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Biomedical subjects

Olle Lindvall

Publications and source records attributed to Olle Lindvall.

At least 37 records · Page 2Linked to original sources
PubMed2005

Forebrain acetylcholine regulates adult hippocampal neurogenesis and learning.

Hippocampus-mediated learning enhances neurogenesis in the adult dentate gyrus (DG), and this process has been suggested to be involved in memory formation. The hippocampus receives abundant cholinergic innervation and acetylcholine (ACh) plays an important role in learning and Alzheimer's disease (AD) pathophysiology. Here, we show that a selective neurotoxic lesion of forebrain cholinergic input with 192 IgG-saporin reduces DG neurogenesis with a concurrent impairment in spatial memory. Conversely, systemic administration of the cholinergic agonist physostigmine increases DG neurogenesis. We find that changes of forebrain ACh levels primarily influence the proliferation and/or the short-term survival rather than the long-term survival or differentiation of the new neurons. We further demonstrate that these newly born cells express the muscarinic receptor subtypes M1 and M4. Our data provide evidence that forebrain ACh promotes neurogenesis, and suggest that the impaired cholinergic function in AD may in part contribute to deficits in learning and memory through reductions in the formation of new hippocampal neurons.

Acetylcholine↗
PubMed2005

Functional properties and synaptic integration of genetically labelled dopaminergic neurons in intrastriatal grafts.

Intrastriatal grafts of fetal ventral mesencephalic tissue, rich in dopaminergic neurons, can reverse symptoms in Parkinson's disease. For development of effective cell replacement therapy, other sources of dopaminergic neurons, e.g. derived from stem cells, are needed. However, the electrophysiological properties grafted cells need to have in order to induce substantial functional recovery are poorly defined. It has not been possible to prospectively identify and record from dopaminergic neurons in fetal transplants. Here we used transgenic mice expressing green fluorescent protein under control of the rat tyrosine hydroxylase promoter for whole-cell patch-clamp recordings of endogenous and grafted dopaminergic neurons. We transplanted ventral mesencephalic tissue from E12.5 transgenic mice into striatum of neonatal rats with or without lesions of the nigrostriatal dopamine system. The transplanted cells exhibited intrinsic electrophysiological properties typical of substantia nigra dopaminergic neurons, i.e. broad action potentials, inward rectifying currents with characteristic 'sag', and spontaneous action potentials. The grafted dopaminergic neurons also received functional excitatory and inhibitory synaptic inputs from the host brain, as shown by the presence of both spontaneous and stimulation-evoked excitatory and inhibitory postsynaptic currents. Occurrence of spontaneous excitatory and inhibitory currents was lower, and of spontaneous action potentials was higher, in neurons placed in the dopamine-depleted striatum than of those in the intact striatum. Our findings define specific electrophysiological characteristics of transplanted fetal dopaminergic neurons, and we provide the first direct evidence of functional synaptic integration of these neurons into host neural circuitries.

Animals↗
PubMed2005

Stem cell therapy for human brain disorders.

Transplantation of stem cells or their derivatives, and mobilization of endogenous stem cells in the adult brain, have been proposed as future therapies for various brain disorders such as Parkinson's disease and stroke. In support, recent progress shows that neurons suitable for transplantation can be generated from stem cells in culture, and that the adult brain produces new neurons from its own stem cells in response to injury. However, from a clinical perspective, the development of stem cell-based therapies for brain diseases is still at an early stage. Many basic issues remain to be solved and we need to move forward with caution and avoid scientifically ill-founded trials in patients. We do not know the best stem cell source, and research on embryonic stem cells and stem cells from embryonic or adult brain or from other tissues should therefore be performed in parallel. We need to understand how to control stem cell proliferation and differentiation into specific cell types, induce their integration into neural networks, and optimize the functional recovery in animal models closely resembling the human disease. All these scientific efforts are clearly justified because, for the first time, there is now real hope that we in the future can offer patients with currently intractable diseases effective cell-based treatments to restore brain function.

Brain Diseases↗
PubMed2004

Recovery and rehabilitation in stroke: stem cells.

The recent demonstration that neurons for transplantation can be generated from stem cells and that the adult brain produces new neurons in response to stroke has raised hope for the development of a stem cell therapy for patients affected with this disorder. In this review we propose a road map to the clinic and describe the different scientific tasks that need to be accomplished to move stem cell-based approaches toward application in stroke patients.

Animals↗
PubMed2004

Status epilepticus severity influences the long-term outcome of neurogenesis in the adult dentate gyrus.

Status epilepticus (SE) is characterized by continual seizure activity that can vary widely in the intensity of convulsions. We induced seizures by applying continuous electrical stimulation to the hippocampus in adult rats to explore the effects of three different SE states on neurogenesis and neuronal death in the hippocampus. Rats exhibiting the most severe SE state (fully convulsive) demonstrated profound increases in cell proliferation in the dentate gyrus (DG) at 1 week post-insult, but the majority of the new neurons had died at 4 weeks. In contrast, rats exhibiting less severe SE states (ambulatory or masticatory, partial convulsive) had the same degree of cell proliferation at 1 week, but most new neurons survived at 4 weeks. As compared to partially convulsive SE rats, fully convulsive SE rats had significantly greater DG pathology. Our data indicate that SE of varying severity triggers similar short-term proliferation of neural progenitors, but that the long-term outcome of neurogenesis is influenced by the degree of insult-induced degeneration in the DG tissue environment.

Animals↗
PubMed2004

Stem cell therapy for human neurodegenerative disorders-how to make it work.

Recent progress shows that neurons suitable for transplantation can be generated from stem cells in culture, and that the adult brain produces new neurons from its own stem cells in response to injury. These findings raise hope for the development of stem cell therapies in human neurodegenerative disorders. Before clinical trials are initiated, we need to know much more about how to control stem cell proliferation and differentiation into specific phenotypes, induce their integration into existing neural and synaptic circuits, and optimize functional recovery in animal models closely resembling the human disease.

Animals↗
PubMed2004

Cell therapy in Parkinson's disease.

The clinical studies with intrastriatal transplants of fetal mesencephalic tissue in Parkinson's disease (PD) patients have provided proof-of-principle for the cell replacement strategy in this disorder. The grafted dopaminergic neurons can reinnervate the denervated striatum, restore regulated dopamine (DA) release and movement-related frontal cortical activation, and give rise to significant symptomatic relief. In the most successful cases, patients have been able to withdraw L-dopa treatment after transplantation and resume an independent life. However, there are currently several problems linked to the use of fetal tissue: 1) lack of sufficient amounts of tissue for transplantation in a large number of patients, 2) variability of functional outcome with some patients showing major improvement and others modest if any clinical benefit, and 3) occurrence of troublesome dyskinesias in a significant proportion of patients after transplantation. Thus, neural transplantation is still at an experimental stage in PD. For the development of a clinically useful cell therapy, we need to define better criteria for patient selection and how graft placement should be optimized in each patient. We also need to explore in more detail the importance for functional outcome of the dissection and cellular composition of the graft tissue as well as of immunological mechanisms. Strategies to prevent the development of dyskinesias after grafting have to be developed. Finally, we need to generate large numbers of viable DA neurons in preparations that are standardized and quality controlled. The stem cell technology may provide a virtually unlimited source of DA neurons, but several scientific issues need to be addressed before stem cell-based therapies can be tested in PD patients.

Animals↗
PubMed2003

Inflammation is detrimental for neurogenesis in adult brain.

New hippocampal neurons are continuously generated in the adult brain. Here, we demonstrate that lipopolysaccharide-induced inflammation, which gives rise to microglia activation in the area where the new neurons are born, strongly impairs basal hippocampal neurogenesis in rats. The increased neurogenesis triggered by a brain insult is also attenuated if it is associated with microglia activation caused by tissue damage or lipopolysaccharide infusion. The impaired neurogenesis in inflammation is restored by systemic administration of minocycline, which inhibits microglia activation. Our data raise the possibility that suppression of hippocampal neurogenesis by activated microglia contributes to cognitive dysfunction in aging, dementia, epilepsy, and other conditions leading to brain inflammation.

Animals↗
PubMed2003

Intraventricular infusion of TrkB-Fc fusion protein promotes ischemia-induced neurogenesis in adult rat dentate gyrus.

BACKGROUND AND PURPOSE: We have previously shown that delivery of brain-derived neurotrophic factor (BDNF) through direct intrahippocampal gene transduction with a viral vector suppresses the formation of new dentate granule cells triggered by global forebrain ischemia. Here, we investigated whether inhibition of endogenous BDNF alters ischemia-induced neurogenesis in the dentate gyrus. METHODS: Rats were subjected to 30 minutes of global forebrain ischemia and then received intraventricular infusion of either the BDNF scavenger, TrkB-Fc fusion protein, or control Hu-Fc for 2 weeks. In parallel, all animals were injected intraperitoneally with the mitosis marker 5-bromo-2'-deoxyuridine-5'-monophosphate (BrdU). Animals were killed at 2 or 6 weeks after the ischemic insult, and neurogenesis was then assessed immunocytochemically with epifluorescence or confocal microscopy. RESULTS: Infusion of TrkB-Fc fusion protein gave rise to elevated numbers of ischemia-generated new neurons, double-labeled with BrdU and the early neuronal marker Hu or the mature neuronal marker NeuN, in the dentate subgranular zone and granule cell layer at 2 and 6 weeks after the insult. CONCLUSIONS: Our findings provide evidence that endogenous BDNF counteracts neuronal differentiation, but not cell proliferation or survival, in ischemia-induced dentate gyrus neurogenesis.

Animals↗
PubMed2003

Health status measurement in Parkinson's disease: validity of the PDQ-39 and Nottingham Health Profile.

We assessed the feasibility and psychometric properties of two commonly used health status questionnaires in Parkinson's disease (PD): the generic Nottingham Health Profile (NHP) and the disease-specific 39-item Parkinson's disease Questionnaire (PDQ-39), from a cross-sectional postal survey of PD patients (N = 81), using traditional and Rasch measurement methodologies. Overall response rate was 88%. Both questionnaires were found feasible, although the NHP performed less well. The PDQ-39 had fewer floor effects and was better able to separate respondents into distinct groups than the NHP, whereas the latter exhibited less ambiguous dimensionality and better targeting of respondents with non-extreme scores. Reliability and validity indices were similar, and potential differential item functioning by age and gender groups was found for both questionnaires. PDQ-39 response alternatives indicated ambiguity. With few exceptions, questionnaire scales were unable to meet recommended standards fully. While preliminary, this study illustrates the need for thorough evaluation of outcome measures and has implications beyond the questionnaires used here. Although promising, both questionnaires warrant further developmental work and stronger support of measurement validity before they could be considered fully suitable for valid use in PD, in particular in earlier stages of the disease.

Activities of Daily Living↗
PubMed2003

Elevated GDNF levels following viral vector-mediated gene transfer can increase neuronal death after stroke in rats.

Previous studies have indicated that administration of glial cell line-derived neurotrophic factor (GDNF) counteracts neuronal death after stroke. However, in these studies damage was evaluated at most a few days after the insult. Here, we have explored the long-term consequences of two routes of GDNF delivery to the rat striatum prior to stroke induced by 30 min of middle cerebral artery occlusion (MCAO): striatal transduction with a recombinant lentiviral vector or transduction of the substantia nigra with a recombinant adeno-associated viral vector and subsequent anterograde transport of GDNF to striatum. Despite high GDNF levels, stereological quantification of striatal neuron numbers revealed no protection at 5 or 8 weeks after MCAO. In fact, anterograde GDNF delivery exacerbated neuronal loss. Moreover, supply of GDNF did not alleviate the striatum-related behavioral deficits. Thus, we demonstrate that the actions of GDNF after stroke are more complex than previously believed and that high levels of this factor, which are neuroprotective in models of Parkinson's disease, can increase ischemic damage. Our findings also underscore the need for quantitative assessment of long-term neuronal survival and behavioral changes to evaluate the therapeutic potential of factors such as GDNF.

Adenoviridae↗
PubMed2003

Death mechanisms in status epilepticus-generated neurons and effects of additional seizures on their survival.

Status epilepticus (SE) increases neurogenesis in the subgranular zone (SGZ) of the adult dentate gyrus, but many of the newborn cells die, partly through caspase-induced apoptosis. Here we provide immunohistochemical evidence indicating that the caspase-evoked death of the new neurons involves the mitochondrial but not the death-receptor-mediated pathway. Cytochrome c released from mitochondria was found in a subset of progenitor cell progeny, while Fas ligand and tumor necrosis factor 1 receptor-associated domain as well as the mitochondria-related, caspase-independent apoptosis-inducing factor were not detected. We also show that additional seizures, induced at different stages during neuronal differentiation of progenitor cell progeny following SE, neither potentiate cell death mechanisms in the SGZ nor compromise the survival of the new cells. Thus, we found similar expression of cytochrome c, active caspase-3, caspase-cleaved PARP, and TUNEL/Hoechst-positive DNA fragmentation, as well as numbers of new cells in the SGZ in rats exposed to additional seizures at days 6 and 7 or days 33 and 34 following SE as in control animals only subjected to SE. We propose that the degree of survival of newly generated neurons is determined primarily by the initial SE insult and the ensuing pathology in the tissue environment, whereas spontaneous seizures play a minor role.

Animals↗
PubMed2003

Suppression of limbic motor seizures by electrical stimulation in thalamic reticular nucleus.

Kindling is a model of temporal lobe epilepsy in which repeated electrical stimulations in limbic areas lead to progressive increase of seizure susceptibility, culminating in generalized convulsions and the establishment of a permanent epileptic syndrome. We studied here the effect of stimulations in the thalamic reticular nucleus (TRN) on the development of seizures and hippocampal hyperexcitability in kindling elicited from the ventral hippocampus in rats. Animals given 12 kindling stimulations per day with 30-min intervals for 4 consecutive days developed generalized convulsions on day 4. Stimulations in TRN delivered simultaneously with those in the hippocampus induced marked suppression of seizure generalization. Similarly, the number of generalized seizures and the duration of behavioral convulsions were reduced when rats subjected to 40 kindling stimulations with 5-min intervals during about 3 h were costimulated in the TRN. The anticonvulsant effect of TRN costimulation was detected also when rats were test-stimulated in the hippocampus at 24 h and 2 and 4 weeks after the initial 40 hippocampal stimulations. Our data provide the first evidence that TRN stimulations can act to suppress limbic motor seizures in hippocampal kindling and suggest a new approach for seizure control in temporal lobe epilepsy.

Animals↗
PubMed2003

Neurogenesis after ischaemic brain insults.

Evidence for neuronal self-repair following insults to the adult brain has been scarce until very recently. Ischaemic insults have now been shown to trigger neurogenesis from neural stem cells or progenitor cells located in the dentate subgranular zone, the subventricular zone lining the lateral ventricle, and the posterior periventricle adjacent to the hippocampus. New neurons migrate to the granule cell layer or to the damaged CA1 region and striatum, where they express morphological markers characteristic of those neurons that have died. Some evidence indicates that these neurons can re-establish connections and contribute to functional recovery.

Animals↗
PubMed2003

Stem cells for cell therapy in Parkinson's disease.

Clinical studies with intrastriatal transplants of human embryonic mesencephalic tissue have provided proof-of-principle for the cell replacement strategy in Parkinson's disease (PD) patients. The grafted dopaminergic neurons can reinnervate the denervated striatum, restore regulated dopamine (DA) release and movement-related frontal cortical activation, and give rise to significant symptomatic relief. However, there are several problems linked to the use of primary embryonic tissue: (i) lack of sufficient amounts of tissue for transplantation in a large number of patients; (ii) variability of functional outcome, with some patients showing major improvement and others modest if any clinical benefit; (iii) occurrence of troublesome dyskinesias in a significant proportion of patients after transplantation. Stem cells could be useful to generate large numbers of DA neurons in standardized and quality-controlled preparations. So far, neurons with at least some dopaminergic characteristics have been generated from stem cells. However, in most cases their survival after grafting in animal PD models has been poor and it is also unclear if they function as normal mesencephalic DA neurons. For the development of a clinically useful cell therapy in PD, it is also necessary to define better criteria for patient selection and how graft placement should be optimized in each patient. Several scientific issues need to be addressed before stem cell-based therapies can be tested in PD patients.

Cell Differentiation↗
PubMed2003

Anterograde delivery of brain-derived neurotrophic factor to striatum via nigral transduction of recombinant adeno-associated virus increases neuronal death but promotes neurogenic response following stroke.

To explore the role of brain-derived neurotrophic factor for survival and generation of striatal neurons after stroke, recombinant adeno-associated viral vectors carrying brain-derived neurotrophic factor or green fluorescent protein genes were injected into right rat substantia nigra 4-5 weeks prior to 30 min ipsilateral of middle cerebral artery occlusion. The brain-derived neurotrophic factor-recombinant adeno-associated viral transduction markedly increased the production of brain-derived neurotrophic factor protein by nigral cells. Brain-derived neurotrophic factor was transported anterogradely to the striatum and released in biologically active form, as revealed by the hypertrophic response of striatal neuropeptide Y-positive interneurons. Animals transduced with brain-derived neurotrophic factor-recombinant adeno-associated virus also exhibited abnormalities in body posture and movements, including tilted body to the right, choreiform movements of left forelimb and head, and spontaneous, so-called 'barrel' rotation along their long axis. The continuous delivery of brain-derived neurotrophic factor had no effect on the survival of striatal projection neurons after stroke, but exaggerated the loss of cholinergic, and parvalbumin- and neuropeptide Y-positive, gamma-aminobutyric acid-ergic interneurons. The high brain-derived neurotrophic factor levels in the animals subjected to stroke also gave rise to an increased number of striatal cells expressing doublecortin, a marker for migrating neuroblasts, and cells double-labelled with the mitotic marker, 5-bromo-2'-deoxyuridine-5'monophosphate, and early neuronal (Hu) or striatal neuronal (Meis2) markers. Our findings indicate that long-term anterograde delivery of high levels of brain-derived neurotrophic factor increases the vulnerability of striatal interneurons to stroke-induced damage. Concomitantly, brain-derived neurotrophic factor potentiates the stroke-induced neurogenic response, at least at early stages.

Analysis of Variance↗