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C Rosenblad

Publications and source records attributed to C Rosenblad.

26 records · Page 2Linked to original sources
PubMed1997

Studies on neuroprotective and regenerative effects of GDNF in a partial lesion model of Parkinson's disease.

Intrastriatal 6-hydroxydopamine injections in rats induce partial lesions of the nigrostriatal dopamine (DA) system which are accompanied by a delayed and protracted degeneration of DA neurons within the substantia nigra. By careful selection of the dose and placement of the toxin it is possible to obtain reproducible and regionally defined partial lesions which are well correlated with stable functional deficits, not only in drug-induced behaviors but also in spontaneous motoric and sensorimotoric function, which are analogous to the symptoms seen in patients during early stages of Parkinson's disease. The intrastriatal partial lesion model has proved to be particularly useful for studies on the mechanisms of action of neurotrophic factors since it offers opportunities to investigate both protection of degenerating DA neurons during the acute phases after the lesion and stimulation of regeneration and functional recovery during the chronic phase of the postlesion period when a subset of the spared nigral DA neurons persist in an atrophic and dysfunctional state. In the in vivo experiments performed in this model glial cell line-derived neurotrophic factor (GDNF) has been shown to exert neurotrophic effects both at the level of the cell bodies in the substantia nigra and at the level of the axon terminals in the striatum. Intrastriatal administration of GDNF appears to be a particularly effective site for induction of axonal sprouting and regeneration accompanied by recovery of spontaneous sensorimotor behaviors in the chronically lesioned nigrostriatal dopamine system.

Animals↗
PubMed1996

Glial cell line-derived neurotrophic factor increases survival, growth and function of intrastriatal fetal nigral dopaminergic grafts.

The ability of transplants of fetal nigral neurons to reverse symptoms in patients with Parkinson's disease is, at least in part, limited by the poor survival of the grafted dopaminergic neurons and the restricted host reinnervation from the graft. Here, we report that glial cell line-derived neurotrophic factor, a novel trophic factor for developing dopaminergic neurons, can increase survival and fibre outgrowth of fetal nigral dopaminergic neurons, and stimulate graft-induced functional recovery after transplantation in a rat model of Parkinson's disease. Injections of rat glial cell line-derived neurotrophic factor adjacent to the graft enhanced graft function, resulting in complete compensation of amphetamine-induced turning behaviour already by two weeks postgrafting as opposed to four weeks in the control group. The total number of surviving tyrosine hydroxylase-positive neurons was about two-fold greater in the glial cell line-derived neurotrophic factor-treated animals compared to the vehicle-injected controls, and the density of tyrosine hydroxylase-positive fibres was found to be increased both in the host striatum (from 37.6 +/- 8.3% to 105.5 +/- 9.7% of intact striatum) as well as inside the graft (55% increase). Moreover, in animals treated with glial cell line-derived neurotrophic factor, the outgrowth of tyrosine hydroxylase-positive fibres was mostly directed towards the injection site. These findings show that supply of exogenous glial cell line-derived neurotrophic factor to the transplantation site improves survival, growth and function of transplanted fetal nigral dopaminergic neurons in the rat Parkinson model.

Animals↗
PubMed1995

Glial cell line-derived neurotrophic factor but not transforming growth factor beta 3 prevents delayed degeneration of nigral dopaminergic neurons following striatal 6-hydroxydopamine lesion.

Glial cell line-derived neurotrophic factor (GDNF) and transforming growth factor beta 3 (TGF-beta 3) are members of the TGF-beta superfamily with high neurotrophic activity on cultured nigral dopamine neurons. We investigated the effects of intracerebral administration of GDNF and TGF-beta 3 on the delayed cell death of the dopamine neurons in the rat substantia nigra following 6-hydroxydopamine lesions of dopaminergic terminals in the striatum. Fluorescent retrograde tracer injections and tyrosine hydroxylase immunocytochemistry demonstrated nigral degeneration with an onset 1 week after lesion, leading to extensive death of nigral neurons 4 weeks postlesion. Administration of recombinant human GDNF for 4 weeks over the substantia nigra at a cumulative dose of 140 micrograms, starting on the day of lesion, completely prevented nigral cell death and atrophy, while a single injection of 10 micrograms 1 week postlesion had a partially protective effect. Continuous administration of TGF-beta 3, starting on the day of lesion surgery, did not affect nigral cell death or atrophy. These findings support the notion that GDNF, but not TGF-beta 3, is a potent neurotrophic factor for nigral dopamine neurons in vivo.

Adrenergic Fibers↗
PubMed1993

Basal forebrain grafts in the hippocampus and neocortex: regulation of acetylcholine release.

The regulation of acetylcholine (ACh) release from cholinergic neurons transplanted to the hippocampus or neocortex was studied by microdialysis in awake rats. Fetal basal forebrain tissue was implanted as a cell suspension or solid graft into the fimbria-fornix-lesioned hippocampus, or as a cell suspension into the frontal cortex after excitotoxic lesion of the nucleus basalis. Several months after transplantation, microdialysis probes were implanted in areas of the hippocampus or frontal cortex reinnervated by the grafts. The grafts restored lesion-induced deficits in steady-state ACh release up to normal or above normal levels in both hippocampus and frontal cortex. The responses to KCl and tetrodotoxin suggested that the ACh release exhibited normal firing-dependent properties. By applying various behaviorally arousing stimuli that normally activate the basal forebrain projection systems, we wished to investigate the functional integration of the grafts in the host brain. In the hippocampus, sensory stimulation, immobilization stress and motor activity all resulted in increased release of graft-derived ACh amounting to 25-65% of the normal response. Variations in ACh levels during the day-night cycle was, however, not observed in the grafted rats. In the frontal cortex, immobilization enhanced the graft-derived ACh release (60% of normal response), whereas the response to sensory stimulation did not reach significance. Since the activity of the normal basal forebrain projection systems is under influence of monoaminergic brainstem afferents, we investigated the effects of systemic administration of amphetamine or apomorphine on ACh release in the hippocampus. Both drugs produced increases in graft-derived ACh release although the response was variable and less pronounced than normal. In conclusion, the graft-derived ACh release was affected by behavioral manipulations and catecholaminergic drugs that normally modify cholinergic septo-hippocampal and basalo-cortical activity. This strongly suggests a high degree of functional integration of the graft in the host brain allowing for a regulated release of transmitter that can be adjusted during ongoing behavior.

Acetylcholine↗
PubMed1993

Basal forebrain grafts in the rat neocortex restore in vivo acetylcholine release and respond to behavioural activation.

Acetylcholine release in the frontal cortex of awake rats after acute or chronic lesions of the nucleus basalis magnocellularis and grafting of cholinergic-rich basal forebrain tissue was studied by in vivo microdialysis. Three to four weeks and five months after a unilateral quisqualic acid lesion of the nucleus basalis, and five months after lesion and cortical implantation of a basal forebrain cell suspension, acetylcholine release was characterized during a range of pharmacological and behavioural manipulations. Neostigmine (5 microM) was added to the perfusion fluid in order to inhibit the degradation of acetylcholine. The extracellular levels of acetylcholine in normal animals increased three- to four-fold when KCl (100 mM) was added to the perfusion medium and was reduced by 80% after addition of tetrodotoxin (1 microM). The nucleus basalis lesion resulted in a 60% reduction in baseline acetylcholine levels compared to normal and the response to KCl-evoked depolarization was significantly reduced. There were no differences between the acute and chronic lesion groups during any of the manipulations performed. Rats with grafts showed baseline levels of acetylcholine about 70% higher than normal, and responded to both KCl (two-fold increased acetylcholine release) and tetrodotoxin (85% reduced levels). All groups showed lower acetylcholine levels during halothane anaesthesia (on average 70-85% reduction). Sensory stimulation by handling resulted in a two-fold increase in acetylcholine release in normal animals, whereas the absolute responses in the lesioned controls were significantly weaker. Rats with grafts increased their acetylcholine release after handling to an extent not different to normal or lesioned controls. Immobilization stress induced an almost two-fold increase in cortical acetylcholine levels in normal rats, whereas the effect in the lesion-only groups was very weak. The grafts responded to the immobilization with an enhanced acetylcholine overflow that was significantly higher than in lesioned controls. The results showed that the reduction in frontocortical acetylcholine release induced by excitotoxic lesions of the nucleus basalis did not recover spontaneously over several months. Intracortical cholinergic-rich grafts obtained from the fetal basal forebrain provided a source of acetylcholine release with firing-dependent properties which could be modulated by behaviourally stressful stimuli. The ability of the grafts to respond to behavioural manipulation strongly suggests that the host brain can functionally influence graft neuronal activity during ongoing behaviour. Host control of graft activity may play a role in the recovery of the lesion-induced deficits seen with these types of grafts.

Acetylcholine↗
PubMed1992

Spatial learning impairments in rats with selective immunolesion of the forebrain cholinergic system.

A monoclonal antibody to the low-affinity NGF receptor, 192 IgG, coupled to a cytotoxin, saporin, was recently introduced as an efficient selective neurotoxin for the NGFr-bearing cholinergic neurones in the rat basal forebrain. In the present study we report that an intracerebroventricular injection of this 192 IgG-saporin conjugate induces a severe, long-lasting spatial learning impairment, as assessed in the Morris water-maze task. This behavioural impairment was associated with 65-90% depletion of choline acetyltransferase activity (ChAT) in the hippocampus and cortex. ChAT activity associated with other cholinergic neurone systems in the brain (striatum, mesencephalon, spinal cord), was left virtually unaffected. This new immunotoxin holds great promise as a tool for selective and efficient lesions of the forebrain cholinergic system in functional and behavioural studies.

Acetylcholinesterase↗
PubMed1978

Formal and informal classroom settings: effects on hyperactivity.

The behavior of hyperactive children was compared to controls in two different classroom settings. One setting (Informal) involved choice and variety of tasks; the other setting (Formal) involved teacher specification of a small number of tasks. As assessed by a composite observational measure of hyperactivity, there were significant differences between the hyperactive and control groups in the Formal but not in the Informal setting. Analyses of five individual categories of hyperactive behavior showed that, with one exception, the hyperactive group tended to display higher frequencies of behavior than did controls in both settings. For two of the categories, the difference between the groups was significantly larger in the Formal than in the Informal setting. Finally, a modified observational code was suggested that differentiated hyperactives from controls equally in the two settings.

Aggression↗