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PubMed1979

Absence of the major dense line in myelin of the mutant mouse "shiverer".

The myelin of the central nervous system (CNS) of the mutant mouse Shiverer is characterized by the absence of the major dense line (MDL). The intraperiod line, as seen in conventional electron micrographs and in freeze-fractured replicas, appears normal. Peripheral myelin, as seen in ventral and dorsal roots of spinal cord, is unaffected by the mutation. During the period of active myelination, the cytoplasm of most oligodendrocytes (ODs) is packed with electron-lucent vacuoles in continuity with the Golgi apparatus and with bundles of microtubules. It is concluded that a metabolic pathway possibly involving the Golgi apparatus, and contributing to the formation of the MDL is selectively affected in this mutant.

Animals↗
PubMed1979

Immunochemical studies of myelin basic protein in shiverer mouse devoid of major dense line of myelin.

The myelin-deficient mutant Shiverer (Shi/Shi) lacks basic protein (MBP) in the myelin of its central nervous system (CNS). Less than 3% of the normal content in MBP is present in a brain extract of Shi/Shi as determined by radioimmunoassay. Indirect immunofluorescence is negative when using specific anti-MBP serum. The importance of Shi/Shi (as compared to other hypomelinating mutants) stems from the specificity of this genetic lesion, i.e. the lack of basic protein.

Animals↗
PubMed1988

Remyelination by transplanted oligodendrocytes of a demyelinated lesion in the spinal cord of the adult shiverer mouse.

Fragments of normal newborn mouse central nervous system (CNS) were transplanted into the spinal cord of adult shiverer mice at distance of 1, 2 or 3 intervertebral spaces from a lysolecithin-induced demyelinating lesion. Remyelination by grafted oligodendrocytes was observed by electron microscopy (EM). This result showed the capability of grafted oligodendrocytes or precursor cells to migrate to a demyelinated lesion and to remyelinate naked axons in an adult host, even in presence of host spontaneous remyelination.

Animals↗
PubMed2005

Myelination and long diffusion times alter diffusion-tensor-imaging contrast in myelin-deficient shiverer mice.

Diffusion tensor imaging (DTI) using variable diffusion times (t(diff)) was performed to investigate wild-type (wt) mice, myelin-deficient shiverer (shi) mutant mice and shi mice transplanted with wt neural precursor cells that differentiate and function as oligodendrocytes. At t(diff) = 30 ms, the diffusion anisotropy "volume ratio" (VR), diffusion perpendicular to the fibers (lambda( perpendicular)), and mean apparent diffusion coefficient ( ) of the corpus callosum of shi mice were significantly higher than those of wt mice by 12 +/- 2%, 13 +/- 2%, and 10 +/- 1%, respectively; fractional anisotropy (FA) and relative anisotropy (RA) were lower by 10 +/- 1% and 11 +/- 3%, respectively. Diffusion parallel to the fibers (lambda(//)) was not statistically different between shi and wt mice. Normalized T(2)-weighted signal intensities showed obvious differences (27 +/- 4%) between wt and shi mice in the corpus callosum but surprisingly did not detect transplant-derived myelination. In contrast, diffusion anisotropy maps detected transplant-derived myelination in the corpus callosum and its spatial distribution was consistent with the donor-derived myelination determined by immunohistochemical staining. Anisotropy indices (except lambda(//)) in the corpus callosum showed strong t(diff) dependence (30-280 ms), and the differences in lambda( perpendicular) and VR between wt and shi mice became significantly larger at longer t(diff), indicative of improved DTI sensitivity at long t(diff). In contrast, anisotropy indices in the hippocampus showed very weak t(diff) dependence and were not significantly different between wt and shi mice across different t(diff). This study provides insights into the biological signal sources and measurement parameters influencing DTI contrast, which could lead to developing more sensitive techniques for detection of demyelinating diseases.

Algorithms↗
PubMed2001

Can non-shivering thermogenesis in brown adipose tissue following NA injection be quantified by changes in overlying surface temperatures using infrared thermography?

We aimed to investigate whether infra red thermography (IRT) can be used to measure and quantify non-shivering thermogenesis (NST) in the short-tailed field vole Microtus agrestis, by directly comparing it with a standard method, i.e. metabolic response following Noradrenaline injection (NA). Mean skin surface temperature overlying Brown adipose tissue (BAT) depot was 0.82 degrees C higher than mean surface temperature that did not overly BAT. The difference in temperature increased by 1.26 degrees C after NA was administered. Mean skin surface temperature overlying BAT increased by 0.32 degrees C after NA was administered; however, surface temperature decreased by 1.32 degrees C after saline was administered. Mean skin surface temperature overlying BAT did not change significantly between warm and cold acclimated voles; in contrast metabolic peak following NA injection significantly increased in cold acclimated voles. There was no significant correlation between change in surface temperature after NA injection and metabolic peak following NA injection. The results of this study suggest that IRT is not a sensitive enough method to measure changes in NST capacity in BAT following NA injection, or to detect changes in NST capacity induced by cold acclimation. However, IRT can distinguish between skin surfaces overlying BAT and skin surfaces that do not.

Journal Article↗
PubMed1986

Recombination within the myelin basic protein gene created the dysmyelinating shiverer mouse mutation.

Shiverer (shi) is an autosomal recessive mutation in the mouse characterized by an almost total lack of central nervous system myelin. While small amounts of other myelin components are present in the brain of the shi mouse, the four forms of myelin basic protein (MBP) are not detectable. Previous investigations by us and others indicate that the MBP gene has undergone a major rearrangement in the shi mutant. Herein, we report in detail the nature and extent of the rearrangement: a 20-kilobase region within the MBP gene is missing in the mutant. We map the 5' breakpoint of the deletion to the second intron and the 3' breakpoint to a site 2 kilobases beyond the last MBP exon. The junction of the upstream and downstream portions of the gene contains only one nucleotide not accounted for by the wild-type MBP gene sequence. The 3' side of the deletion occurs in the 3rd of 11 tandem repeats of a 31-base-pair sequence. This region is rich in alternating purine and pyrimidine stretches, sequences that have been associated with both Z-DNA structures and gene rearrangements. The recombination junction shares several features with the junctions characterized by Anderson et al. [Anderson, R., Kato, S. & Camerini-Otero, D. (1984) Proc. Natl. Acad. Sci. USA 81, 206-210] in mouse L cells and is consistent with their model for a partially homologous recombination event. The structure of the shi recombination junction suggests that the donor DNA molecules were aligned in a partially homologous region before staggered cutting and joining occurred.

Animals↗
PubMed1999

"Global" cell replacement is feasible via neural stem cell transplantation: evidence from the dysmyelinated shiverer mouse brain.

Many diseases of the central nervous system (CNS), particularly those of genetic, metabolic, or infectious/inflammatory etiology, are characterized by "global" neural degeneration or dysfunction. Therapy might require widespread neural cell replacement, a challenge not regarded conventionally as amenable to neural transplantation. Mouse mutants characterized by CNS-wide white matter disease provide ideal models for testing the hypothesis that neural stem cell transplantation might compensate for defective neural cell types in neuropathologies requiring cell replacement throughout the brain. The oligodendrocytes of the dysmyelinated shiverer (shi) mouse are "globally" dysfunctional because they lack myelin basic protein (MBP) essential for effective myelination. Therapy, therefore, requires widespread replacement with MBP-expressing oligodendrocytes. Clonal neural stem cells transplanted at birth-using a simple intracerebroventricular implantation technique-resulted in widespread engraftment throughout the shi brain with repletion of MBP. Accordingly, of the many donor cells that differentiated into oligodendroglia-there appeared to be a shift in the fate of these multipotent cells toward an oligodendroglial fate-a subgroup myelinated up to 52% (mean = approximately 40%) of host neuronal processes with better compacted myelin of a thickness and periodicity more closely approximating normal. A number of recipient animals evinced decrement in their symptomatic tremor. Therefore, "global" neural cell replacement seems feasible for some CNS pathologies if cells with stem-like features are used.

Animals↗
PubMed1991

The ectopic expression of myelin basic protein isoforms in Shiverer oligodendrocytes: implications for myelinogenesis.

The myelin basic proteins (MBPs) are a set of peripheral membrane polypeptides that are required for the compaction of the major dense line of central nervous system myelin. We have used primary cultures of oligodendrocytes from MBP-deficient shiverer mice as host cells for the expression by cDNA transfection of each of the four major MBP isoforms. The distributions of the encoded polypeptides were studied by immunofluorescence and confocal microscopy and compared with patterns of MBP expression in normal mouse oligodendrocytes in situ and in culture. The exon II-containing 21.5- or 17-kD MBPs were distributed diffusely in the cytoplasm and in the nucleus of the transfectants, closely resembling the patterns obtained in myelinating oligodendrocytes in 9-d-old normal mouse brains. By contrast, the distribution of the 14- and 18.5-kD MBPs in the transfectants was confined to the plasma membrane and mimicked the distribution of MBP in cultures of normal adult oligodendrocytes. Our results strongly suggest that the exon II-containing MBPs are expressed first and exclusively during oligodendrocyte maturation, where they may play a role in the early phase of implementation of the myelination program. In contrast, the 14- and 18.5-kD MBPs that possess strong affinity for the plasma membrane are likely to be the principle inducers of myelin compaction at the major dense line.

Animals↗
PubMed1984

Immunoreactive myelin basic proteins are not detected when shiverer mutant Schwann cells and fibroblasts are co-cultured with normal neurons.

Shiverer (shi) is an autosomal recessive mutation in mice that results in hypomyelination in the central nervous system (CNS) but normal myelination in the peripheral nervous system (PNS). Myelin basic proteins (MBPs) are virtually absent in both PNS and CNS. It is not known whether the cellular target in the PNS is the myelin-forming Schwann cell or another cell type which secondarily affects the Schwann cell. To determine the cellular target of the shi gene, we have adapted tissue culture techniques that allow co-culture of pure populations of mouse sensory neurons of one genotype with Schwann cells and fibroblasts of another genotype under conditions that permit myelin formation. These cultures were stained immunocytochemically as whole mounts to determine whether MBPs were expressed under various in vitro conditions. In single-genotype cultures, presence or absence of MBPs was consistent with earlier in vivo results: +/+ cultures were MBP-positive and shi/shi cultures were MBP-negative. In mixed-genotype cultures, visualization of MBPs in myelin accorded with the genotype of the non-neuronal Schwann cells and fibroblasts and not with the neurons--those cultures that contained +/+ non-neuronal cells were MBP-positive and those with shi/shi non-neuronal cells were MBP-negative, independent of the neuronal genotype. These results rule out neurons or circulating substances as mediators of the influence of the shi genetic locus on MBP synthesis and deposition in peripheral myelin.

Animals↗
PubMed1991

The shiverer mouse mutation shi/shi: rescue and preimplantation detection.

The shiverer mouse mutation has been used as a model in this series of experiments. Germ-line therapy of this disorder has been demonstrated by producing mice transgenic for the wild-type gene for myelin basic protein (MBP). The mutation has also been diagnosed in preimplantation mouse blastocysts.

Animals↗
PubMedDate not supplied

Shiverer: an autosomal recessive mutant mouse with myelin deficiency.

Shiverer is an autosomal recessive trait in the mouse characterized by early generalized tremors that become prominent in the hindquarters with age. Seizure behavior begins after weaning and increases in frequency during the animal's shortened lifespan. The most prominent pathological feature is a deficiency of myelin and myelin basic protein in the central nervous system.

Animals↗
PubMed1983

Myelin basic protein deposition in the optic and sciatic nerves of dysmyelinating mutants quaking, jimpy, Trembler, mld, and shiverer during development.

An ontogenetic survey of the basic protein of myelin, common to both central and peripheral nervous systems, was carried out on normal C57Bl and five dysmyelinating mutant mice. Myelin basic protein (MBP) was quantified by radioimmunoassay in the optic and sciatic nerves of mice from birth to adult stages, giving special attention to the premyelinating and early myelination periods. In the optic nerves of normal mice, MBP was already detectable at birth but the active period of myelin deposition was shown to occur after day 10 postnatal. The timing and rate of accumulation of MBP were normal in Trembler. In contrast, they were abnormal in the other mutants. In the quaking mouse, the active period of MBP deposition was delayed, and its final concentration represented no more than 12% of normal in the adult. No active period of MBP deposition was observed in the other mutants. In the jimpy mouse, a slow accumulation of MBP resulted in a final concentration reaching 2% of the normal value at 25 days. In mild and shiverer mice, the MBP was hardly detectable. In the sciatic nerves of normal mice, the active period of MBP deposition occurred between days 3 and 12 postnatal. No substantial changes occurred in the period of 2 months--2 years.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1966

Body temperature, shivering, blood pressure and heart rate during a standard cold stress in Australia and Antarctica.

1. Four men of European descent were exposed naked to an air temperature of 10 degrees C for 2 hr in Australia, and again after 24 weeks' residence at Mawson, Antarctica.2. Their ability to maintain rectal temperature during the test cold exposure significantly improved at Mawson. Shivering and cold diuresis did not change. The response of skin temperature did not change significantly except for a small increase in toe temperature. Bradycardia caused by the cold exposure was significantly greater at Mawson, but the rise in blood pressure did not change. Spontaneous fluctuations in rectal temperature that occurred during the cold exposure were intensified at Mawson.3. The results confirm those of a previous study at Mawson, and are attributed to general acclimatization to cold. It is suggested that tissue insulation increased as a result of enhanced vasoconstriction.

Acclimatization↗
PubMed1974

Inhibition of thermoregulatory non-shivering thermogenesis by trauma in cold-acclimated rats.

1. Heat production and blood flow in the interscapular brown adipose tissue of 3 degrees C acclimated rats have been measured by the heated thermo-couple technique.2. When the environmental temperature (T(a)) was reduced from 30 to 3 degrees C heat production by the brown adipose tissue began to increase at the lower limit of the thermoneutral zone and then increased linearly.3. Blood flow also increased when T(a) was reduced but was not so well correlated with T(a). There was however a good positive correlation between blood flow and heat production.4. During the first hour after a 4 hr period of bilateral hind-limb ischaemia in a 20 degrees C environment the percentage of rats not producing heat in the interscapular brown adipose tissue increased and the tissue blood flow fell.5. By varying the T(a) of the injured rat it was found that the T(a) at which heat transfer from the interscapular brown adipose tissue commenced was significantly lower than in the controls although the slope of the regression lines relating heat production and T(a) was unaltered.6. Blood flow also increased in the injured rat when T(a) was lowered but the increase in the tissue blood flow per unit increase in heat production was less than in the controls.7. In a 5 degrees C environment heat production in the interscapular brown adipose tissue of the injured rat was further increased by the S. C. injection of L-isoprenaline or L-noradrenaline.8. It is concluded that the central control of thermoregulatory non-shivering thermogenesis is inhibited after injury in the rat.

Adipose Tissue, Brown↗
PubMed1986

Suppression of non-shivering thermogenesis in the rat by heat-seeking behaviour during cold exposure.

Changes in rectal temperature (Tre) during cold exposure (0 +/- 1 degrees C) were observed in three groups of rats: heat-seeking, no-behaviour and semi-restrained groups. Significant increases in Tre were observed in the no-behaviour and the semi-restrained groups during cold exposure. In the heat-seeking behaviour group Tre remained constant during cold exposure. The increased Tre in the semi-restrained group during cold exposure was markedly attenuated by the systemic injection of beta-blocker (propranolol: 10 mg/kg, I.P.), indicating that this increase of Tre was caused by activation of non-shivering thermogenesis (n.s.t.). Furthermore, the rise in Tre in the semi-restrained group was preceded by a greater increase in the temperature of the interscapular brown adipose tissue. Using the autoradiographic [14C]deoxyglucose technique, it was revealed that the enhanced n.s.t. in the no-behaviour and the semi-restrained groups was accompanied by a significant increase of metabolic activity in the anterior part of the ventromedial hypothalamus. We conclude that during cold exposure motionlessness of slightly restrained animals increase n.s.t. when thermoregulatory behaviour to gain heat is not available. This increased n.s.t. is mediated by activation of hypothalamic function.

Animals↗
PubMed1988

Conversion of normal behavior to shiverer by myelin basic protein antisense cDNA in transgenic mice.

Myelin basic proteins (MBPs) are coded by the single gene necessary for myelin formation in the central nervous system of the mouse. An antisense MBP mini-gene was constructed and used to determine the function of antisense DNA in transgenic mice. Several transgenic offspring of a founder transgenic mouse, AS100, were converted from the normal to mutant shiverer phenotype. Antisense MBP messenger RNA was expressed in these mice, and the endogenous MBP messenger RNA, the MBP, and the myelination in the central nervous system were reduced.

Animals↗
PubMed1997

The shiverer mutation affects the persistence of Theiler's virus in the central nervous system.

Theiler's virus persists in the white matter of the spinal cord of genetically susceptible mice and causes primary demyelination. The virus persists in macrophages/microglial cells, but also in oligodendrocytes, the myelin-forming cells. Susceptibility/resistance to this chronic infection has been mapped to several loci including one tentatively located in the telomeric region of chromosome 18, close to the myelin basic protein locus (Mbp locus). To determine if the MBP gene influences viral persistence, we inoculated C3H mice bearing the shiverer mutation, a 20-kb deletion in the gene. Whereas control C3H mice were of intermediate susceptibility, C3H mice heterozygous for the mutation were very susceptible, and those homozygous for the mutation were completely resistant. This resistance was not immune mediated. Furthermore, C3H/101H mice homozygous for a point mutation in the gene coding for the proteolipid protein of myelin, the rumpshaker mutation, were resistant. These results strongly support the view that oligodendrocytes are a necessary viral target for the establishment of a persistent infection by Theiler's virus.

Animals↗
PubMed1995

Nitrogen narcosis attenuates shivering thermogenesis.

Thermoregulatory responses of eight healthy subjects (six men and two women) were compared when they were head-out immersed in 15 degrees C water at both 1 and 6 ATA. Both trials were conducted in a hyperbaric chamber. During the immersions, esophageal temperature (T(es)) and skin temperature at two sites (chest and calf) were recorded at minute intervals. Oxygen uptake was determined at 5-min intervals with the Douglas bag method. The order of the two trials was alternated. The rate of T(es) cooling was greater during the 6-ATA trial [2.1 +/- 0.5 degrees C/h (SE)] than during the 1-ATA trial (1.3 +/- 0.5 degrees C/h; P < 0.01). Despite the greater rate of core cooling, and presumably a greater thermal drive for shivering, the oxygen uptake response for a similar decrement in T(es) was lower during exposure to 6 than to 1 ATA (P < 0.05). Also, for similar displacement in T(es), the subjects perceived the immersions at 6 ATA to be less cold than those at 1 ATA (P < 0.05). It is concluded that the development of hypothermia in compressed-air divers may be due, in large part, to the attenuation of heat production and cold perception. Most likely, the observed effects on the autonomic responses and thermal perception are due to an inhibitory action of hyperbaric nitrogen on central neural structures involved in temperature regulation.

Adult↗