Börje Bjelke

Characterization and MRI study of surfactant-coated superparamagnetic nanoparticles administered into the rat brain

A pre-clinical studyhas been carried out for the utilization of magnetite (Fe O ) nanoparticles as a diagnostic tracer for MRI. Surfactant-coated Fe O nanoparticles have been synthesized by a chemical coprecipitation method with a narrow particle size of around 6 nm. Preliminaryexperiments demonstrated the feasibilityof using superparamagnetic Fe O nanoparticles as contrast agents in MR imaging. 2001 Elsevier Science B.V. All rights reserved.

Asphyctic lesion: proliferation of tyrosine hydroxylase-immunoreactive nerve cell bodies in the rat substantia nigra and functional changes in dopamine neurotransmission

Asphyxia was induced in male rat pups by performing a delayed cesarean section on pregnant Sprague-Dawley rats. Oxygen saturation and heart rate were recorded during induction of asphyxia. Animals were sacrificed at 3 weeks of age. Brain sections were stained for tyrosine-hydroxylase (TH), dopamine-and-cyclic-AMP-regulated-phosphoprotein-32 (DARPP-32) immunoreactivity (IR) and thionein. Increasing time of asphyxia caused a reduction in the number of nerve cell bodies in the CA1 and CA3 regions of the hippocampus reflecting neuronal death. Furthermore, asphyxia resulted in an increased number of TH-IR nerve cell bodies indicative of a proliferation of dopaminergic neurons in the zona compacta of the substantia nigra. Finally, a significant decrease in rearing was observed in asphyctic animals during the habituation phase, as well as following apomorphine-induced (1 mg/kg s.c.) postsynaptic dopamine receptor stimulation. On the other hand, the apomorphine-induced increase in locomotion was enhanced in asphyctic animals. The implications of these findings for hyperkinesia and attention deficits in disorders resulting from asphyxia are discussed.

Endothelin-1 induced lesions of the frontoparietal cortex of the rat. A possible model of focal cortical ischemia

ENDOTHELIN 1 (ET-1) was unilaterally applied onto the surface of the dorsal frontoparietal cortex of the rat. Cortical blood flow measurements using laser-Doppler flowmetry demonstrated dose-dependent reductions of frontoparietal cortical blood flow. Histological analysis demonstrated dose-related lesions and the time course was followed using MRI. The lesions appear to be associated with a large penumbra area indicated by morphological characteristics. Thus, cortical surface exposure to ET-1 may produce graded lesions of the frontoparietal cortex related to local ischemia.

Communication between the Perilymphatic Scalae and Spiral Ligament Visualized by in vivo MRI

We evaluated the transport of Gadolinium-diethylenetriaminepentaacetate-bismethylamide (Gd-DTPA-BMA) through the round window (RW) membrane into the perilymphatic space with 4.7-T MRI in an animal study and 1.5-T MRI in humans. After administration of Gd-DTPA-BMA onto the intact RW membrane of guinea pig, Gd-DTPA-BMA uptake was observed in the basal turn and part of the second turn within 40 min. The scala tympani, scala vestibuli, the fibrous part of the spiral ligament and semicircular canal all showed uptake of Gd-DTPA-BMA. All turns of the cochlea were filled with Gd within 10 min in the perforated RW membrane administration group and within 30 min in the intravenous administration group. In patients who accepted middle ear injection of Gd-DTPA-BMA, uptake was observed within 2 h in the basal turn and semicircular canal. After 12 h the apex did still not show any uptake. Gd-DTPA-BMA is transported from the RW to the semicircular canal, the scala tympani and scala vestibuli without passing the helicotrema.

Intraseptal muscarinic ligands and galanin: influence on hippocampal acetylcholine and cognition

The cholinergic neurons in the septohippocampal projection are implicated in hippocampal functions such as spatial learning and memory. The aim of this study was to examine how septohippocampal cholinergic transmission is modulated by muscarinic inputs and by the neuropeptide galanin, co-localized with acetylcholine (ACh) in septohippocampal cholinergic neurons, and how spatial learning assessed by the Morris water maze test is affected. Muscarinic inputs to the septal area are assumed to be excitatory, whereas galanin is hypothesized to inhibit septohippocampal cholinergic function. To test these hypotheses, compounds were microinjected into the medial septum and hippocampal ACh release was assessed by microdialysis probes in the ventral hippocampus of the rat. Blockade of septal muscarinic transmission by intraseptal scopolamine increased hippocampal ACh release suggesting that septal cholinergic neurons are under tonic inhibition. Stimulation of septal muscarinic receptors by carbachol also increased hippocampal ACh release. Despite this increase, both scopolamine and carbachol tended to impair hippocampus-dependent spatial learning. This finding also suggests a revision of the simplistic notion that an increase in hippocampal ACh may be facilitatory for learning and memory. Galanin infused into the medial septum enhanced hippocampal ACh release and facilitated spatial learning, suggesting that septal galanin, contrary to earlier claims, does not inhibit but excites septohippocampal cholinergic neurons. Galanin receptor stimulation combined with muscarinic blockade in the septal area resulted in an excessive increase of hippocampal ACh release combined with an impairment of spatial learning. This finding suggests that the level of muscarinic activity within the septal area may determine the effects of galanin on hippocampal cognitive functions. In summary, a limited range of cholinergic muscarinic transmission may contribute to optimal hippocampal function, a finding that has important implications for therapeutic approaches in the treatment of disorders of memory function.

Antisense oligonucleotide to c-fos induces ipsilateral rotational behaviour to d-amphetamine.

The immediate-early genes, especially c-fos, have been suggested to have an important role in neuronal plasticity and memory. However, it has been difficult to determine if in fact c-fos can participate in control of behaviour. Here we can report that direct unilateral infusion into the rat neostriatum of an antisense phosphothioate oligodeoxynucleotide to c-fos mRNA leads to the rapid induction of ipsilateral rotational behaviour after d-amphetamine administration. This is associated with an elimination of the in vivo expression of Fos-like immunoreactivity within the infused region of neostriatum. Following infusion of these oligodeoxynucleotides labelled with fluorescein isothiocyanate they appear with a nuclear and cytoplasmic location in a large number of nerve cells, many of which are immunoreactive for dopamine and cyclic AMP regulated phosphoprotein. The present findings suggest that the immediate-early gene c-fos has a role also in control of behavioural activity, as illustrated in D1 receptor containing striatal neurones.

Functional recovery after brain lesion-contralateral neuromodulation: an FMRI study

Behavioral recovery takes place even after permanent damage to the entire brain region normally controlling sensorimotor hind limb function in the rat. In our study, 2 weeks after full behavioral recovery from an experimental unilateral permanent brain damage, the topographic representation of the previous paretic hindlimb was investigated by fMRI. The analysis showed that during electrical stimulation of the previously paretic hindlimb, two normally inactive brain regions were now being activated. One region was the non-damaged contralateral sensori-motor cortex and the other region was located lateral to the lesion. These results suggest that behavioral recovery can be explained by functional reorganization and neuromodulation of the brain.

Dopaminergic transmission in the rat retina: evidence for volume transmission

The study was designed to determine whether dopaminergic neurotransmission in the retina can operate via volume transmission. In double immunolabelling experiments, a mismatch as well as a match was demonstrated in the rat retina between tyrosine hydroxylase (TH) and dopamine (DA) immunoreactive (ir) terminals and cell bodies and dopamine D2 receptor-like ir cell bodies and processes. The match regions were located in the inner nuclear and plexiform layers (D2 ir cell bodies plus processes). The mismatch regions were located in the ganglion cell layer, the outer plexiform layer, and the outer segment of the photoreceptor layer, where very few TH ir terminals can be found in relation to the D2 like ir processes. In similar experiments analyzing D1 receptor like ir processes versus TH ir nerve terminals, mainly a mismatch in their distribution could be demonstrated, with the D1 like ir processes present in the outer plexiform layer and the outer segment where a mismatch in D2 like receptors also exists. The demonstration of a mismatch between the localization of the TH terminal plexus and the dopamine D2 and D1 receptor subtypes in the outer plexiform layer, the outer segment and the ganglion cell layer (only D2 immunoreactivity (IR)) suggests that dopamine, mainly from the inner plexiform layer, may reach the D2 and D1 mismatch receptors via diffusion in the extracellular space. After injecting dopamine into the corpus vitreum, dopamine diffuses through the retina, and strong catecholamine (CA) fluorescence appears in the entire inner plexiform layer and the entire outer plexiform layer, representing the match and mismatch DA receptor areas, respectively. The DA is probably bound to D1 and D2 receptors in both plexiform layers, since the DA receptor antagonist chlorpromazine fully blocks the appearance of the DA fluorescence, while only a partial blockade is found after haloperidol treatment which mainly blocks D2 receptors. These results indicate that the amacrine and/or interplexiform DA cells, with sparse branches in the outer plexiform layer, can operate via volume transmission in the rat retina to influence the outer plexiform layer and the outer segment, as well as other layers of the rat retina such as the ganglion cell layer.

Long-term effects of perinatal asphyxia on basal ganglia neurotransmitter systems studied with microdialysis in rat ☆

Asphyxia was induced in pups delivered by caesarean section on pregnant Sprague-Dawley rats. Rats within the last day of gestation were anaesthetised and hysterectomized. The uterus horns including the foetuses were placed in a water bath for various periods of time. Following asphyxia the uterus horns were opened. The pups were removed, stimulated to breathe, left to recover and given to surrogate mothers. Control and asphyctic pups were obtained from each mother. Rats surviving asphyctic periods longer than 20 min at 37 degrees C showed chronic deficits in the release of neurotransmitters monitored with microdialysis in the basal ganglia. The main change observed in 6-month-old male rats that underwent severe perinatal asphyxia was a marked decrease in striatal dopamine release, monitored under basal and D-amphetamine stimulated conditions, as compared with control (normal- or caesarean-delivered) rats. Striatal glutamate and aspartate levels were also decreased following asphyxia. In the substantia nigra, the main effect of asphyxia was a decrease of both gamma-aminobutyric acid (GABA) and aspartate levels. Thus, this study provides evidence that perinatal asphyxia leads to chronic deficits in neurotransmission in the basal ganglia.

Inhalation of Low Concentrations of Toluene Induces Persistent Effects on a Learning Retention Task, Beam-Walk Performance, and Cerebrocortical Size in the Rat

The organic solvent toluene is widely used in industry. The threshold limit value for extended occupational exposure to toluene is presently set to 200 ppm in the United States. We have investigated the effect of an inhalation exposure of 80 ppm for 4 weeks (6 h/day, 5 days/week), followed by a postexposure period of at least 4 weeks, on behavior and brain features in the rat. Toluene exposure appeared to affect spatial memory, since toluene-exposed rats showed a longer time in the correct quadrant in a Morris swim maze. This effect may indicate that the exposed rats used their praxis strategy longer before they started to look for the platform elsewhere. Toluene-exposed rats showed trends for increases in both locomotion and rearing behaviors and a significantly reduced beam-walk performance. The area of the cerebral cortex, especially the parietal cortex, was decreased by 6-10% in toluene-exposed rats, as shown by magnetic resonance imaging of living rats and autoradiograms of frozen brain sections. The K(D) and B(max) values of the dopamine D(3) agonist [(3)H]PD 128907 were not affected by toluene, as measured in caudate-putamen and subcortical limbic area using biochemical receptor binding assays and in caudate-putamen and islands of Calleja using quantitative receptor autoradiography. Hence, previously demonstrated persistent effects by toluene on the binding characteristics of radioligands binding to both D(2) and D(3) receptors seem to indicate a persistent effect of toluene selectively on dopamine D(2) receptors. Taken together, the present results indicate that exposure to low concentrations of toluene leads to persistent effects on cognitive, neurological, and brain-structural properties in the rat.