Intrastriatal Mesencephalic Grafts Affect Neuronal Activity in Basal Ganglia Nuclei and Their Target Structures in a Rat Model of Parkinson’s Disease

Abstract

Nigrostriatal dopamine (DA) lesions lead to changes of neuronal activity in basal ganglia nuclei such as the globus pallidus (GP, the rodent homolog of lateral globus pallidus), entopeduncular nucleus (EP, the rodent homolog of medial globus pallidus), substantia nigra pars reticulata (SNR), and subthalamic nucleus (STN). We investigated in rats whether embryonic mesencephalic DA neurons grafted in the striatum may affect the lesion-induced alterations of neuronal activity in these structures. Regional neuronal activity was determined by use of quantitative cytochrome oxidase histochemistry. It was also examined in lesioned rats whether the grafts may regulate the expression of c-Fos after systemic administration of apomorphine in the basal ganglia nuclei as well as their target structures, including the ventromedial thalamic nucleus (VM), superior colliculus (SC), and pedunculopontine nucleus (PPN). Lesioned rats exhibited an increased activity of CO in the GP, EP, SNR, and STN ipsilateral to the lesion. Intrastriatal nigral grafts reversed the increases in the CO activity in the EP and SNR, whereas the grafts failed to affect the enzyme activity in the GP or STN. Apomorphine induced an increased expression of c-Fos in the GP, STN, VM, SC, and PPN on the lesioned side. The enhanced expression of this protein in all the structures except for the STN was attenuated by nigral grafts. The present results indicate that intrastriatal DA neuron grafts can normalize the lesion-induced changes of neuronal activity in the output nuclei of the basal ganglia as well as their target structures.

Enhancement of Sensorimotor Behavioral Recovery in Hemiparkinsonian Rats with Intrastriatal, Intranigral, and Intrasubthalamic Nucleus Dopaminergic Transplants

“…Thalamocortical disinhibition is thought to result from lesions of the STN, which produces hemiballismus (Hamada and DeLong, 1992;Vidakovic et al, 1994;Albin et al, 1995). The STN has been observed to be overactive in animal models of PD (Bergman et al, 1994;Hassani et al, 1996;Nakao et al, 1998). However, Henderson and Dunnett (1998) have questioned the prediction of this model of STN hyperactivity as a result of Parkinsonianinduced GPe disinhibition.…”

“…Reinnervation of the STN by dopaminergic grafts may also be of benefit in functional recovery. There is recent evidence that upregulation of cytochrome oxidase and c-fos activity in the STN is not normalized in 6-hydroxydopamine (6-OHDA)-lesioned rats by intrastriatal grafts (Nakao et al, 1998). Failure to restore dopaminergic input to basal ganglia nuclei, such as the STN, may be an important factor limiting the efficacy of clinical transplantation for PD.…”

Visualization, direct isolation, and transplantation of midbrain dopaminergic neurons

“…Young adult male Sprague-Dawley rats, weighing 180-200 g at the start of the experiment, were used. Unilateral lesions of the ascending mesostriatal DA pathway were made by intracerebral injections of 6-hydroxydopamine as described (19). Two weeks after the lesion surgery, amphetamine (0.25 mg͞kg i.p.…”

“…The cell viability, assessed with a trypan blue dye exclusion test, was over 95% just before grafting, and the concentration was 10,000-13,000 cells per l. Recipient rats were divided into two groups: lesion control (n ϭ 4) and transplantation (n ϭ 7). In the transplantation group, two stereotaxic deposits, of 2 l of cell suspension each, were injected into the lesioned striatum as described (19,21). All of the engrafted rats were given i.p.…”

“…Sections of the brain with grafts were cut and processed for TH immunohistochemistry as described (19,21). The number of TH-immunoreactive neurons in each graft was counted under bright-field illumination on every third section.…”