| 1. |
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| 2. |
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| 3. |
- Dunnett, S. B, et al.
(författare)
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Mechanisms and use of neural transplants for brain repair
- 2017
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Ingår i: Functional Neural Transplantation IV Translation to Clinical Application, Part A. - : Elsevier. - 9780128117385 ; 230, s. 1-51
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Bokkapitel (refereegranskat)abstract
- Under appropriate conditions, neural tissues transplanted into the adult mammalian brain can survive, integrate, and function so as to influence the behavior of the host, opening the prospect of repairing neuronal damage, and alleviating symptoms associated with neuronal injury or neurodegenerative disease. Alternative mechanisms of action have been postulated: nonspecific effects of surgery; neurotrophic and neuroprotective influences on disease progression and host plasticity; diffuse or locally regulated pharmacological delivery of deficient neurochemicals, neurotransmitters, or neurohormones; restitution of the neuronal and glial environment necessary for proper host neuronal support and processing; promoting local and long-distance host and graft axon growth; formation of reciprocal connections and reconstruction of local circuits within the host brain; and up to full integration and reconstruction of fully functional host neuronal networks. Analysis of neural transplants in a broad range of anatomical systems and disease models, on simple and complex classes of behavioral function and information processing, have indicated that all of these alternative mechanisms are likely to contribute in different circumstances. Thus, there is not a single or typical mode of graft function; rather grafts can and do function in multiple ways, specific to each particular context. Consequently, to develop an effective cell-based therapy, multiple dimensions must be considered: the target disease pathogenesis; the neurodegenerative basis of each type of physiological dysfunction or behavioral symptom; the nature of the repair required to alleviate or remediate the functional impairments of particular clinical relevance; and identification of a suitable cell source or delivery system, along with the site and method of implantation, that can achieve the sought for repair and recovery.
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| 4. |
- Dunnett, S B, et al.
(författare)
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Intracerebral grafting of neuronal cell suspensions. IV. Behavioural recovery in rats with unilateral implants of nigral cell suspensions in different forebrain sites
- 1983
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Ingår i: Acta Physiologica Scandinavica. ; Suppl. 522, s. 29-38
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Tidskriftsartikel (refereegranskat)abstract
- Single and multiple implants of nigral cell suspensions were grafted to the forebrains of rats with unilateral 6-hydroxydopamine-induced dopamine denervations. Control lesions alone induced a marked behavioural asymmetry, as assessed by amphetamine- and apomorphine-induced rotation, sensorimotor tests and side bias in an unbaited T-maze, and the animals were hyperactive to a low dose of apomorphine. Single suspension placements into different denervated striatal regions were capable of reversing the behavioural asymmetries dependent upon the specific placement for each test. Multiple suspension grafts were capable of reversing all behavioural asymmetries, and additionally abolished the supersensitive hyperactivity to apomorphine. By contrast, single suspension grafts placed into the substantia nigra or lateral hypothalamus had no detectable effect on any functional measure. The results indicate that nigral suspension grafts can be at least as effective as solid grafts in reversing the functional deficits induced by dopamine denervation, provided that placements are selected within appropriate dopamine terminal regions of the forebrain (e.g. caudate-putamen or nucleus accumbens).
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| 5. |
- Dunnett, S B, et al.
(författare)
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Intracerebral grafting of neuronal cell suspensions. V. Behavioural recovery in rats with bilateral 6-OHDA lesions following implantation of nigral cell suspensions.
- 1983
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Ingår i: Acta Physiologica Scandinavica. ; Suppl. 522, s. 39-48
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Tidskriftsartikel (refereegranskat)abstract
- Bilateral 6-hydroxydopamine-induced lesions of the ascending forebrain dopamine neurones induce a behavioural syndrome in rats which includes profound aphagia, adipsia, akinesia and bilateral sensorimotor neglect. Such animals will die unless maintained by intragastric feeding. Three experiments are reported in which we have attempted to ameliorate this syndrome with single or multiple placements of nigral cell suspensions into the forebrains of rats with bilateral dopamine depletions. Although the grafts were efficient in reversing the sensorimotor and akinetic impairments, and produced a significant increase in eating, the grafted rats remained hypophagic and adipsic. The results indicate that although many components of the bilateral dopamine denervation syndrome can be reversed by intrastriatal nigral suspension grafts, the severe eating and drinking deficits remain unameliorated.
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| 6. |
- Dunnett, Stephen B, et al.
(författare)
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Introduction (Part I)
- 2012
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Ingår i: Functional Neural Transplantation III : Primary and stem cell therapies for brain repair. Part 1 - Primary and stem cell therapies for brain repair. Part 1. - 0079-6123. - 9780444595751 ; 200, s. 3-5
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Bokkapitel (refereegranskat)
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| 7. |
- Dunnett, Stephen B, et al.
(författare)
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Introduction (Part II)
- 2012
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Ingår i: Functional Neural Transplantation III : Primary and Stem Cell Therapies for Brain Repair, Part II - Primary and Stem Cell Therapies for Brain Repair, Part II. - 0079-6123. - 9780444595447 ; 201, s. 3-5
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Bokkapitel (refereegranskat)
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| 8. |
- Lindgren, H. S., et al.
(författare)
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The effect of additional noradrenergic and serotonergic depletion on a lateralised choice reaction time task in rats with nigral 6-OHDA lesions
- 2014
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886 .- 1090-2430. ; 253, s. 52-62
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Tidskriftsartikel (refereegranskat)abstract
- Parkinson's disease (PD) patients often suffer from visuospatial deficits, which have been considered a disruption of the representation of external space. The lateralised choice reaction time (CRT) task is an operant task for rodents in which similar deficits can be assessed. It has been demonstrated that specific parameters in this task is disrupted after unilateral injections of 6-hydroxydopamine (6-OHDA), which have been associated with the dopamine (DA) depletion that inevitably follows this type of lesion. However, studies have demonstrated that this type of lesion also affects the serotonergic (5HT) and noradrenergic (NA) systems. However, the impact of these systems on parameters in the CRT task had not yet been investigated.To this end, rats were pretrained on the CRT task before receiving selective lesions of the DAergic system, either alone or in combination with depletion of the NA or 5HT system. All rats with a 6-OHDA lesion displayed a gradual decline in the selection, initiation and execution of lateralised movements compared to sham-lesion controls on the side contralateral to the lesion. They also displayed a reduced number of useable trials as well as an increased number of procedural errors. Interestingly, the group with an additional noradrenergic lesion was significantly slower in reacting to lateralised stimuli throughout the testing period compared to the other two groups with a 6-OHDA lesion. There was however no difference between the three different lesion groups in the other parameters assessed in the task.These data confirm previous findings demonstrating that the majority of the parameters assessed in the lateralised CRT task are strongly dependent on DA. However, this study has also shown that the NAergic system may play an important role in contributing to the attentive performance influencing the capacity to react to the presented lateralised stimuli. © 2013 Elsevier Inc.
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| 9. |
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| 10. |
- Björklund, Anders, et al.
(författare)
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Intracerebral grafting of neuronal cell suspensions. I. Introduction and general methods of preparation.
- 1983
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Ingår i: Acta Physiologica Scandinavica. ; Suppl. 522, s. 1-7
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Tidskriftsartikel (refereegranskat)abstract
- The steps involved in the grafting of mesencephalic and septal embryonic tissue in the form of dissociated cell suspensions are described in detail. This includes dissection of the donor embryos, incubation in trypsin, mechanical dissociation, and stereotaxic injection into the brains of adult recipient rats. Some of the technical problems and limitations are discussed.
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| 11. |
- Björklund, Anders, et al.
(författare)
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Intracerebral grafting of neuronal cell suspensions. II. Survival and growth of nigral cells implanted in different brain sites
- 1983
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Ingår i: Acta Physiologica Scandinavica. ; Suppl. 522, s. 9-18
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Tidskriftsartikel (refereegranskat)abstract
- Dissociated dopamine-rich cell suspensions were prepared from the ventral mesencephalon of rat embryos and injected in one or several sites in striatal and non-striatal regions in the dopaminergically denervated brain of adult rats. While the grafts survived well in all sites, the dopamine fibre outgrowth was markedly different depending on whether the grafts occurred in an area normally innervated by the mesencephalic dopamine neurones (i.e. neostriatum or nc. accumbens) or in areas not normally innervated by these neurones (i.e. parietal cortex, lateral hypothalamus or substantia nigra). Moreover, in grafts placed at different sites along the trajectory of the nigrostriatal pathway the outgrowing fibres remained confined to the graft, and there was little evidence that the implanted neurones could elongate their axons along the pathway of the nigrostriatal tract to reach the striatum from a distance. Thus, the intracerebral suspension grafts provided efficient reinnervation of a denervated target only when placed in the immediate vicinity of the target area. The results of multiple graft placements indicate that a relatively complete restoration of a lost innervation should be possible to achieve in large areas of the brain, such as the striatal complex, with the suspension grafting technique.
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| 12. |
- Björklund, Anders, et al.
(författare)
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Intracerebral grafting of neuronal cell suspensions. VI. Survival and growth of intrahippocampal implants of septal cell suspensions
- 1983
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Ingår i: Acta Physiologica Scandinavica. ; Suppl. 522, s. 49-58
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Tidskriftsartikel (refereegranskat)abstract
- The survival and growth of intrahippocampal septal suspension grafts were investigated by acetylcholine esterase (AChE) histochemistry in animals with lesions of the intrinsic septohippocampal cholinergic pathways. AChE was demonstrable in the grafts after the first postoperative week, and AChE-positive fibres were seen to extend into the host hippocampus by 3 weeks. Rapid fibre outgrowth occurred between 3 weeks and 3 months after grafting, and continued at a slower rate thereafter. By 6 months a fairly complete reinnervation of the initially denervated hippocampus was achieved in most specimens, and this persisted at 14 months, the longest postoperative time analysed. A comparison between the development of the AChE-positive neurones in the suspension grafts with that seen during ontogeny in situ suggested that the grafted neurones lagged behind normal development by at least 1 week. Similar to our previous observations on septal grafts implanted as solid tissue pieces, the pattern of the newly-formed AChE-positive innervation in the host hippocampal formation, established from the septal suspension grafts, was remarkably similar to that of the normal AChE-positive septal innervation. This pattern became established as soon as the graft-derived fibres first grew in, suggesting that the ingrowing axons extended and ramified preferentially into those hippocampal subfields which normally receive an AChE-positive innervation from the septal-diagonal band area.
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| 13. |
- Björklund, Anders, et al.
(författare)
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Intracerebral grafting of neuronal cell suspensions. VII. Recovery of choline acetyltransferase activity and acetylcholine synthesis in the denervated hippccampus reinnervated by septal suspension implants
- 1983
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Ingår i: Acta Physiologica Scandinavica. ; Suppl. 522, s. 59-66
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Tidskriftsartikel (refereegranskat)abstract
- The time-course and magnitude of fibre outgrowth from septal suspension grafts injected into the previously denervated hippocampal formation was monitored by measurements of choline acetyltransferase (ChAT), and the activity of the grafted neurons was assessed by measurements of [14C]acetylcholine (ACh) synthesis from [14C]glucose in vitro. Graft-derived ChAT activity was barely detectable 10 days after grafting, but increased sharply between 10 days and 1 month in the areas of the hippocampus located close to the septal implants. By 6 months ChAT activity was restored to near normal levels in all segments of the previously denervated hippocampus. The overall hippocampal [14C]ACh synthesis was also restored to normal levels in the grafted animals, and estimates of the ACh turnover rate suggested that the transmitter machinery of the newly established "septo-hippocampal" connections operated at a rate similar to that of the intrinsic septohippocampal pathway. The intrahippocampal septal suspension grafts, similar to the intrastriatal nigral grafts, thus seem to be capable of maintaining function at a relatively "physiological" level despite their abnormal positions.
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| 14. |
- Clarke, D J, et al.
(författare)
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Synaptogenesis of grafted cholinergic neurons
- 1987
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Ingår i: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923 .- 1749-6632. ; 495:1, s. 268-282
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Tidskriftsartikel (refereegranskat)
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| 15. |
- Dunnett, S. B, et al.
(författare)
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Preface
- 2017
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Ingår i: Functional Neural Transplantation IV Translation to Clinical Application, Part B. - 0079-6123. - 9780128138793 ; 231
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 16. |
- Dunnett, S., et al.
(författare)
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Preface
- 2017
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Ingår i: Functional Neural Transplantation IV Translation to Clinical Application, Part A. - 0079-6123. ; 230
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 17. |
- Gage, F H, et al.
(författare)
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Intracerebral grafting of neuronal cell suspensions. VIII. Cell survival and axonal outgrcwth of dcpaminergic and cholinergic cells in the aged brain.
- 1983
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Ingår i: Acta Physiologica Scandinavica. ; Suppl. 522, s. 67-75
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Tidskriftsartikel (refereegranskat)abstract
- Neuronal cell suspensions prepared from the ventral mesencephalon and the septal-diagonal band area of rat embryos were implanted into the depth of the intact neostriatum or hippocampus of 21-23 month old female rats. Graft survival, assessed 3-4 months after grafting, was comparable to that seen in our previous studies of young adult recipients. Fibre outgrowth into the host brain was evaluated in animals which were subjected to lesions of the intrinsic nigrostriatal or septohippocampal system 6-10 days before killing. Dense dopamine fibre outgrowth was seen within a zone of up to about 1 mm radius around the nigral implants, and dense growth of acetylcholine esterase (AChE) positive fibres occurred up to about 2 mm away from the septal implants. The overall magnitude of fibre outgrowth was less than that generally seen in previously denervated targets in young adult recipients, but it appeared to be as extensive as in young recipients when the grafts are placed in non-denervated targets. The distribution of the AChE-positive fibres from the septal implants in the host hippocampus suggested that the pattern found in the non-denervated target of the aged recipients was more diffuse, and partly different, from normal, and that age-dependent synapse loss in intrinsic connections may influence the patterning of the graft-derived innervation.
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| 18. |
- Kirkeby, A., et al.
(författare)
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Strategies for bringing stem cell-derived dopamine neurons to the clinic : A European approach (STEM-PD)
- 2017
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Ingår i: Functional Neural Transplantation IV Translation to Clinical Application, Part A. - : Elsevier. - 0079-6123. - 9780128117385 ; 230, s. 165-190
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Bokkapitel (refereegranskat)abstract
- The treatment of Parkinson's disease (PD) has for over 50 years relied on dopaminergic therapies that are highly effective especially in the early years of the condition, but ultimately are limited by the development of side effects that relate to the nonphysiological stimulation of dopamine receptors including in nonstriatal areas. Targeted regenerative therapies designed to restore specifically the lost dopaminergic innervation of the striatum would therefore represent a major advance in treating PD. Transplantation of human fetal ventral midbrain tissue to the striatum of PD patients has provided proof-of-principle that such an approach can provide long-term clinical benefits with a reduced dependency on any oral dopaminergic agents. However, fetal tissue is associated with several ethical and logistical problems and therefore does not represent a realistic route to the clinical treatment of PD in the future. As a result, alternative cell sources have been explored and the methods for producing authentic midbrain dopaminergic neurons from pluripotent cells have now advanced to a stage which makes it possible to efficiently and reproducibly produce DA progenitors at a much higher purity than can be obtained from human fetal tissue. A stem cell-based therapy for PD therefore has the potential to circumvent many of the problems currently associated with fetal tissue grafting. Here, we describe the challenges faced and the strategies that have been pursued in our European effort to bring a human embryonic stem cell (hESC)-derived dopamine cell product to clinical trial for PD.
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| 19. |
- Kokaia, Z., et al.
(författare)
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Transplantation of reprogrammed neurons for improved recovery after stroke
- 2017
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Ingår i: Functional Neural Transplantation IV Translation to Clinical Application, Part B. - : Elsevier. - 0079-6123. - 9780128138793 ; 231, s. 245-263
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Bokkapitel (refereegranskat)abstract
- Somatic cells such as fibroblasts, reprogrammed to induced pluripotent stem cells, can be used to generate neural stem/progenitor cells or neuroblasts for transplantation. In this review, we summarize recent studies demonstrating that when grafted intracerebrally in animal models of stroke, reprogrammed neurons improve function, probably by several different mechanisms, e.g., trophic actions, modulation of inflammation, promotion of angiogenesis, cellular and synaptic plasticity, and neuroprotection. In our own work, we have shown that human skin-derived reprogrammed neurons, fated to cortical progeny, integrate in stroke-injured neuronal network and form functional afferent synapses with host neurons, responding to peripheral sensory stimulation. However, whether neuronal replacement plays a role for the improvement of sensory, motor, and cognitive deficits after transplantation of reprogrammed neurons is still unclear. We conclude that further preclinical studies are needed to understand the therapeutic potential of grafted reprogrammed neurons and to define a road map for their clinical translation in stroke.
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| 20. |
- Leanza, G, et al.
(författare)
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Selective immunolesioning of the basal forebrain cholinergic system disrupts short-term memory in rats
- 1996
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Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 8:7, s. 1535-4154
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Tidskriftsartikel (refereegranskat)abstract
- Selective depletion of nerve growth factor receptor-bearing neurons in the basal forebrain cholinergic system nuclei by the immunotoxin 192 IgG-saporin offers a new and highly useful tool for the study of the role of the forebrain cholinergic system in cognitive functions. In the present study, we have tested the effects of 192 IpG-saporin in an operant delayed matching-to-position task which has previously been used to discriminate between delay-dependent learning impairments and delay-independent disturbances of non-mnemonic processes. Rats were first trained to criterion performance and then received intraventricular injections of 5 microg of 192 IgG-saporin 4 weeks prior to a second testing session. Rats with 192 IgG-saporin lesions displayed a significant delay-dependent decline in performance compared to normal controls, indicating a deficit in short-term memory. Administration of the muscarinic blocker scopolamine (0.5 mg/kg, i.p.) produced more pronounced impairment in the performance of the normal control rats across all delays, and induced further impairment also in animals with 192 IgG-saporin lesions. These effects were not observed following control injections of methyl scopolamine, suggesting that the impairment induced by scopolamine was due to the blockade of central muscarinic receptors. No improvement in performance was observed in either group following systemic treatment with the muscarinic cholinergic agonist arecoline (1.00 mg/kg). Biochemical and morphological analyses confirmed the selective and severe (>90-95%) depletion of cholinergic neurons throughout the septal-diagonal band area and the nucleus basalis region by the intraventricular 192 IgG-saporin treatment. Although the immunotoxin was observed to produce additional damage to the cerebellar Purkinje cells, no gross motor abnormalities were observed that could contribute to the effects on accuracy in the task used here. In conclusion, the results show that selective combined lesions of the basal forebrain cholinergic neurons in the septal-diagonal band area and nucleus basalis produce long-lasting impairments in short-term memory, thus providing further support for a role of this system in cognitive functions.
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| 21. |
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| 22. |
- Schmidt, R H, et al.
(författare)
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Intracerebral grafting of neuronal cell suspensions. III. Activaty of intrastriatal nigral suspension implants as assessed by measurements of dopamine synthesis and metabolism
- 1983
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Ingår i: Acta Physiologica Scandinavica. ; Suppl. 522, s. 19-28
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Tidskriftsartikel (refereegranskat)abstract
- The activity of intrastriatal grafts of nigral cell suspensions has been monitored biochemically, using radioenzymatic assays of dopamine, its major acidic metabolite, DOPAC, and DOPA accumulation after DOPA-decarboxylase inhibition. Implants of 4-9 microliter of nigral cell suspension restored striatal DA levels by an average of 13-18%, with the highest individual values reaching about 50% of control. DOPAC was restored from about 5% in the lesioned controls to about 20% of normal in the grafted animals. The DOPAC: DA ratios and the DOPA accumulation measures indicated that the grafted DA neurons were spontaneously active and that the transmitter turnover rate was on the average some 50-100% higher than the intact intrinsic nigrostriatal DA neurones. These results thus provide evidence that the intrastriatal nigral suspension grafts are capable of restoring dopaminergic neurotransmission in the previously denervated striatum.
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| 23. |
- Thompson, Lachlan, et al.
(författare)
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Survival, differentiation, and connectivity of ventral mesencephalic dopamine neurons following transplantation
- 2012
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Ingår i: Functional Neural Transplantation III : Primary and Stem Cell Therapies for Brain Repair, Part I - Primary and Stem Cell Therapies for Brain Repair, Part I. - 0079-6123. - 9780444595751 ; 200, s. 61-95
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Bokkapitel (refereegranskat)abstract
- The reconstruction of midbrain dopamine (DA) circuitry through intracerebral transplantation of new DA neurons contained in embryonic ventral mesencephalon (VM) is a promising therapeutic approach for Parkinson's disease (PD). Although some of the early open-label trials have provided proof-of-principal that VM grafts can provide sustained improvement of motor function in some patients, subsequent trials showed that the functional response can be highly variable. This chapter reviews an extensive body of basic and clinical research on the survival, differentiation, and connectivity of DA neurons in VM grafts, and also looks at how these parameters are affected by certain host- and donor-specific variables. We also review how technical advances in the tools available to study the integration of grafted DA neurons, such as transgenic reporter mice, have made significant contributions to our understanding of the capacity of different DA neuronal subtypes for target-directed growth and innervation of appropriate host brain structures. Our established and on-going understanding of the capacity of grafted DA neurons to structurally and functionally integrate following transplantation forms an important basis for the refinement and optimization of VM grafting procedures, and also the development of new procedures based on the use of stem cells.
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| 24. |
- Zander, K.K., et al.
(författare)
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Indigenous cultural and natural resources management and mobility in Arnhem Land, northern Australia
- 2014
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Ingår i: Human Ecology. - : Springer. - 0300-7839 .- 1572-9915. ; 42:3, s. 443-453
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Tidskriftsartikel (refereegranskat)abstract
- Many programmes formally engage Australian Indigenous people in land and sea management to provide environmental services. There are also many Indigenous people who 'look after country' without rewards or payment because of cultural obligations. We investigated how Indigenous peoples' mobility in and around two communities (Maningrida and Ngukurr) is affected by their formal or informal engagement in cultural and natural resource management (CNRM). Understanding factors that influence peoples' mobility is important if essential services are to be provided to communities efficiently. We found that those providing formal CNRM were significantly less likely to stay away from settlements than those 'looking after their country' without payment or reward. Paying Indigenous people to engage with markets for CNRM through carbon farming or payments for environmental services (PES) schemes may alter traditional activities and reduce mobility, particularly movements away from communities that extend the time spent overnight on country. This could have both environmental and social consequences that could be managed through greater opportunities for people to engage in formal CNRM while living away from communities and greater recognition of the centrality of culture to all Indigenous CNRM, formal or otherwise.
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