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PubMed1995

Hypomyelination alters K+ channel expression in mouse mutants shiverer and Trembler.

Voltage-gated K+ channels are localized to juxtaparanodal regions of myelinated axons. To begin to understand the role of normal compact myelin in this localization, we examined mKv1.1 and mKv1.2 expression in the dysmyelinating mouse mutants shiverer and Trembler. In neonatal wild-type and shiverer mice, the focal localization of both proteins in axon fiber tracts is similar, suggesting that cues other than mature myelin can direct initial K+ channel localization in shiverer mutants. In contrast, K+ channel localization is altered in hypomyelinated axonal fiber tracts of adult mutants, suggesting that abnormal myelination leads to channel redistribution. In shiverer adult, K+ channel expression is up-regulated in both axons and glia, as revealed by immunocytochemistry, RNase protection, and in situ hybridization studies. This up-regulation of K+ channels in hypomyelinated axon tracts may reflect a compensatory reorganization of ionic currents, allowing impulse conduction to occur in these dysmyelinating mouse mutants.

Aging↗
PubMed1988

The role of myelination in learning performance observed in two strains of myelin-deficient mutant mice (shiverer and mld).

In order to study whether myelination is involved in learning performance, the behavior of myelin-deficient mutant mice (shiverer and mld) was examined. Shiverer is a deletion mutant of the myelin basic protein (MBP) gene causing severe myelin deficits due to the complete absence of MBP, while mld, allelic mutant to shiverer, shows lowered MBP expression, resulting in less severe effects. Shiverer clearly showed deficits in successive reversal learning, while mld showed less deficits in the learning performance. Both mutant mice showed no deficits in the radial maze performance, which is though to show the natural foraging behavior of rodents. These results suggest that myelin formation is related to learning but not to natural behavior.

Animals↗
PubMed2000

The effect of short-term fasting on shivering thermogenesis in Japanese quail chicks (Coturnix coturnix japonica): indications for a significant role of diet-induced/growth related thermogenesis.

(1) The effect of short-term fasting on metabolism and shivering thermogenesis was studied in 9-day-old Japanese quail. (2) After 31 h of fasting, heat production decreased 39% and body temperature over 2 degrees C in the thermoneutral zone. The difference in heat production between control and fasting groups decreased with decreasing ambient temperature. (3) Despite the lower metabolic rate, the amplitudes of shivering EMGs were higher in fasted chicks, especially in pectoralis. This indicates that fasted quails used shivering to compensate the decrease in diet-induced/growth related thermogenesis. (4) In cold, conductance of control birds decreased simultaneously with increasing heat production while in fasted chicks, conductance decreased to its minimum before heat production was activated. (5) Japanese quail chicks adapt quickly to short-term fasting by decreasing metabolism but they maintain their ability to thermoregulate in cold. Diet-induced/growth related thermogenesis has a significant role in thermoregulation since it reduces the need of shivering thermogenesis.

Journal Article↗
PubMed1998

Efferent projection from the preoptic area for the control of non-shivering thermogenesis in rats.

1. To investigate the characteristics of efferent projections from the preoptic area for the control of non-shivering thermogenesis, we tested the effects of thermal or chemical stimulation, and transections of the preoptic area on the activity of interscapular brown adipose tissue in cold-acclimated and non-acclimated anaesthetized rats. 2. Electrical stimulation of the ventromedial hypothalamic nucleus (VMH) elicited non-shivering thermogenesis in the brown adipose tissue (BAT); warming the preoptic area to 41.5 C completely suppressed the thermogenic response. 3. Injections of d, l-homocysteic acid (DLH; 0.5 mM, 0.3 microliter) into the preoptic area also significantly attenuated BAT thermogenesis, whereas injections of control vehicle had no effect. 4. Transections of the whole hypothalamus in the coronal plane at the level of the paraventricular nucleus induced rapid and large rises in BAT and rectal temperatures. This response was not blocked by pretreatment with indomethacin. The high rectal and BAT temperatures were sustained more than 1 h, till the end of the experiment. Bilateral knife cuts that included the medial forebrain bundle but not the paraventricular nuclei elicited similar rises in BAT and rectal temperatures. Medial knife cuts had no effect. 5. These results suggest that warm-sensitive neurones in the preoptic area contribute a larger efferent signal for non-shivering thermogenesis than do cold-sensitive neurones, and that the preoptic area contributes a tonic inhibitory input to loci involved with non-shivering thermogenesis. This efferent inhibitory signal passes via lateral, but not medial, hypothalamic pathways.

Acclimatization↗
PubMed1983

The effect of the shiverer mutation on myelin basic protein expression in homozygous and heterozygous mouse brain.

We report (a) that the shiverer mutation has pleiotropic phenotypic effects on myelin basic protein expression in the CNS of homozygous (shi/shi) mice and (b) that each of the effects of the shiverer allele is expressed co-dominantly with the wild-type allele in heterozygous (+/shi) animals. First, the total amount of myelin basic protein, as determined by radioimmunoassay, that accumulates in the CNS is approximately 0.1% of the wild-type amount in shi/shi animals and approximately 50% in +/shi animals. Second, the four major forms of myelin basic protein, with molecular weights of 21,500, 18,500, 17,000, and 14,000, that are present in wild-type mouse CNS are undetectable in either whole brain or purified myelin of shi/shi animals, and each of the four proteins is reduced commensurately in brain and myelin of +/shi animals. Third, the small amount of myelin basic protein-related material that does accumulate in the shi/shi brain consists of several polypeptides, with molecular weights ranging from 25,000 to 100,000, the pattern of which is different from that found in wild-type brain. The pattern of myelin basic protein-related polypeptides in +/shi brain is a composite of the wild type and the shiverer mutant. Fourth, messenger RNA from shi/shi brain, when translated in vitro, encodes a set of myelin basic protein-related polypeptides qualitatively similar to that encoded by wild-type messenger RNA, except that the 18,500 and 14,000 translation products are greatly reduced, while other myelin basic protein-related translation products are spared. The pattern of myelin basic protein-related translation products for +/shi messenger RNA is intermediate between the patterns for +/+ and shi/shi messenger RNAs. The results suggest that the genetic lesion in the shiverer mutation impinges on the structural gene (or genes) encoding myelin basic protein or on a cis-acting regulatory element controlling that gene (or genes).

Animals↗
PubMed1985

Molecular genetic analysis of myelin-deficient mice: shiverer mutant mice show deletion in gene(s) coding for myelin basic protein.

The gene expression of myelin basic proteins (MBPs) in shiverer mutant mice was investigated by the Northern and Southern hybridization techniques. In the control mice RNA molecules from the brains which were about 2,300 nucleotides in length were hybridized to cDNA of 1.8 kb encoding for a mouse MBP, but RNA from the brains of 3-week-old shiverer mutant mice contained no detectable amount of MBP transcripts hybridizing to this probe. Moreover the shiverer mutant mice lost several restriction fragments that hybridized to the same probe in the control mice when each of the five restriction enzymes, i.e., HindIII, PstI, PvuII, AccI, and StuI, was used. These data suggest that the shiverer mutation may correspond to the deletion of a large portion of MBP exon(s) in the gene, and this deletion causes inefficient transcription leading to the depletion of MBPs in the myelin and the dysmyelination observed in these mice.

Animals↗
PubMed1998

Shivering thermogenesis in the pigeon: the effects of activity, diurnal factors, and feeding state.

Shivering (electromyographic activity of the pectoral muscle), oxygen consumption, and body temperature were measured from undisturbed pigeons for periods of several weeks, and segments from the midparts of each phase of the light-dark cycle were compared at various ambient temperatures and feeding regimes. Behavior was recorded with a video camera. None of the observed types of behavior (e.g., walking, preening, feeding, drinking, pecking, defecation) induced spurious electrical activity in the pectoral muscle. On the other hand, none of these behaviors directly inhibited ongoing shivering. There was no difference in the mean level of shivering between the light (L) and dark (D) phases of the day in any of the conditions, although body temperature was 2 degreesC higher during L. Measurements of integrated electromyogram (EMG) with high temporal resolution (28 samples/s) showed that, at 1 degreesC, shivering in the pectoral muscle was present for more than 98% of the time. Plots of oxygen consumption against root mean square EMG were obtained in each condition by a filtering procedure that excludes data points in which oxygen consumption is affected by motor activity. These plots showed that the increase in heat production induced by a unit increase in pectoral EMG was lower in D than in L and that it was further lowered by fasting. The amplitude spectra of raw EMG signals were similar in all conditions. Spectra of demodulated (rectified, low-pass filtered) EMG showed a distinct rhythmicity around 8 Hz at 21 degreesC that was further enhanced by fasting but absent at 1 degreesC. This suggests that the degree of synchronization and pattern of recruitment of motor units are specific for various temperatures and feeding regimes, and may partly explain the variable relation between heat production and muscle electrical activity. The results emphasize the advantages of long-term measurements for understanding the control of thermogenesis in birds.

Animals↗
PubMed2001

Rumpshaker behaves like juvenile-lethal Plp mutations when combined with shiverer in double mutant mice.

The phenotypes of double mutant mice whose genomes are homozygous for an Mbp (myelin basic protein) mutation and hemizygous for a juvenile-lethal Plp (proteolipid protein) mutation were compared in earlier studies. The results suggested that the shiverer Mpb mutation might have some unexplained ability to partially rescue oligodendrocytes (OLs) from the 'death sentence' that is imposed by the Plp mutations. Conversely, they also indicated that the juvenile-lethal Plp mutations may normalize shiverer OL morphology by reducing the numbers of microprocesses. The Plp mutation rumpshaker produces a mild hypomyelination without reduction in OL numbers and a normal lifespan. This report describes double mutant mice combining two Mbp mutations with rumpshaker, utilizing a common B6C3F1 hybrid-based genetic background. Initial studies on B6C3F1 rumpshaker optic nerve and spinal cord white matter showed unanticipated signs of OL death, with morphologic criteria suggestive of an apoptotic mechanism. In shiverer*rumpshaker double mutant mice, this small class of dying cells could not be identified. White matter morphology was similar to that of mice expressing only the shiverer mutation, except that OL microprocesses were far less abundant. This evidence suggests that, despite their distinctive phenotypic differences, rumpshaker may share more characteristics with the juvenile-lethal Plp mutations than has previously been recognized.

Animals↗
PubMed1997

Regulation of cytoskeleton by myelin components: studies on shiverer oligodendrocytes carrying an Mbp transgene.

Oligodendrocytes from the shiverer mutant mouse are missing most of the myelin basic protein (Mbp) gene. In axon-free cultures, they produce membrane sheets with abnormally assembled microtubule and actin-based structures. This suggests that an Mbp gene product may have an important role in regulating the organization and stability of the wild-type oligodendrocyte cytoskeleton. We now present evidence extending these observations, using cultured oligodendrocytes that carry both the shiverer mutation and the Mbp1 transgene which partially corrects their deficit. Shiverer oligodendrocytes that carry one dose of the Mbp1 transgene abnormally express MBP along major cytoskeletal vein-like structures in processes and sheets. Shiverer oligodendrocytes that carry two doses of the Mbp1 transgene contain two types of membrane sheet regions, i.e. regions filled with aberrant punctate foci of MBP, and regions with normal domains of MBP. Immunocytochemical staining data show that the distribution of cytoskeleton and associated 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNPase) is dependent upon how MBP is organized. Bundling of actin filaments occurs only around MBP domains, and the colocalization of CNPase along microtubular structures also appears to be regulated by MBP domains in sheets. Multinucleated oligodendrocytes are observed, a likely result of the inability of dividing pro-oligodendrocytes to bundle actin filaments. In addition, the ability of MBP to mediate extracellular signals that modulate cytoskeleton appears to be dependent upon MBP's organization. Transduction of the galactocerebroside signaling pathway, which results in the destabilization of microtubules but not actin filaments, occurs only in sheets containing MBP domains. The distribution of MBP, however, does not affect the myelin/oligodendrocyte-specific protein signaling pathway, which results in growth of microtubular structures and extensive destabilization of the actin cytoskeleton.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1995

Cytoskeleton in myelin-basic-protein-deficient shiverer oligodendrocytes.

Production of CNS myelin by oligodendrocytes requires the regulated synthesis and assembly of cytoskeletal components. However, the molecular signals that mediate this process are not known. Here we use the shiverer mutant mouse, which is missing a large segment of the myelin basic protein (MBP) gene, to investigate the possible role in cytoskeletal assembly of an MBP gene product or of other myelin components whose expression may be linked to that of MBP. In axon-free cultures, we find that approximately half of shiverer oligodendrocytes have enlarged cell bodies, abnormal processes and fail to elaborate extensive membrane sheets. In those membrane sheets that are elaborated by shiverer oligodendrocytes, microtubular structures are abnormal in size and distribution. Additionally, 2',3'-cyclic nucleotide 3'-phosphohydrolase and microfilaments are not colocalized with microtubular structures as they would be in mature wild-type membrane sheets. These observations suggest that an MBP gene product has a direct or indirect role in regulating various aspects of cytoskeleton assembly in wild-type oligodendrocytes. In the absence of this signal, oligodendrocytes apparently do not normally assemble cytoskeleton; this may be one important basis for the abnormal morphology of intact shiverer CNS.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗
PubMed1986

Transplantations of newborn CNS fragments into the brain of shiverer mutant mice: extensive myelination by transplanted oligodendrocytes. II. Electron microscopic study.

As already demonstrated by immunohistochemistry, oligodendrocytes from newborn normal mice are able to survive, migrate and myelinate when transplanted into the newborn shiverer (shi/shi) mouse brain. The survival of the grafted cells and their interaction with the host brain were studied at different times after transplantation. Normal myelin was found in the host parenchyma basing our observation on the morphological difference between normal and shiverer myelin: the shiverer myelin deprived of major dense line appears uncompacted as compared to normal myelin. Myelin formed by transplanted oligodendrocytes was detected around the graft and, after immunohistochemical prelocalization, at considerable distance from the site of implantation. Normal and shiverer myelin were detected around axons adjacent to each other or around the same axon. These results confirm and extend at the ultrastructural level our previous data obtained by immunohistochemistry.

Animals↗
PubMed1985

Peripheral nerves in shiverer----dystrophic mouse chimeras: evidence that a non-Schwann cell component is required for axon ensheathment in vivo.

Peripheral nerves in dystrophic mice express multiple axon ensheathment abnormalities. If an intrinsic deficiency expressed within the Schwann cells themselves were to account for this neuropathy, then such cells, existing in a chimera preparation, would be expected to express the same ensheathment abnormalities, whereas a coexisting population of non-dystrophic Schwann cells should not be similarly affected. The genotype of myelinated Schwann cells in shiverer----dystrophic chimera was established with immunocytochemical techniques. Shiverer myelin lacks the P1 component of myelin basic protein (MBP), whereas dystrophic myelin appears to contain normal levels of MBP. No correlation between the ensheathment characteristics of the chimera spinal roots and the genotype of the local Schwann cell population was found; both dystrophic Schwann cell populations expressing normalized ensheathment characteristics and shiverer Schwann cells failing to respond to the local presence of naked axons were observed. These results require that a defective extra Schwann cell component is involved in the pathogenesis of the dystrophic neuropathy. Moreover, the normal realization of that component appears to be a necessary prerequisite for shiverer Schwann cells to achieve full ensheathment competence. Although a definitive identification of the cell type(s) that expresses the dy gene locus has not been achieved in this chimera preparation, the observations are consistent with defective endoneurial fibroblast function.

Animals↗
PubMed1988

Shivering and nonshivering thermogenesis in exercised cold-deacclimated rats.

Norepinephrine (NE)-induced increase in oxygen consumption (VO2) and colonic temperature (Tc) was greater in cold-acclimated rats housed at 4 degrees C for 4 weeks (CA) than warm-acclimated controls housed at 24 degrees C for 4 weeks (WA). On the other hand, shivering activity measured at 4 degrees C was less in CA than in WA, while propranolol administration eliminated the difference between these two groups by enhancing shivering in CA. Wet weight and protein content of interscapular brown adipose tissue (IBAT) were greater in CA than in WA. Following cold acclimation, CA were deacclimated at 24 degrees C for 5 weeks. During deacclimation, half of this latter group were forced to run (15 m.min-1 for 1 h) every day (CD-T) while the remaining rats remained sedentary (CD-S). Shivering activity assessed at 4 degrees C 4 weeks after commencing cold deacclimation was significantly less in CD-T than in CD-S and the difference disappeared following propranolol injection. VO2 and Tc responses to NE injection measured 1, 2 and 5 weeks after commencing cold deacclimation did not differ between CD-S and CD-T. Although IBAT weight was lighter in CD-T than in CD-S, its total protein content was not different between the latter two groups of rats. These results suggest that a greater degree of NE-independent nonshivering thermogenesis (NST) is retained in rats that are exercised during the process of deacclimation as compared with animals that are sedentary. This difference in NST would not seem to be directly related to BAT thermogenic capacity.

Acclimatization↗
PubMed1984

Cardiovascular and blood gas responses to shivering produced by external and central cooling in the pigeon.

Cardiovascular and blood gas responses of pigeons to spinal cord cooling (35-36 degrees C) were measured at thermoneutral (28 degrees C) and low (5 degrees C) ambient temperatures. Spinal cord cooling at thermoneutral temperatures caused immediate shivering and increases in heat production (223%), heart rate (152%) and cardiac output (169%), but blood pressure and stroke volume did not change. PaCO2 and PvCO2 increased slightly during the cooling; PaO2 and CaO2 decreased slightly while PvO2 and CvO2 decreased considerably (10 Torr and 1.7 mmol . l-1, respectively), resulting in a greater a-v difference in O2 content. Ambient cooling produced responses comparable to spinal cord cooling. Simultaneous spinal cord and ambient cooling produced similar responses that were generally greater in magnitude than either kind of cooling alone. Consequently, heart rate, cardiac output and O2 extraction from the blood were all significantly, linearly related to heat production over the wide range studied. Comparisons are made between cardiovascular responses of birds to shivering and exercise in regards to the relative importance of increases in heart rate, stroke volume and blood pressure. It is suggested that exercise and shivering may effect cardiovascular responses through similar receptor mechanisms.

Animals↗
PubMed1986

The effects of hypoxia on the metabolic and cardiorespiratory responses to shivering produced by external and central cooling in the pigeon.

Respiratory, cardiovascular and blood gas responses of pigeons to spinal cord cooling (36 +/- 1 degrees C), to ambient cooling (Ta = 5 degrees C) and to simultaneous spinal cord and ambient cooling were measured at three different levels of fractional inspired oxygen concentration (FIO2 = 0.209, 0.10 and 0.07). Shivering and the 'extra' VO2 provoked by ambient and/or spinal cord cooling were more or less reduced during hypoxic exposure depending on the intensity of cold stress and hypoxic states. At FIO2 = 0.10 shivering was markedly reduced and sometimes inhibited, whereas at FIO2 = 0.07 any pattern of cold tremor was inhibited. The accompanying cardiorespiratory responses were similar to those of thermoneutral controls exposed to the same FIO2. The amount by which VO2 was reduced in the pigeons exposed to hypoxia during ambient and/or spinal cord cooling was correlated, at both levels of hypoxia, to the thermoregulatory VO2 (viz. the 'extra' VO2 produced by cooling) prior to exposure to the hypoxic gas. The effect of hypoxia on shivering and associated cardiorespiratory adjustments was rapid and was completely reversible on return to air. We conclude that the thermoregulatory system in pigeons is sensitive to hypoxia, as is the case for mammals. The FIO2 that begins to inhibit thermoregulatory and metabolic responses to cold is lower in birds, perhaps as a result of the better ability of the bird to increase intrapulmonary gas and blood O2 convective transports when exposed to hypoxic gas.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Shivering during sleep: relationship between muscle blood flow and fiber type composition.

The present study considers in rabbit: i) the relationship between muscle blood flow (BF) increase and fiber-type composition during shivering; ii) the influence of the vigilance states (Quiet Wakefulness, QW; Synchronized Sleep, SS; Desynchronized Sleep, DS) on this relationship. The results show that muscle BF increase during shivering is proportional to the slow-twitch oxidative (SO) fiber component in QW and SS; in DS the proportionality is lost. This is in accordance with the disappearance of shivering, together with all thermoregulatory effector responses, in this sleep state. Another muscle circulation pattern occurring at low ambient temperature, the relationship between BF increase and muscle depth, also disappears in DS. This confirms that the integrative control of muscle circulation, like other integrative mechanisms, is impaired during DS.

Analysis of Variance↗
PubMed1989

Meperidine to control shivering associated with platelet transfusion reaction.

Shivering may be part of a febrile non-haemolytic reaction to blood product transfusion. Shivering can increase oxygen consumption up to 500 per cent which may be detrimental to patients with decreased myocardial reserve. A case is presented of a reaction to platelet transfusion characterized by shivering, tachycardia and hypertension in a patient with a recent myocardial infarction in whom the metabolic and haemodynamic effects were considered to be potentially disastrous. Intravenous injection of meperidine was rapidly effective in treating these changes.

Adult↗
PubMed1978

Prevention of post-anaesthesia shivering.

This study involves ventilation of the lungs with warmed humidifed anaesthetic gases during prolonged elective abdominal operations. Tympanic, oesophageal and toe temperatures were compared bewteen twenty warmed and twenty un-warmed patients at various times during operation and recovery. Fifty per cent (10/20) unwarmed patients shivered in the recovery room, while none of the warmed patients shivered. Our data indicate that pulmonary ventilation with warm humidified anaesthetic gases provides heat transfer by the lungs, preventing hypothermia during operation and post -anaesthesia shivering is prevented by maintaining the patient normothermic in both the operating room and the recovery room.

Anesthesia, General↗