Two loci, Tmevp2 and Tmevp3, located on the telomeric region of chromosome 10, control the persistence of Theiler's virus in the central nervous system of mice.
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Theiler's virus persistently infects the white matter of the spinal cord in susceptible strains of mice. This infection is associated with inflammation and primary demyelination and is studied as a model of multiple sclerosis. The H-2D gene is the major gene controlling viral persistence. However, the SJL/J strain is more susceptible than predicted by its H-2(s) haplotype. An (SJL/J x B10. S)F1 x B10.S backcross was analyzed, and one quantitative trait locus (QTL) was located in the telomeric region of chromosome 10 close to the Ifng locus. Another one was tentatively mapped to the telomeric region of chromosome 18, close to the Mbp locus. We now report the study of 14 congenic lines that carry different segments of these two chromosomes. Although the presence of a QTL on chromosome 18 was not confirmed, two loci controlling viral persistence were identified on chromosome 10 and named Tmevp2 and Tmevp3. Furthermore, the Ifng gene was excluded from the regions containing Tmevp2 and Tmevp3. Analysis of the mode of inheritance of Tmevp2 and Tmevp3 identified an effect of sex, with males being more infected than females. (+info)
Sonic hedgehog signaling is required during the appearance of spinal cord oligodendrocyte precursors.
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Spinal cord oligodendrocyte precursors arise in the ventral ventricular zone as a result of local signals. Ectopic oligodendrocyte precursors can be induced by sonic hedgehog (Shh) in explants of chick dorsal spinal cord over an extended developmental period. The role of Shh during normal oligodendrocyte development is, however, unclear. Here we demonstrate that Shh is localized to the ventral spinal cord immediately prior to, and during the appearance of oligodendrocyte precursors. Continued expression of Shh is required for the appearance of spinal cord oligodendrocyte precursors as neutralization of Shh signaling both in vivo and in vitro during a defined developmental period blocked their emergence. The inhibition of oligodendrocyte precursor emergence in the absence of Shh signaling was not the result of inhibiting precursor cell proliferation, and the neutralization of Shh signaling after the emergence of oligodendrocyte precursors had no effect on the appearance of additional cells or their subsequent differentiation. Similar concentrations of Shh induce motor neurons and oligodendrocytes in dorsal spinal cord explants. However, in explants from early embryos the motor neuron lineage is preferentially expanded while in explants from older embryos the oligodendrocyte lineage is preferentially expanded. (+info)
Cortical control of spinal pathways mediating group II excitation to human thigh motoneurones.
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1. The possibility was investigated that cortical excitation to human thigh motoneurones is relayed via lumbar premotoneurones. 2. Test responses were evoked by transcranial magnetic stimulation (TMS) in voluntarily contracting quadriceps (Q) and semitendinosus (ST) muscles: either a motor evoked potential (MEP) in surface recordings or a peak of cortical excitation in the post-stimulus time histogram (PSTH) of single motor units was used. These test responses were conditioned by stimuli to the common peroneal (CP) or gastrocnemius medialis (GM) nerves. 3. CP stimulation evoked a large biphasic facilitation of the Q MEP, with early, short-lasting, low-threshold (0.6-0.8 x motor threshold (MT)) and late, longer lasting and higher threshold (1.2-1.5 x MT) peaks separated by a period of depression. GM nerve stimulation evoked a similar early depression and late facilitation in the ST MEP. 4. CP-induced effects in the Q H reflex were different (smaller late facilitation not preceded by any depression), suggesting that CP and cortical volleys interact at a premotoneuronal level to modify the Q MEP. 5. Peaks of cortical excitation evoked by TMS in single motor unit PSTHs were modulated by the conditioning volley like the MEPs with, in Q motor units, early and late CP-induced facilitations separated by a depression, and in ST motor units a late GM-induced facilitation. Facilitations on combined stimulation (i) were greater than the sum of effects by separate stimuli and (ii) never affected the initial part of the cortical peak. 6. It is concluded that the features of the reported facilitatory interactions between cortical and peripheral volleys are consistent with interactions in a population of lumbar excitatory premotoneurones co-activated by group I and group II afferents. The potency of the effects suggests that a significant part of the cortical excitation to motoneurones of thigh muscles is relayed via these interneurones. 7. It is argued that the early depression in ST motoneurones and the separation of the two peaks of facilitation in Q motoneurones reflect a cortical facilitation of spinal inhibitory interneurones projecting on excitatory premotoneurones. (+info)
Axon guidance of outgrowing corticospinal fibres in the rat.
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This review is concerned with the development of the rat corticospinal tract (CST). The CST is a long descending central pathway, restricted to mammals, which is involved both in motor and sensory control. The rat CST is a very useful model in experimental research on the development of fibre systems in mammals because of its postnatal outgrowth throughout the spinal cord as well as its experimental accessibility. Hence mechanisms underlying axon outgrowth and subsequent target cell finding can be studied relatively easily. In this respect the corticospinal tract forms an important example and model system for the better understanding of central nervous system development in general. (+info)
Anomalous L-type calcium channels of rat spinal motoneurons.
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Single channel patch-clamp recordings show that embryonic rat spinal motoneurons express anomalous L-type calcium channels, which reopen upon repolarization to resting potentials, displaying both short and long reopenings. The probability of reopening increases with increasing voltage of the preceding depolarization without any apparent correlation with inactivation during the depolarization. The probability of long with respect to short reopenings increases with increasing length of the depolarization, with little change in the total number of reopenings and in their delay. With less negative repolarization voltages, the delay increases, while the mean duration of both short and long reopenings decreases, remaining longer than that of the openings during the preceding depolarization. Open times decrease with increasing voltage in the range -60 to +40 mV. Closed times tend to increase at V > 20 mV. The open probability is low at all voltages and has an anomalous bell-shaped voltage dependence. We provide evidence that short and long reopenings of anomalous L-type channels correspond to two gating modes, whose relative probability depends on voltage. Positive voltages favor both the transition from a short-opening to a long-opening mode and the occupancy of a closed state outside the activation pathway within each mode from which the channel reopens upon repolarization. The voltage dependence of the probability of reopenings reflects the voltage dependence of the occupancy of these closed states, while the relative probability of long with respect to short reopenings reflects the voltage dependence of the equilibrium between modes. The anomalous gating persists after patch excision, and therefore our data rule out voltage-dependent block by diffusible ions as the basis for the anomalous gating and imply that a diffusible cytosolic factor is not necessary for voltage-dependent potentiation of anomalous L-type channels. (+info)
Spinal effects of the calmodulin inhibitor calmidazolium on dorsal horn neurons in the rat.
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Drugs able to inhibit calmodulin activation can prevent some consequences of the rise in intracellular calcium. It has recently been shown that intrathecal injection of calmodulin inhibitors induce analgesia in rats. We study here the effect induced by the calmodulin inhibitor, calmidazolium, on the activity of dorsal horn neurons driven by noxious and non-noxious stimuli. Extracellular recordings of convergent (n = 12), low-threshold mechanoreceptive (n = 5) and proprioceptive (n = 5) units were made in the presence of calmidazolium. Calmidazolium (600 micrograms) reduced the noxious (50 degrees C) heat-evoked responses obtained in convergent neurons. On the contrary, the non-noxious tactile responses obtained in low-threshold mechanoreceptive neurons as well as the joint movement-evoked responses obtained in proprioceptive units remained unmodified. We conclude that calmidazolium can block nociceptive processing in the spinal cord and that this fact can help to explain the analgesic effects that intrathecal W-7 and calmidazolium induce in behavioral tests. (+info)
Analgesia-producing mechanism of processed Aconiti tuber: role of dynorphin, an endogenous kappa-opioid ligand, in the rodent spinal cord.
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The analgesia-producing mechanism of processed Aconiti tuber was examined using rodents whose nociceptive threshold was decreased by loading repeated cold stress (RCS). The antinociceptive effect of processed Aconiti tuber (0.3 g/kg, p.o.) in RCS-loaded mice was antagonized by pretreatment with a kappa-opioid antagonist, nor-binaltorphimine (10 mg/kg, s.c.), and was abolished by an intrathecal injection of anti-dynorphin antiserum (5 microg). The Aconiti tuber-induced antinociception was inhibited by both dexamethasone (0.4 mg/kg, i.p.) and a dopamine D2 antagonist, sulpiride (10 mg/kg, i.p.), in RCS-loaded mice, and it was eliminated by both an electric lesion of the hypothalamic arcuate nucleus (HARN) and a highly selective dopamine D2 antagonist, eticlopride (0.05 microg), administered into the HARN in RCS-loaded rats. These results suggest that the analgesic effect of processed Aconiti tuber was produced via the stimulation of kappa-opioid receptors by dynorphin released in the spinal cord. It was also shown that dopamine D2 receptors in the HARN were involved in the expression of the analgesic activity of processed Aconiti tuber. (+info)
Implantable spinal cord stimulator to treat the ischemic manifestations of thromboangiitis obliterans (Buerger's disease).
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Thromboangiitis obliterans (Buerger's disease) is a segmental inflammatory vasculitis that involves the small-sized and medium-sized arteries, veins, and nerves. It is causally related to tobacco use. The diagnosis is usually made on the basis of the presence of distal arterial disease in individuals who smoke and in whom other disease entities have been excluded. The most effective treatment for Buerger's disease is smoking cessation. Without strict adherence to tobacco avoidance, disease progression is likely. Methods to control ischemic pain include medications, sympathectomy, or surgical revascularization. The effect of sympathectomy is unpredictable, and the chances of a successful revascularization procedure are rare because distal target vessels often are extensively diseased. Herein, we describe a patient whose condition did not respond to the usual conservative therapy but did respond dramatically to the implantation of a permanent spinal cord stimulator. Although these devices have been used for more than 20 years in various other peripheral arterial diseases, their use in Buerger's disease has been limited. (+info)