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.

Spatial learning depends on both the addition and removal of new hippocampal neurons.

The role of adult hippocampal neurogenesis in spatial learning remains a matter of debate. Here, we show that spatial learning modifies neurogenesis by inducing a cascade of events that resembles the selective stabilization process characterizing development. Learning promotes survival of relatively mature neurons, apoptosis of more immature cells, and finally, proliferation of neural precursors. These are three interrelated events mediating learning. Thus, blocking apoptosis impairs memory and inhibits learning-induced cell survival and cell proliferation. In conclusion, during learning, similar to the selective stabilization process, neuronal networks are sculpted by a tightly regulated selection and suppression of different populations of newly born neurons.

Astrogliosis has Different Dynamics after Cell Transplantation and Mechanical Impact in the Rodent Model of Parkinson's Disease.

BACKGROUND: Transplantation of fetal mesencephalic tissue is a well-established concept for functional reinnervation of the dopamine-depleted rat striatum. However, there is no extensive description of the glial response of the host brain following this procedure. AIMS: The present study aimed to quantitatively and qualitatively analyse astrogliosis surrounding intrastriatal grafts and compare it to the reaction to mechanical injury with the transplantation instrument only. STUDY DESIGN: Animal experimentation. METHODS: The standard 6-hydroxydopamine-induced unilateral model of Parkinson's disease was used. The experimental animals received transplantation of a single-cell suspension of E14 ventral mesencephalic tissue. Control animals (sham-transplanted) were subjected to injury by the transplantation cannula, without injection of a cell suspension. Histological analyses were carried out 7 and 28 days following the procedure by immunohistochemistry assays for tyrosine hydroxylase and glial fibrillary acidic protein. To evaluate astrogliosis, the cell density and immunopositive area were measured in distinct zones within and surrounding the grafts or the cannula tract. RESULTS: Statistical analysis revealed that astrogliosis in the grafted striatum increased from day 7 to day 28, as shown by a significant change in both cell density and the immunopositive area. The cell density increased from 816.7±370.6 to 1403±272.1 cells/mm2 (p<0.0001) аnd from 523±245.9 to 1164±304.8 cells/mm2 (p<0.0001) in the two zones in the graft core, and from 1151±218.6 to 1485±210.6 cells/mm2 (p<0.05) for the zone in the striatum immediately adjacent to the graft. The glial fibrillary acidic protein-expressing area increased from 0.3109±0.1843 to 0.7949±0.1910 (p<0.0001) and from 0.1449±0.1240 to 0.702±0.2558 (p<0.0001) for the same zones in the graft core, and from 0.5277±0.1502 to 0.6969±0.1223 (p<0.0001) for the same area adjacent to the graft zone. However, astrogliosis caused by mechanical impact only (control) did not display such dynamics. This finding suggests an influence of the grafted cells on the host's glia, possibly through cross-talk between astrocytes and transplanted neurons. CONCLUSION: This bidirectional relationship is affected by multiple factors beyond the mechanical trauma. Elucidation of these factors might help achieve better functional outcomes after intracerebral transplantation.

Optimising plasticity: environmental and training associated factors in transplant-mediated brain repair.

With progressively ageing populations, degeneration of nerve cells of the brain, due to accident or disease, represents one of the major problems for health and welfare in the developed world. The molecular environment in the adult brain promotes stability limiting its ability to regenerate or to repair itself following injury. Cell transplantation aims to repair the nervous system by introducing new cells that can replace the function of the compromised or lost cells. Alternatives to primary embryonic tissue are actively being sought but this is at present the only source that has been shown reliably to survive grafting into the adult brain and spinal cord, connect with the host nervous system, and influence behaviour. Based on animal studies, several clinical trials have now shown that embryonic tissue grafts can partially alleviate symptoms in Parkinson's disease, and related strategies are under evaluation for Huntington's disease, spinal cord injury, stroke and other CNS disorders. The adult brain is at its most plastic in the period following injury, offering a window of opportunity for therapeutic intervention. Enriched environment, behavioural experience and grafting can each separately influence neuronal plasticity and recovery of function after brain damage, but the extent to which these factors interact is at present unknown. To improve the outcome following brain damage, transplantation must make use of the endogenous potential for plasticity of both the host and the graft and optimise the external circumstances associated with graft-mediated recovery. Our understanding of mechanisms of brain plasticity subsequent to brain damage needs to be associated with what we know about enhancing intrinsic recovery processes in order to improve neurobiological and surgical strategies for repair at the clinical level. With the proof of principle beginning to emerge from clinical trials, a rich area for innovative research with profound therapeutic application, even broader than the specific context of transplantation, is now opening for investigation.