Continuous High-Frequency Stimulation of the Subthalamic Nucleus Improves Cell Survival and Functional Recovery Following Dopaminergic Cell Transplantation in Rodents.

Subthalamic nucleus (STN) high-frequency stimulation (HFS) is a routine treatment in Parkinson's disease (PD), with confirmed long-term benefits. An alternative, but still experimental, treatment is cell replacement and restorative therapy based on transplanted dopaminergic neurons. The current experiment evaluated the potential synergy between neuromodulation and grafting by studying the effect of continuous STN-HFS on the survival, integration, and functional efficacy of ventral mesencephalic dopaminergic precursors transplanted into a unilateral 6-hydroxydopamine medial forebrain bundle lesioned rodent PD model. One group received continuous HFS of the ipsilateral STN starting a week prior to intrastriatal dopaminergic neuron transplantation, whereas the sham-stimulated group did not receive STN-HFS but only dopaminergic grafts. A control group was neither lesioned nor transplanted. Over the following 7 weeks, the animals were probed on a series of behavioral tasks to evaluate possible graft and/or stimulation-induced functional effects. Behavioral and histological data suggest that STN-HFS significantly increased graft cell survival, graft-host integration, and functional recovery. These findings might open an unexplored road toward combining neuromodulative and neuroregenerative strategies to treat severe neurologic conditions.

Subthalamic nucleus lesion improves cell survival and functional recovery following dopaminergic cell transplantation in parkinsonian rats.

Subthalamic nucleus (STN) modulation is currently the gold standard in the treatment of Parkinson's disease (PD) cases refractory to medication. Cell transplantation is a tissue-restorative approach and is a promising strategy in the treatment of PD. One of the obstacles to overcome in cell therapy is the poor dopaminergic cell survival. Our experiment investigates the impact of a partial subthalamotomy prior to ventral mesencephalic (VM) embryonic cell transplantation on dopaminergic cell survival and functional outcome. Unilateral dopamine depletion was carried out in rats, via medial forebrain bundle (MFB) injection of 6-hydroxydopamine, and half of the animals went on to receive unilateral excitotoxic lesions of the STN/Zone Incerta (ZI) causing partial lesion of these structures on the same side as the MFB lesion. All MFB-lesioned animals, with or without the STN/ZI lesion, received striatal ipsilateral embryonic VM cell grafts. The data suggest that the STN/ZI lesion could boost the dopamine cell survival in the grafts by 2.6-fold compared with the control grafted-only group. Moreover, performance on the drug-induced rotation and the spontaneous behavior tests were ameliorated on the STN/ZI-lesioned group to a significantly greater extent than the grafted-only group. These data suggest that the STN/ZI partial lesion optimized the striatal environment, promoting an improvement in cell survival. Further studies are needed to see whether the synergy between STN modulation via deep brain stimulation and cell therapy might have clinical applications in the management of PD.

Graft-mediated functional recovery on a skilled forelimb use paradigm in a rodent model of Parkinson's disease is dependent on reward contingency.

The Staircase test measures lateralised deficits in skilled paw reaching in rodents, and there is a long-standing discrepancy in the literature on whether the paradigm is sensitive to graft-mediated functional recovery in the rodent model of Parkinson's disease. The aim of the current study was to evaluate the critical influence of test conditions like pellet density on dopamine-dependent graft-mediated functional recovery. Rats were pre-trained on the Staircase test with a configuration of 8 pellets in each of the 6 wells bilaterally prior to receiving unilateral 6-OHDA lesions of the medial forebrain bundle. Later, the lesioned animals received E14 VM grafts into the striatum, and were tested on the Staircase test under one of two test configurations: bilaterally, either with 10 (HIGH) or with 2 (LOW) pellets per well. Subsequent sessions included unilateral forced-choice testing under the same pellet configuration, and second bilateral and forced-choice sessions with the pellet density configurations switched around between the groups (Cross-over). Animals were also tested on the Corridor and the Cylinder test, and subjected to drug-induced rotation. Graft-mediated functional recovery was observed in the pellets taken criteria only under the HIGH pellet configuration during the bilateral and the forced choice condition. When tested under the LOW configuration, the graft provided no measurable benefit. The presence of VM grafts reduced lateralised motor deficits in the Cylinder test, the adjacent version of the Corridor test, and drug-induced rotation. Our results confirm that VM transplants can partially restore skilled forelimb sensorimotor deficits under specific testing configuration.

Improvement in hippocampal kindling analysis through computational processing data.

The kindling phenomenon is classically investigated in epileptology research. The present study aims to provide further information about hippocampal kindling through computational processing data. Adult Wistar rats were implanted with dorsal hippocampal and frontal neocortical electrodes to perform the experiment. The processing data was obtained using the Spike2 and Matlab softwares. An inverse relationship between the number of 'wet dog shakes' and the Racine's motor stages development was found. Moreover it was observed a significant increase in the afterdischarge (AD) duration and its frequency content. The highest frequencies were, however, only reached at the beginning of behavioral seizures. During the primary AD, fast transients (ripples) were registered in both hippocampi superimposed to slower waves. This experiment highlights the usefulness of computational processing applied to animal models of temporal lobe epilepsy and supports a relevant role of the high frequency discharges in temporal epileptogenesis.

Improvement in hippocampal kindling analysis through computational processing data / Aprimorando a análise do modelo de kindling hipocampal com o auxílio de processamento computacional

The kindling phenomenon is classically investigated in epileptology research. The present study aims to provide further information about hippocampal kindling through computational processing data. Adult Wistar rats were implanted with dorsal hippocampal and frontal neocortical electrodes to perform the experiment. The processing data was obtained using the Spike2 and Matlab softwares. An inverse relationship between the number of "wet dog shakes" and the Racine's motor stages development was found. Moreover it was observed a significant increase in the afterdischarge (AD) duration and its frequency content. The highest frequencies were, however, only reached at the beginning of behavioral seizures. During the primary AD, fast transients (ripples) were registered in both hippocampi superimposed to slower waves. This experiment highlights the usefulness of computational processing applied to animal models of temporal lobe epilepsy and supports a relevant role of the high frequency discharges in temporal epileptogenesis.

O fenômeno de kindling é classicamente utilizado no campo da epileptologia experimental. Este trabalho objetiva aprofundar a análise do modelo kindling hipocampal através de processamento computacional. Ratos wistar adultos receberam eletrodos hipocampais dorsais e neocorticais frontais para a realização do experimento. O processamento dos dados encontrados foi realizado pelos softwares Matlab e Spike2. Encontrou-se uma relação inversa entre wet dog shakes e o desenvolvimento dos estágios motores de Racine. A duração e o conteúdo de freqüência das pós-descargas hipocampais aumentaram durante o processo, sendo observadas descargas de alta freqüência (ripples) em ambos os hipocampos durante as pós-descargas primárias, superimpostas a ondas lentas. As mais altas freqüências, entretanto, foram apenas atingidas com o início das crises epilépticas. A utilização de sistemas computacionais para a confecção e análise do modelo de epilepsia temporal é ressaltada e reforça-se a relevância do papel das altas freqüências na epileptogênese temporal.