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Biomedical subjects

K Kristensson

Publications and source records attributed to K Kristensson.

266 records · Page 15Linked to original sources
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Persistent changes in behaviour and brain serotonin during ageing in rats subjected to infant nasal virus infection.

Suckling rats were infected intranasally with the temperature-sensitive mutant G41 strain of vesicular stomatitis virus. The rats survived but demonstrated lifelong learning deficits in the Morris maze and impaired exploratory behaviour in the open field test. When examined at 18 months of age they had a severe loss of neurons in the medial and dorsal raphe nuclei in the brain stem and reduced levels of serotonin and its metabolite 5-hydroxyindole acetic acid in the cerebral neocortex and hippocampus. The levels of noradrenaline, dopamine, homovanillic acid, 3,4-dihydroxyphenylacetic acid, choline acetyltransferase and glutamate decarboxylase were largely unaffected. The permanent disturbance in brain serotonin metabolism did not cause any histological changes in the cerebral cortex. Thus there were no neurofibrillary tangles or amyloid plaques as has been reported as a late effect of chemically induced lesion to the cholinergic system in the rat brain. It is concluded that the brain serotonergic system is especially vulnerable to an episode of virus attack along olfactory pathways and that the neurochemical and behavioural alterations caused by such an episode persist during a major part of the animal's life span.

Aging↗
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Immunohistochemical and behaviour pharmacological analysis of rats inoculated intranasally with vesicular stomatitis virus.

A temperature-sensitive mutant of vesicular stomatitis virus was inoculated intranasally into infant Sprague-Dawley rats aged 9 to 17 days. Rats receiving the virus at 9 days of age had an extensive spread of infection throughout the brain and the animals died after a few days. Rats inoculated at day 11 postnatally survived and the infection was limited to the olfactory pathways, hypothalamus, diagonal bands and the anterior raphe nuclei. Stereological measurements showed that the volume of infected neurons constituted 67 +/- 10% of the total neuronal volume in the dorsal raphe nucleus. Double-labelling experiments revealed that both 5-hydroxytryptamine- and substance P-immunoreactive neurons contained the virus antigen. The motor stimulant effect of amphetamine was studied at 3 months post infection. The increase in amphetamine-induced frequency and duration of rearing was significantly attenuated in infected rats and the amphetamine-induced locomotion was slightly reduced.

Administration, Intranasal↗
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The lipid compositions of different regions of rat brain during development and aging.

The lipid contents in different regions of the rat brain were analyzed from birth to the age of 2 years. The total brain phospholipid content increased threefold during the first 20 postnatal days. The cholesterol content elevated extensively during the first 2 months of life and, after this period, remained unchanged. The level of dolichol increased almost 100-fold during the first 10 months of life and continued to increase thereafter. Some modifications in the dolichol isoprenoid pattern were also observed. An increase in the brain ubiquinone level occurred during the first few months of life, but no further change was observed after this period. Ubiquinone-9 and -10 constituted 70 and 30%, respectively, of the total ubiquinone in all regions and all subcellular fractions. The alpha-tocopherol content increased during the first 3 weeks of life and was unchanged thereafter. These results demonstrate characteristic changes in the lipid contents of various regions of rat brain during development and aging.

Aging↗
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Increased levels of myelin basic protein transcripts in virus-induced demyelination.

In multiple sclerosis, a demyelinating disease of young adults, there is a paucity of myelin repair in the central nervous system (CNS) which is necessary for the restoration of fast saltatory conduction in axons. Consequently, this relapsing disease often causes marked disability. In similar diseases of small rodents, however, remyelination can be quite extensive, as in the demyelinating disease caused by the A59 strain of mouse hepatitis virus (MHV-A59), a coronavirus of mice. To investigate when and where oligodendrocytes are first triggered to repair CNS myelin in such disease, we have used a complementary DNA probe specific for one major myelin protein gene, myelin basic protein (MBP), which hybridizes with the four forms of MBP messenger RNA in rodents. Using Northern blot and in situ hybridization techniques, we previously found that MBP mRNA is first detected at about 5 days after birth, peaks at 18 days and progressively decreases to 25% of the peak levels in the adult. We now report that in spinal cord sections of adult animals with active demyelination and inflammatory cells, in situ hybridization reveals a dramatic increase in probe binding to MBP-specific mRNA at 2-3 weeks after virus inoculation and before remyelination can be detected by morphological methods. This increase of MBP-specific mRNA is found at the edge of the demyelinating area and extends into surrounding areas of normal-appearing white matter. Thus, in situ hybridization with myelin-specific probes appears to be a useful method for detecting the timing, intensity and location of myelin protein gene reactivation preceding remyelination. This method could be used to elucidate whether such a reactivation occurs in multiple sclerosis brain tissue. Our results suggest that in mice, glial cells react to a demyelinating process with widespread MBP mRNA synthesis which may be triggered by a diffusible factor released in the demyelinated areas.

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Activation of natural killer cells: underlying molecular mechanisms revealed.

Natural killer (NK) cells, the third major lymphocyte population, are important effector cells against certain infections and tumours. They have also been implicated as a link between innate and adaptive immune responses. In recent years, much attention has been paid to the NK cell inhibitory receptors and their interaction with major histocompatibility complex class I molecules on target cells. This review summarizes recent findings on regulation of NK cell activity with an emphasis on NK cell stimulatory receptors. A particular emphasis is devoted to the receptor NKG2D that is expressed on all NK cells.

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Arrest of myelination and demyelination in rabbit retina induced by herpes simplex virus infection.

Herpes simplex virus was injected into the vitreous of suckling and adult rabbits. In the suckling rabbits the infection caused an arrested myelination of the strip. Further, the infected strips showed degenerative changes with splitting and distension of myelin sheaths which then disintegrated. Ultrastructurally, herpes simplex virus particles were found in both oligodendroglial cells and in astrocytes in the bundles. No increase in intraocular pressure was recorded during the inflammation. The infection spread along optic pathways to the opposite side. Inflammatory cells appeared at the surface and infiltrated the degenerating strip. Especially in the contralateral eye, an extensive inflammatory cell infiltration was seen among bundles of nerve fibres which showed partly well-preserved myelin and partly with signs of demyelination reminiscent of the picture of experimental allergic encephalomyelitis in the epiretinal strip.

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Uptake and retrograde axonal transport of horseradish peroxidase in normal and axotomized motor neurons during postnatal development.

The axonal uptake and somatopetal transport of horseradish peroxidase (HRP) was studied during early postnatal development of facial neurons in mice and rats. HRP injected systemically or locally into the muscles of the vibrissae, diffused into the region of the immature neuromuscular junction and was incorporated into vesicles in the axon terminals on the first and third postnatal days, at a time when synaptic vesicles were already present. HRP later was found in the nerve cell bodies of the facial nucleus in the brain stem indicating a somatopetal transport of the tracer in axons. The response of facial neurons to nerve transection changed from rapid neuronal death to prolonged survival between the 6th and 10th postnatal day. HRP was transferred to nerve cell bodies after topical application to the proximal stump of transected facial nerves in rats 3 days-of-age. In the perikaryon it was localized to vesicles and vacuoles with no signs of leakage into the cytoplasm. In the light of our findings different hypotheses for the mechanism of the neuronal death in the immature animals are discussed.

Aging↗
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Neuronal uptake of iron: somatopetal axonal transport and fate of cationized and native ferritin, and iron-dextran after intramuscular injections.

Mice were injected into the muscles of the vibrissae with native ferritin (NF), cationized ferritin (CF) and iron-dextran. CF adsorbed on to the surface of the axon terminal at the neuromuscular junction, while NF did not. Both CF and NF were incorporated into vesicles and vacuoles at the synapse, but CF uptake was detected after injections at much lower concentrations than NF. In contrast to NF, CF was also found histochemically in cell bodies of facial neurones after a single i.m. injection, showing that the electrical charge of a molecule is one factor of importance for its potential to be incorporated in axons and transported somatopetally. Repeated i.m. injection of iron-dextran into suckling mice resulted in a marked iron load of Schwann cells and nerve cell bodies. This produced no signs of toxicity and the nerve fibre developed normally. Iron had disappeared from the nerve cell bodies after 25 days, while in Schwann cells it still persisted after 223 days.

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Asymmetric budding of viruses in ependymal and choroid plexus epithelial cells.

Sendai virus injected intracerebrally into 3-week-old mice caused infection of ependymal and choroid plexus epithelial cells. Budding of mature viruses occurred only from the apical surfaces of these cells. The viral peplomere proteins, haemagglutinin-neuraminidase and fusion, were concentrated on the apical portion of the ependymal cells, while the nucleocapsid-associated polymerase protein was dispersed throughout the cytoplasm. This indicates that intracellular routing of the virus envelope glycoproteins to the cell surface may be one of the factors that determines the site of virus budding. Vesicular stomatitis and vaccinia viruses, on the other hand, budded or egressed predominantly from the baso-lateral cell surfaces.

Animals↗
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Cytofluorometric quantification of somatopetal axonal transport: effects of a conditioning lesion and 2,5-hexanedione.

Cytofluorometric quantification of axonally transported fluorescein isothiocyanate (FITC)-labelled wheat germ agglutinin (WGA) from the injection site in the snout area was performed in the facial nucleus at various times during regeneration of one of the facial nerves. Measurements were made on single neurons on both operated and non-operated sides in three different groups of mice 8, 12 and 16 days after a nerve crush, Group 1: (control group) animals with a nerve crush, Group 2: animals with a conditioning lesion (nerve injury) made 3 days before the nerve crush, and Group 3: animals exposed daily to 2,5-hexanedione from 2 weeks before nerve crush until killing. A conditioning lesion caused a more rapid return of transport in regenerating nerves but there was no evidence for an increase in the total amount of transported FITC-WGA. For mice exposed to 2,5-hexanedione a transient increase of tracer transport in regenerating nerves could be demonstrated on day 12 after nerve crush. On day 16, however, a reduction of transport was seen in both operated and non-operated nerves. This study shows that it is possible experimentally to manipulate the influx of macromolecules to the nerve cell body from the periphery during nerve regeneration, and the present method offers the opportunity to study quantitatively the effects of various treatments on reinnervation of a muscle.

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Selective infections of olfactory and respiratory epithelium by vesicular stomatitis and Sendai viruses.

Following intranasal instillation of vesicular stomatitis virus (VSV) in mice there was an extensive infection of the olfactory epithelium in contrast to a minimal involvement of the respiratory epithelium. Sendai virus (SV), on the other hand, caused an extensive infection of the respiratory epithelium and only minimal infection of the olfactory mucous membrane. VSV budded from basolateral surfaces of supporting cells and olfactory neurons, but not from their apical surfaces or the ciliated bulbous endings of the olfactory neuron dendrites. This asymmetric release of VSV favoured neuroinvasion. The virus spread along the olfactory nerves to the glomeruli in the olfactory bulbs after which it propagated transneuronally into the rest of the brain. SV budded only from the apical surface of respiratory epithelial cells, was released into the air passages, and there were no signs of invasion into the olfactory bulbs. Inoculation of the olfactory mucous membrane is a useful procedure for studies on selectivity of attack on peripheral neurons by viruses and on mechanisms of virus invasion of the nervous system in vivo.

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Invasion of cranial nerves and brain stem by herpes simplex virus inoculated into the mouse tongue.

Herpes simplex virus type 1 (HSV) of a highly or slightly neuropathogenetic strain was inoculated into the tongues of mice. After appropriate survival times, the animals were killed and portions of the facial and trigeminal nerves as well as the brain stem were examined with virus isolation and immunocytochemistry for the presence of HSV. Both virus strains were demonstrated in the geniculate and trigeminal ganglia and in the CNS portion of the facial and trigeminal nerves, as well as in various brain stem areas including the trigeminal tract and nucleus, the facial and hypoglossal nuclei, and nuclei in the reticular formation. The results indicate that HSV is transported to the CNS by efferent and afferent axons of the tongue and subsequently via transneuronal passage to various brain stem nuclei. These findings provide an anatomic basis for a putative relationship between HSV and cranial nerve dysfunction.

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Viruses and behavioural changes: a review of clinical and experimental findings.

This review focuses on behavioural neurovirology. Profound changes in behaviour are observed following infection of the central nervous system by some viruses. Irritability, insomnia, hyperactivity and learning disability are some of the behavioural disturbances that have been described in both humans and animals with central nervous system infection. The reticular core neurons which innervate the entire brain play an important role in regulating behaviour. Some of these neurons--locus coeruleus, raphe and diagonal bands--send projections to the olfactory bulbs and can be targets for exogenous agents attacking the olfactory epithelium. In infant rats, vesicular stomatitis virus is transported along the olfactory pathway by retrograde transport and reaches the reticular core neurons causing destruction of raphe, diagonal bands and, to a lesser extent, the locus coeruleus. As the neurons degenerate, the viral antigens disappear and the animals sustain severe deficits in neurotransmitter levels and behaviour. Such a "hit and run" effect of the virus suggests the possibility that a similar mechanism may be operating in some human disorders. Apart from their intrinsic interest as possible aetiological factors, viruses may provide valuable tools in experimental work seeking to correlate behaviour, morphology and neurotransmitter function.

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