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Showing papers by "Anders Björklund published in 1998"


Journal ArticleDOI
TL;DR: The results indicate that the four-site intrastriatal 6-OHDA lesion may be a relevant model of the neuropathology seen in parkinsonian patients in a manifest symptomatic stage of the disease and may be particularly useful experimentally since it leaves a significant portion of the nigrostriatal projection intact which can serve as a substrate for regeneration and functional recovery in response to growth promoting and neuroprotective agents.

660 citations


Journal ArticleDOI
TL;DR: Rats sustaining unilateral near‐complete 6‐hydroxydopamine lesions of the mesostriatal dopamine pathway received daily injections of 3,4 dihydroxyphenyl‐l‐alanine (L‐DOPA, 8 mg/kg plus 15mg/kg benserazide) for 3 weeks and gradually developed abnormal involuntary movements.
Abstract: Rats sustaining unilateral near-complete 6-hydroxydopamine lesions of the mesostriatal dopamine pathway received daily injections of 3, 4 dihydroxyphenyl-l-alanine (L-DOPA, 8 mg/kg plus 15 mg/kg benserazide) for 3 weeks. During this period, about 50% of the rats gradually developed abnormal involuntary movements, lasting for 2-3 h following each L-DOPA dose. Rats were killed 3 days after the last L-DOPA injection, and sections through the striatum were processed for in situ hybridization histochemistry. Within the L-DOPA-treated group, levels of preproenkephalin (PPE) mRNA, glutamic acid decarboxylase (GAD67) mRNA, and prodynorphin (PDyn) mRNA in the dopamine-denervated caudate-putamen, as well as GAD67 mRNA expression in the globus pallidus ipsilateral to the 6-hydroxydopamine (6-OHDA) lesion, were higher in dyskinetic than non-dyskinetic animals, and positively correlated with the rats' dyskinesia scores. By contrast, striatal preprotachykinin mRNA expression and D2 receptor-radioligand binding were not significantly associated with dyskinesia. Among all these markers, PDyn mRNA levels showed the most pronounced treatment-dependence (three times higher in the L-DOPA-treated group than in saline-injected lesion-only controls), and the strongest correlation with the rats' dyskinesia scores (r2 = 0.82). However, a multiple regression equation including the three factors, GAD67 mRNA levels in the GP, GAD67 mRNA in the lateral CPu, and striatal PDyn mRNA, gave a better fit for dyskinesia scores than PDyn mRNA alone (r2 = 0.92). The results show that L-DOPA-induced dyskinesia is associated with overexpression of PDyn and GAD67 mRNA in the striatal projection neurons, and GAD67 mRNA levels in the globus pallidus. Due to its treatment-dependent expression, and strong correlation with the associated dyskinetic symptoms, striatal PDyn mRNA, in particular, may play a role in the mechanisms of behavioural sensitization brought about by the drug.

637 citations


Journal ArticleDOI
TL;DR: It is suggested that neurturin (NTN), a homolog of GDNF, is expressed in the nigrostriatal system, and that NTN exerts potent effects on survival and function of midbrain DA neurons and point to the possibility that GDNF and NTN may exert redundant trophic influences on nigral DA neurons acting via a receptor complex that includes GFRα1.
Abstract: Glial cell line-derived neurotrophic factor (GDNF) exhibits potent effects on survival and function of midbrain dopaminergic (DA) neurons in a variety of models. Although other growth factors expressed in the vicinity of developing DA neurons have been reported to support survival of DA neurons in vitro, to date none of these factors duplicate the potent and selective actions of GDNF in vivo. We report here that neurturin (NTN), a homolog of GDNF, is expressed in the nigrostriatal system, and that NTN exerts potent effects on survival and function of midbrain DA neurons. Our findings indicate that NTN mRNA is sequentially expressed in the ventral midbrain and striatum during development and that NTN exhibits survival-promoting actions on both developing and mature DA neurons. In vitro, NTN supports survival of embryonic DA neurons, and in vivo, direct injection of NTN into the substantia nigra protects mature DA neurons from cell death induced by 6-OHDA. Furthermore, administration of NTN into the striatum of intact adult animals induces behavioral and biochemical changes associated with functional upregulation of nigral DA neurons. The similarity in potency and efficacy of NTN and GDNF on DA neurons in several paradigms stands in contrast to the differential distribution of the receptor components GDNF Family Receptor alpha1 (GFRalpha1) and GFRalpha2 within the ventral mesencephalon. These results suggest that NTN is an endogenous trophic factor for midbrain DA neurons and point to the possibility that GDNF and NTN may exert redundant trophic influences on nigral DA neurons acting via a receptor complex that includes GFRalpha1.

347 citations


Journal ArticleDOI
TL;DR: The results suggest that the neuronal diversity of the adult striatum may derive both from the lateral ganglionic eminence, providing DARPP-32-expressing projection neurons as well as somatostatin-containing interneurons, and the early stage medial ganglionics eminence specifically contributing the cholinergic interneuron.

174 citations


Journal ArticleDOI
TL;DR: The results suggest that EGF-responsive progenitor cells can respond to host derived environmental cues, differentiate into cells with glial-like features, and become integrated in the developing recipient brain.

141 citations


Journal ArticleDOI
TL;DR: In this paper, the authors examined the effects of unemployment on mental health in Denmark, Finland, Norway and Sweden, using cross-sectional, longitudinal, and time-series data, and discussed studies that investigated the duration-dependence issue in exit rates out of unemployment.
Abstract: In this article we examine research on effects of unemployment on mental health in Denmark, Finland, Norway and Sweden. We describe studies that use cross-sectional, longitudinal and time-series data, and we discuss studies that investigated the duration-dependence issue in exit rates out of unemployment. Not surprisingly, cross-sectional studies reveal that unemployed persons have worse mental health than do others. Most longitudinal studies suggest that unemployment is associated with deteriorating mental health, even though it is somewhat unclear how long such an effect persists. Most duration-dependence studies were done using Swedish data. It turns out that unemployment benefits and labour-market policies affect the pattern of exit rates out of unemployment.

120 citations


Journal ArticleDOI
TL;DR: In this article, the authors showed that long-term supply of NGF from ex vivo transduced immortalized neural progenitor cells locally within the nucleus basalis and septum can prevent the subsequent development of age-dependent neuronal atrophy and behavioral impairments when the animals reach advanced age.
Abstract: Nerve growth factor (NGF) is able to restore spatial learning and reverse forebrain cholinergic neuron atrophy when administered intracerebrally to behaviorally impaired aged rats. In the present study, behaviorally unimpaired, middle-aged rats (14–16 months old) received transplants of ex vivo transduced, clonal NGF-secreting immortalized neural progenitor cells, bilaterally in the nucleus basalis and septum. During the subsequent 9 months the aged control animals developed the expected impairment in spatial learning in the water maze task, whereas the animals with NGF-secreting grafts maintained a performance level not different from the 12-month-old control rats. The marked age-induced atrophy (−25%) of the cholinergic neurons in medial septum and nucleus basalis, seen in the aged control rats, was not present in the NGF-treated aged animals. 3H-labeled thymidine autoradiography showed that the transduced cells survived well and had become integrated into the host tissue surrounding the injection sites, and reverse transcription–PCR analysis revealed expression of the NGF transgene, at both 4 and 9 months postgrafting, in the grafted tissue. The results show that long-term supply of NGF from ex vivo transduced immortalized neural progenitor cells locally within the nucleus basalis and septum can prevent the subsequent development of age-dependent neuronal atrophy and behavioral impairments when the animals reach advanced age.

85 citations


01 Jan 1998
TL;DR: Results show that long-term supply of NGF from ex vivo transduced, clonal NGF-secreting immortalized neural progenitor cells locally within the nucleus basalis and septum can prevent the subsequent development of age-dependent neuronal atrophy and behavioral impairments when the animals reach advanced age.
Abstract: Nerve growth factor (NGF) is able to restore spatial learning and reverse forebrain cholinergic neuron atro- phy when administered intracerebrally to behaviorally impaired aged rats. In the present study, behaviorally unimpaired, middle- aged rats (14-16 months old) received transplants of ex vivo transduced, clonal NGF-secreting immortalized neural progen- itor cells, bilaterally in the nucleus basalis and septum. During the subsequent 9 months the aged control animals developed the expected impairment in spatial learning in the water maze task, whereas the animals with NGF-secreting grafts maintained a performance level not different from the 12-month-old control rats. The marked age-induced atrophy (225%) of the cholinergic neurons in medial septum and nucleus basalis, seen in the aged control rats, was not present in the NGF-treated aged animals. 3 H-labeled thymidine autoradiography showed that the trans- duced cells survived well and had become integrated into the host tissue surrounding the injection sites, and reverse transcription- PCR analysis revealed expression of the NGF transgene, at both 4 and 9 months postgrafting, in the grafted tissue. The results show that long-term supply of NGF from ex vivo transduced immortalized neural progenitor cells locally within the nucleus basalis and septum can prevent the subsequent development of age-dependent neuronal atrophy and behavioral impairments when the animals reach advanced age. Studies in rodents have shown that the basal forebrain cholinergic system undergoes progressive degenerative changes with advanc- ing age, and that the magnitude of these changes generally is

82 citations


Journal ArticleDOI
TL;DR: Results demonstrate that incorporation of neural progenitors across the ventricular wall in the embryonic host is strictly developmentally regulated, dependent on their position along the antero‐posterior axes and in the case of progenitor from the LGE is mediated by cell‐surface molecules expressed on the transplanted cells.
Abstract: During development, telencephalic neural progenitors acquire positional specification and give rise to distinct structures such as the striatum and cortex. Here, we examine, in vivo, the influence of developmental stage, cell-surface molecules and regional differences along the dorso-ventral and antero-posterior axes on the selective incorporation of neural progenitors derived from different regions of the developing brain, utilizing a cross-species in utero transplantation paradigm. Striatal progenitors derived from the embryonic day (E) 12-14 mouse lateral ganglionic eminence (LGE) were observed consistently to incorporate into the developing striatum as early as 24-48 h following intraventricular injection into the E15-17 rat host. By removing cell-surface molecules from the LGE progenitors, the pattern of incorporation was remarkably different with no preferential striatal incorporation. Cortical progenitors with intact cell-surface molecules, by contrast, displayed little telencephalic (including striatal) incorporation as compared with precursors from the LGE. However, both progenitors from cortex and LGE incorporated widely into diencephalic and mesencephalic structures. The capacity for integration of precursors derived from the LGE and cortex gradually decreased during development of the host and was minimal in the postnatal day (P) 1 host. Unlike the telencephalic precursors, the vast majority of progenitors derived from the midbrain and cerebellar primordium (with cell-surface molecules intact) incorporated into diencephalic and midbrain nuclei with only a few cells observed in the telencephalon. These results demonstrate that incorporation of neural progenitors across the ventricular wall in the embryonic host is strictly developmentally regulated, dependent on their position along the antero-posterior axes and in the case of progenitors from the LGE is mediated by cell-surface molecules expressed on the transplanted cells.

55 citations



Journal ArticleDOI
TL;DR: Foetal cholinergic grafts implanted at multiple sites into both the hippocampus and fronto‐parietal neocortex, bilaterally, completely reversed the acquisition deficit in place navigation in the water maze, to an extent that greatly exceeded that previously seen in animals with non‐selective lesions.
Abstract: Impairments in learning and memory, induced by surgical or excitotoxic lesions of the septo-hippocampal or basalo-cortical pathways, can be ameliorated by grafts of cholinergic-rich foetal basal forebrain tissue into the hippocampus and/or neocortex. However, the effects of such grafts have been only partial, which may be due to the non-specific nature of the lesioning procedures used in these studies, known to destroy both cholinergic and non-cholinergic neuronal projections. In the present study, we have explored the effects of cholinergic-rich grafts in rats subjected to selective cholinergic lesions, induced by intraventricular injections of the immunotoxin 192 IgG-saporin. This lesion, which selectively destroyed 85-95% of the cholinergic neurons in both the septal-diagonal band and nucleus basalis, produced a long-lasting, substantial impairment in both the acquisition of spatial reference memory in the Morris water maze task and delay-dependent short-term memory performance, as seen in a delayed matching-to-position test. Foetal cholinergic grafts (but not control grafts of cerebellar tissue) implanted at multiple sites into both the hippocampus and fronto-parietal neocortex, bilaterally, completely reversed the acquisition deficit in place navigation in the water maze, to an extent that greatly exceeded that previously seen in animals with non-selective lesions. Most notably, however, the impairment in short-term memory was only partially and inconsistently affected, and only at the longest delay times. The morphological analysis, performed at about 7 months after transplantation, showed that the grafts had re-established a close to normal cholinergic innervation in the initially denervated cortical and hippocampal territories. It is proposed that the differential effects of cholinergic-rich transplants on different aspects of cognitive performance may define intrinsic limitations to the functional capacity of the ectopically placed grafts, which may be due to incomplete integration of the grafted cholinergic neurons into functional regulatory circuitries normally available to the basal forebrain cholinergic system.

Journal ArticleDOI
TL;DR: The results suggest the presence of a highly favourable substrate for glial migration along developing fibre tracts, but, more importantly, indicates the potential for certain glia to respond to particular (region-specific) distal cues within the developing brain.


Journal ArticleDOI
TL;DR: The present results suggest that overexpression of NGF during development may promote the survival of distinct populations of central cholinergic neurones into adulthood.
Abstract: Nerve growth factor (NGF) is a maintenance factor for cholinergic neurones in the brain, but its properties as a developmental survival factor are largely unknown. The low accessibility of the developing mammalian brain to experimental manipulation makes it difficult to increase NGF levels during the early phases of brain development. In the present study we have used an in utero, ex-vivo gene transfer approach to explore NGF actions during development of the cholinergic system in the rat brain. Significantly increased numbers of cholinergic neurones were found only in the mesopontine complex in animals receiving NGF-secreting transplants, whereas the cholinergic neurones in the basal forebrain and striatum were not clearly affected. The present results suggest that overexpression of NGF during development may promote the survival of distinct populations of central cholinergic neurones into adulthood.