in multiple disorders with devastating consequences for the patients. Infantile infections with streptococcus, measles, or herpes can cause striatal necrosis associated with dystonia or dyskinesia; and in patients with Huntington's disease the striatum undergoes massive degeneration, leading to behavioral, psychological and movement issues, ultimately resulting in death. Currently, only supportive therapies are available for striatal degeneration. Clinical trials have shown some efficacy using transplantation of fetal-derived primary striatal progenitors. Large banks of fetal progenitors that give rise to medium spiny neurons (MSNs), the primary neuron of the striatum, are needed to make transplantation therapy a reality. However, fetal tissue is of limited supply, has ethical concerns, and is at risk of graft immunorejection. An alternative potential source of MSNs is induced pluripotent stem cells (iPSCs), adult somatic tissues reprogrammed back to a stem cell fate. Multiple publications have demonstrated the ability to differentiate striatal MSNs from iPSCs.
Previous publications have demonstrated that the efficacy of fetal progenitor transplants is critically dependent upon the age of the donor embryo/fetus as well as the age of the transplant recipient. With the advent of iPSC technology, a question that remains unanswered concerns the graft's “age,” which is crucial since transplanting pluripotent cells has an inherent risk of over proliferation and teratoma formation. Therefore, in order to also determine the effect of transplant recipient age on the graft, iPSCs were differentiated to three stages along a striatal differentiation paradigm and transplanted into the striatum of both neonatal and adult immunodeficient mice. This study demonstrated that increased murine transplant-recipient age (adult vs neonate) resulted in decreased graft survival and volume/rostro-caudal spread after six weeks in vivo, regardless of “age” of the cells transplanted. Importantly, this study implicates that the in vivo setting may provide a better neurogenic niche for iPSC-based modeling as compared to the in vitro setting. Together, these results recapitulate findings from fetal striatal progenitor transplantation studies and further demonstrate the influence of the host environment on cellular survival and maturation.
Amphetamine induced rotation in the assessment of lesions and grafts in the unilateral rat model of Parkinson's disease
2007, European Neuropsychopharmacology
In the unilateral rat model of Parkinson's disease (PD), amphetamine induced rotation is widely used as an index of both lesion deficits and of graft-derived recovery. We have analysed the time course of the rotational response in lesioned rats, and in rats with lesions and dopamine grafts. In lesioned rats, the rotation exhibited a typical dose-dependent response, with low rates of rotation in the first 10 min after injection, rising gradually to a maximum after 20–30 min. Grafted rats exhibited a peak of rotation in the first 10 min after injection, which then fell to a minimum after 30 min. We demonstrate that the response seen in grafted rats is both drug and dose-dependent and show that the rotational profile results from interaction of the grafted and intact striata which exhibit differential temporal responses to the amphetamine.
Simultaneous intrastriatal and intranigral grafting (double grafts) in the rat model of Parkinson's disease
2000, Brain Research Reviews
Experimental and clinical studies of neural transplantation in Parkinson's disease have focused on the placement of fetal dopaminergic grafts not in their ontogenic site (substantia nigra) but in the main nigral target area (striatum). The reason for this is the apparent inability of intranigral nigral grafts to extend axons for long distances reinnervating the ipsilateral striatum. This review presents previous work by our laboratory [I. Mendez, M. Hong, Reconstruction of the striato-nigro-striatal circuitry by simultaneous double dopaminergic grafts: a tracer study using fluorogold and horseradish peroxidase, Brain Res. 778 (1997) 194–205; I. Mendez, D. Sadi, M. Hong., Reconstruction of the nigrostriatal pathway by simultaneous intrastriatal and intranigral dopaminergic transplants, J. Neurosci. 16 (1996) 7216–7227] using a new transplantation strategy aimed at restoring dopaminergic innervation of the nigra and striatum by simultaneous dopaminergic transplants placed in the substantia nigra and ipsilateral striatum (double grafts) in the 6-hydroxydopamine lesioned adult rat brain. These double grafts achieve not only greater striatal reinnervation than the standard intrastriatal grafts but also produce a faster and more complete behavioural recovery six weeks after transplantation. Injection of the retrograde tracer fluorogold into the striatum and nigra resulted in fluorescent labeled cells within the intranigral graft and the intrastriatal graft and surrounding striatum, respectively suggesting that these double grafts promote at least partial reconstruction of the nigrostriatal dopaminergic pathway. This double graft strategy may have potential implications in clinical neural transplantation for Parkinson's disease.
Transplantation in the rat model of Parkinson's disease: Ectopic versus homotopic graft placement
2000, Progress in Brain Research
This chapter discusses the attempts to improve the functional efficacy of fetal nigral transplants, focusing on three major questions. First, to what extent is it possible to use multiple intrastriatal grafts to obtain a more complete reinnervation of the striatal complex in the 6-hydroxydopamine (6-OHDA)-lesioned rat, and will such more complete reinnervation provide functional improvements over and beyond that seen after standard more limited transplants? Second, to what extent can dopamine (DA) neurone transplants, placed homotopically in the substantia nigra, induce functional recovery in the 6-OHDA lesion model, and whether their axons can be encouraged to grow to the striatum? Third, to what extent can grafts of inhibitory GABAergic neurons be used to restore function in the rat Parkinson model? Transplantation of fetal DA neurones into the striatum in rats with complete DA-denervating lesions can restore striatal DA fibre densities to approximately 60%–70% of normal levels throughout the striatal complex. Incomplete functional recovery is reported in ectopic grafting. The results summarized in the chapter suggest that intranigral grafting of GABA-rich striatal tissue can induce some functional recovery in drug-induced rotational behavior and in skilled forelimb use. GABA released within the striatal output nuclei may provide a tonic inhibition of striatal outflow, similar to that obtained by high-frequency deep brain stimulation, and may thus offer a new route for therapeutic intervention in Parkinson's disease.
Effects of amphetamine and cocaine treatment on c-fos, Jun-B, and Krox- 24 expression in rats with intrastriatal dopaminergic grafts
1999, Experimental Neurology
Activation of dopaminergic (DA) transmission by psychostimulants increases c-fos expression. d-Amphetamine-induced c-fos activation is reduced in the neostriatum deprived of DA afferents. Dopaminergic grafts implanted into the denervated neostriatum induce a c-fos hyperexpression when challenged with d-amphetamine, which is correlated with the exaggerated compensation of d-amphetamine-induced rotation. The aim of the present study was to test the generality of this phenomenon and the effects of DA grafts on the expression of three immediate early gene-coded proteins (c-Fos, Jun-B, Krox-24) following a challenge with either d-amphetamine or cocaine. c-fos basal expression was low in the neostriatum and was increased by the administration of psychostimulants. These effects were blocked by the DA lesion and restored by the DA grafts. A c-fos hyperexpression was observed within the grafted neostriatum, which was correlated with the compensation of d-amphetamine- or cocaine-induced rotation. Basal levels of Jun-B- and Krox-24-LI nuclei were high within the neostriatum. Administration of d-amphetamine or cocaine did not influence the expression of these IEG-coded proteins. Jun-B expression was not affected by the surgical procedure. In contrast, lesion of DA afferents of neostriatum decreased Krox-24 basal expression, an effect reversed by the grafts. Thus, the expression of c-fos but not Jun-B or Krox-24 appeared to be a good marker for the rotational behavior exhibited by DA-grafted rats challenged with drugs that increased DA transmission. This generalized c-fos overshoot indicates an abnormal activation of postsynaptic neurons by dopamine and points to its value as an indicator of the deleterious effects of DA grafts.
Reformation of the nigrostriatal pathway by fetal dopaminergic micrografts into the substantia nigra is critically dependent on the age of the host
1999, Experimental Neurology
The aim of this study was to determine whether the growth of axons along the nigrostriatal pathway from fetal dopamine cells, transplanted into the substantia nigra of young postnatal 6-OHDA-lesioned rats, is dependent on the age of the host brain. Neonatal rats were lesioned bilaterally by intraventricular injection of 6-OHDA at postnatal day 1 (P1) and received grafts of E14 ventral mesencephalon at day 3 (group P3), day 10 (group P10), or day 20 (group P20) into the right substantia nigra. One lesioned group was left untransplanted. Six months after surgery the animals were subjected to analysis of drug-induced rotation following injection of amphetamine, apomorphine, a D1 agonist (SKF38393), or a D2 agonist (Quinpirole). Animals transplanted intranigrally at day 3 and day 10 showed a strong amphetamine-induced rotational bias toward the side contralateral to the transplant. Animals transplanted into substantia nigra at P20, like the lesioned control animals, showed no rotational bias. Apomorphine and selective D1 and D2 agonists induced ipsilateral turning behavior in the P3 and P10 group, but not in the P20 or the lesion control groups. Immunofluorescence histochemistry in combination with retrograde axonal tracing, using FluoroGold injection into the ipsilateral caudate-putamen showed colocalization of tyrosine hydroxylase and FluoroGold in large numbers of transplanted neurons in the animals transplanted at postnatal day 3 and postnatal day 10, which was not observed in the group P20. The lesion control group showed a 90% complete lesion of the TH-positive cells in the substantia nigra while largely sparing the neurons in the ventral tegmental area. The results indicate that intranigral grafts can be placed accurately and survive well within the substantia nigra region at various time points during postnatal development. Furthermore, embryonic dopamine neurons have the ability to extend axons along the nigrostriatal pathway and reconnect with the dopamine-depleted striatum when transplanted at postnatal day 3 and postnatal day 10, but not at postnatal day 20.

View all citing articles on Scopus

View full text

Anatomical and behavioral comparison of unilateral dopamine-rich grafts implanted into the striatum of neonatal and adult rats

Abstract

Prog. Brain Res.

Brain Res.

Brain Res.

Devl Brain Res.

Brain Res.

Neurosci. Lett.

Devl Brain Res.

Brain Res.

Neuroscience

Behav. Brain Res.

Neuroscience

Neuroscience

Neuroscience

Devl Brain Res.

Estimation of nuclear population from microtome sections

Anat. Rec.

Development of intracerebral dopaminergic grafts: a combined immunohistochemical and autoradiographic study of its time course and environ mental influences

J. comp. Neurol.

Development of brain stem in the rat. V. Thymidine-radioautoradiographic study of the time of origin of neurons in the midbrain tegmentum

J. comp. Neurol.

Distribution of the extracellular space during postnatal maturation of rat cerebral cortex

Anat. Rec.

Evolution of the extracellular space in immature neurons

Experientia

Intracerebral grafting of neuronal cell suspensions. V. Behavioural recovery in rats with bilateral 6-OHDA lesions following implantation of nigral cell suspensions

Acta physiol. scand., Suppl.

Time-course of recovery of dopamine neuron activity during reinnervation of the denervated striatum by fetal mesencephalic grafts as assessed by in vivo voltammetry

Expl Brain Res.

Transplant-derived astrocytes migrate into host lumbar and cervical spinal cord after implantation of E14 fetal cerebral cortex into adult thoracic spinal cord

J. Neurosci. Res.

Histogenesis of the substantia nigra, ventral tegmental area of Tsai and interpeduncular nucleus: an autoradiographic study of the mesencephalon in the rat

J. comp. Neurol.