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1.
We have previously reported on our investigation of motoneuron cell death (MCD) in the rat nucleus ambiguus (NA). This article focuses on the other major upper respiratory tract motor nucleus: the hypoglossal. The hypoglossal nucleus (XII) contains motoneurons to the tongue and, as such, plays a critical role in defining patterns of respiration, deglutition, and vocalization. Motoneuron counts were made in XII in a developmental series of rats. In addition, the neural tracer fast DiI was used to ensure that all hypoglossal motoneurons had migrated into the nucleus at the time cell death was assessed. Furthermore, an antibody to γ-aminobutyric acid (GABA) was used to determine the potential effect of inadvertently counting large interneurons on motoneuron counts. Cell death in XII was shown to occur entirely prenatally with a loss of 35% of cells between embryonic day 16 (E16) and birth. Fast DiI tracings of the prenatal hypoglossal nerve indicated that all motoneurons were present in a well-defined nucleus by E15. Immunocytochemical staining for GABA demonstrated considerably fewer interneurons than motoneurons in XII. These findings in XII, in comparison with those previously reported for NA, demonstrate differences in the timing and amount of cell death between upper respiratory tract motor nuclei. These differences establish periods during which one nucleus may be preferentially insulted by environmental or teratogenic factors. Preferential insults may underlie some of the upper respiratory tract incoordination pathologies seen in the newborn such as the sudden infant death syndrome (SIDS). © 1995 John Wiley & Sons, Inc.  相似文献   

2.
Naturally occurring motoneuron cell death during development is a well-described phenomenon and the existence of a survival factor provided by target muscles has been postulated. Blockade of activity by chronic application of a neuromuscular junction blocker rescues almost all motoneurons from cell death. The present study was conducted in order to examine the possibility that the motoneuron survival-promoting activity in muscles increases following activity blockade. Cell culture was used to assess the degree of motoneuron survival-promoting activity present in muscle extracts. Embryonic chick motoneurons were labeled by injecting the water-insoluble fluorescent dye, DiI (Molecular Probes, Inc.) into the spinal nerves both before and during the cell death period. The labeled cells extending long neurites were counted after 2 days of culture as viable motoneurons in low-density heterogeneous cell cultures. The culture medium, Ham F12/DMEM (1:1 mixture) supplemented with 10% horse serum, 5% chick serum, and 5% fetal calf serum, was employed as a basic culture medium for assessing motoneuron survival factor, since it supported the survival of a significantly higher number of motoneurons derived from embryos before cell death than those during the cell death period, thus representing the motoneuron's requirement for survival factor in vivo. The number of surviving motoneurons clearly increased in proportion to the amount of muscle extract added to the culture medium. In comparison with control chick embryos, the dose-response relation between the number of surviving motoneurons and the amount of muscle extract added did not change when embryos were used after chronic application of curare. These results therefore indicate that survival factor derived from target muscle is crucial to the in vitro motoneurons during the cell death period, but do not support the idea that inactive muscle contains a higher amount of the survival factor.  相似文献   

3.
The present study investigated the effects of spinal cord stimulation, neuromuscular blockade, or a combination of the two on neuromuscular development both during and after the period of naturally occurring motoneuron death in the chick embryo. Electrical stimulation of the spinal cord was without effect on motoneuron survival, synaptogenesis, or muscle properties. By contrast, activity blockade rescued motoneurons from cell death and altered synaptogenesis. A combination of spinal cord stimulation and activity blockade resulted in a marked increase in motoneuron death, and also altered synaptogenesis similar to that seen with activity blockade alone. Perturbation of normal nerve–muscle interactions by activity blockade may increase the vulnerability of developing motoneurons to excessive excitatory afferent input (spinal cord stimulation) resulting in excitotoxic-induced cell death. © 1993 John Wiley & Sons, Inc.  相似文献   

4.
A chronic neuromuscular blockade during those embryonic stages when naturally occurring spinal motoneuron death occurs, results in the prevention of this cell loss. The excess motoneurons are maintained as long as the neuromuscular blockade is continued; once embryonic neuromuscular activity resumes, however, the excess motoneurons undergo a delayed period of cell death. By contrast, the resumption of neuromuscular activity in these same preparations after hatching did not result in a delayed cell death. The excess motoneurons, prevented from dying in the embryo, persisted for as long as 4 days postnatally despite the presence of considerable limb motility. The maintenance of motoneurons may be regulated differently before and after hatching.  相似文献   

5.
Approximately half of the motoneurons generated during normal embryonic development undergo programmed cell death. Most of this death occurs during the time when synaptic connections are being formed between motoneurons and their target, skeletal muscle. Subsequent muscle activity stemming from this connection helps determine the final number of surviving motoneurons. These observations have given rise to the idea that motoneuron survival is dependent upon access to muscle derived trophic factors, presumably through intact neuromuscular synapses. However, it is not yet understood how the muscle regulates the supply of such trophic factors, or if there are additional mechanisms operating to control the fate of the innervating motoneuron. Recent observations have highlighted target independent mechanisms that also operate to support the survival of motoneurons, such as early trophic-independent periods of motoneuron death, trophic factors derived from Schwann cells and selection of motoneurons during pathfinding. Here we review recent investigations into motoneuron cell death when the molecular signalling between motoneurons and muscle has been genetically disrupted. From these studies, we suggest that in addition to trophic factors from muscle and/or Schwann cells, specific adhesive interactions between motoneurons and muscle are needed to regulate motoneuron survival. Such interactions, along with intact synaptic basal lamina, may help to regulate the supply and presentation of trophic factors to motoneurons.  相似文献   

6.
A sexual dimorphism in the number of motoneurons in the spinal nucleus of the bulbocavernosus (SNB) of rats is engendered by a sex difference in ontogenetic cell death. Testicular secretions, specifically androgenic steroids, reduce SNB motoneuron death in males. The fate of the target muscles generally mirrors that of the motoneurons, and androgens appear to exert their effects upon the target muscles, sparing the motoneurons as a secondary consequence. Treatment with ciliary neurotrophic factor can also spare SNB motoneurons in newborn females, raising the possibility that this factor normally mediates androgen's effect upon motoneuron survival. The ontogeny of calcitonin gene-related peptide immunoreactivity is delayed in SNB cells compared with other motoneurons and is further delayed in the SNB cells of females. In both sexes, calcitonin gene-related peptide is detected after the period of SNB motoneuron death is complete. A sex difference in motoneuron number is also seen in the human homologue of the SNB and, because ontogenetic death of motoneurons in humans overlaps the period of androgen secretion, may arise in a manner similar to that in the rat SNB.  相似文献   

7.
Treatment of chick embryos with neuromuscular blocking agents such as curare during periods of naturally occurring motoneuron death results in a striking reduction of this normal cell loss. Inactivity-induced changes in motoneuron survival were found to be associated with increased levels of AChRs and AChR-clusters in skeletal muscle and with increased focal sites of AChE that are innervated ('synaptic sites'). Treatment of embryos with curare after the normal cell death period (E12-E15) resulted in no change in motoneuron survival. Although AChR-clusters and focal sites of AChE were increased in these embryos on E16, many of these sites were uninnervated. Treatment of embryos with nicotine or decamethonium (E6-E10) also reduced neuromuscular activity but did not alter motoneuron survival nor did such treatment alter AChRs. The different effects of curare vs nicotine and decamethoniam on motoneuron survival and AChRs may be related to the fact that the former is a competitive blocker whereas the latter two drugs are depolarizing blockers. Finally, treatment of embryos (E6-9) with doses of curare (1 mg daily) that allow for the almost complete recovery of neuromuscular activity a few days following treatment (by E16) resulted in the gradual loss of the excess motoneurons that were present on E10, and by E16 the number of remaining AChR clusters and focal sites of AChE were also decreased to levels comparable to control values. Inactivity-induced changes in AChRs or AChR-clusters may be an important factor in the reduced motoneuron death that accompanies neuromuscular blockade during critical stages of development. These receptor changes very likely reflect increased synaptogenesis in the muscles of paralyzed embryos which in turn may act to reduce motoneuron death by providing increased access to muscle-derived neurotrophic molecules.  相似文献   

8.
A sexual dimorphism in the number of motoneurons in the spinal nucleus of the bulbocavernosus (SNB) of rats is engendered by a sex difference in ontogenetic cell death. Testicular secretions, specifically androgenic steroids, reduce SNB motoneuron death in males. The fate of the target muscles generally mirrors that of the motoneurons, and androgens appear to exert their effects upon the target muscles, sparing the motoneurons as a secondary consequence. Treatment with ciliary neurotrophic factor can also spare SNB motoneurons in newborn females, raising the possibility that this factor normally mediates androgen's effect upon motoneuron survival. The ontogeny of calcitonin gene-related peptide immunoreactivity is delayed in SNB cells compared with other motoneurons and is further delayed in the SNB cells of females. In both sexes, calcitonin gene-related peptide is detected after the period of SNB motoneuron death is complete. A sex difference in motoneuron number is also seen in the human homologue of the SNB and, because ontogenetic death of motoneurons in humans overlaps the period of androgen secretion, may arise in a manner similar to that in the rat SNB. © 1992 John Wiley & Sons, Inc.  相似文献   

9.
In vertebrates, approximately 50% of the lumbosacral motoneurons die during a short period of development that coincides with synaptogenesis in the limb. Although it has been postulated that these motoneurons die because they fail to obtain adequate trophic support from the muscles, it is not clear how this factor is supplied. The mechanism by which activity blockade prevents motoneurons cell death is also unknown. In order to begin to understand the nature of these proposed trophic interactions, we have examined the temporal sequence of axonal invasion and ramification within two muscles of the chick hindlimb, the predominantly slow iliofibularis and the fast posterior iliotibialis, during the cell death period. We found striking differences in intramuscular nerve ingrowth and branching between fast and slow muscle. We also observed differences in the molecular composition of fast and slow myotubes that may contribute to the nerve pattern differences. In addition, we observed a progressive increase in the degree of intramuscular nerve fasciculation as well as a precise temporal sequence of nerve branching. The earliest detectable response to chronic curarization was a dramatic decrease in the degree of intramuscular nerve fasciculation. Activity blockade also greatly enhanced nerve branching within the muscles from the time that nerve branches normally formed, and, additionally, interfered with the normal cessation of axon growth. Our results support the idea that nerve endings are the sites of trophic uptake. Furthermore, although our results do not allow us to exclude other activity-dependent influences on motoneuron survival, they suggest the following testable hypotheses: (1) the normal regulation of motoneuron survival may result from the precise control of intramuscular nerve branching, (2) activity blockade may increase motoneuron survival by enhancing intramuscular nerve branching, and (3) anything which affects this complex process of nerve branching may also alter motoneuron survival.  相似文献   

10.
In the stick insect Carausius morosus identified nonspiking interneurons (type E4) were investigated in the mesothoracic ganglion during intraand intersegmental reflexes and during searching and walking.In the standing and in the actively moving animal interneurons of type E4 drive the excitatory extensor tibiae motoneurons, up to four excitatory protractor coxae motoneurons, and the common inhibitor 1 motoneuron (Figs. 1–4).In the standing animal a depolarization of this type of interneuron is induced by tactile stimuli to the tarsi of the ipsilateral front, middle and hind legs (Fig. 5). This response precedes and accompanies the observed activation of the affected middle leg motoneurons. The same is true when compensatory leg placement reflexes are elicited by tactile stimuli given to the tarsi of the legs (Fig. 6).During forward walking the membrane potential of interneurons of type E4 is strongly modulated in the step-cycle (Figs.8–10). The peak depolarization occurs at the transition from stance to swing. The oscillations in membrane potential are correlated with the activity profile of the extensor motoneurons and the common inhibitor 1 (Fig. 9).The described properties of interneuron type E4 in the actively behaving animal show that these interneurons are involved in the organization and coordination of the motor output of the proximal leg joints during reflex movements and during walking.Abbreviations CLP reflex, compensatory leg placement reflex - CI1 common inhibitor I motoneuron - fCO femoral chordotonal organ - FETi fast extensor tibiae motoneuron - FT femur-tibia - SETi slow extensor tibiae motoneuron  相似文献   

11.
Chronic treatment of chick embryos with neuromuscular blocking agents, such as curare, rescues motoneurons from naturally occurring cell death. In the present study, embryos treated with curare from E6 to E9 had 35% more motoneurons than controls on E10 and 42% more than controls on E16. Previous studies have shown that several aspects of motoneuron differentiation occur normally in curare-treated embryos. We report here that dendrite growth and arborization is also unaltered on E10 and E16 following curare treatment. A quantitative analysis of afferent synapses on motoneurons shows that the packing density of both axosomatic and axodendritic synapses is also normal on E10 in curare-treated embryos, despite the greater number of motoneurons present. This indicates that the interneurons that provide presynaptic input to motoneurons are able to compensate for the increased number of synaptic sites made available by curare treatment. However, by E16 the packing density of synapses is reduced by about half. Because motoneurons and their dendrites continue to grow between E10 and E16, the further increase in synaptic sites made available in curare-treated embryos apparently exceeds the compensatory capacity of presynaptic interneurons on E16. One can conclude from these results that the increased survival of motoneurons in curare-treated embryos is not owing to an increase in afferent synapses. Motoneurons in these embryos continue to survive in the face of either no change (E10) or a reduction (E16) in the number of axodendritic and axosomatic synapses. Therefore, increased motoneuron survival in this situation is very likely regulated primarily by motoneuron-target interactions.  相似文献   

12.
13.
Previous work has shown that during chick embryonic development, large changes occur in the density of specific, motoneuronal calcium currents just prior to the period of naturally occurring motoneuron cell death. Here we report on calcium currents in mouse motoneurons isolated from embryos at the time of peak cell death and also during a subsequent developmental stage when supernumerary synapses are being eliminated. In mouse motoneurons, the density of high-voltage-activated calcium current increases significantly after the phase of cell death, during the period of synapse elimination.  相似文献   

14.
We have used calcium imaging to visualize the spatiotemporal organization of activity generated by in vitro spinal cord preparations of the developing chick embryo and the neonatal mouse. During each episode of spontaneous activity, we found that chick spinal neurons were activated rhythmically and synchronously throughout the transverse extent of the spinal cord. At the onset of a spontaneous episode, optical activity originated in the ventrolateral part of the cord. Back-labeling of spinal interneurons with calcium dyes suggested that this ventrolateral initiation was mediated by activation of a class of interneurons, located dorsomedial to the motor nucleus, that receive direct monosynaptic input from motoneurons. Studies of locomotor-like activity in the anterior lumbar segments of the neonatal mouse cord revealed the existence of a rostrocaudal wave in the oscillatory component of each cycle of rhythmic motoneuron activity. This finding raises the possibility that the activation of mammalian motoneurons during locomotion may share some of the same rostrocaudally organized mechanisms that evolved to control swimming in fishes.  相似文献   

15.
The parasitic wasp Ampulex compressa stings a cockroach Periplaneta americana in the neck, toward the head ganglia (the brain and subesophageal ganglion). In the present study, our aim was to identify the head ganglion that is the target of the venom and the mechanisms by which the venom blocks the thoracic portion of the escape neuronal circuitry. Because the escape responses elicited by a wind stimulus in brainless and sham-operated animals were similar, we propose that the venom effect is on the subesophageal ganglion. Apparently, the subesophageal ganglion modulates the thoracic portion of the escape circuit. Recordings of thoracic interneuron responses to the input from the abdominal giant interneurons showed that the thoracic interneurons receive synaptic drive from these interneurons in control and in stung animals. Unlike normal cockroaches, which use both fast and slow motoneurons for producing rapid escape movements, stung animals activate only the slow motoneuron. However, we show that in stung animals, the fast motoneuron still can be recruited with bath application of pilocarpine, a muscarinic agonist. These results indicate that the descending control from the subesophageal ganglion is presumably exerted on the premotor thoracic interneurons to motoneurons connection of the thoracic escape circuitry. Accepted: 19 December 1998  相似文献   

16.
We have examined c-Jun protein expression by immunocytochemistry in normal and pathologically induced cell death by focusing primarily on the developing neuromuscular system of the chick embryo. Several commercially available antibodies against c-Jun were used in combination with the TUNEL technique or propidium iodide staining for detection of cells undergoing programmed cell death (PCD). Among these, a rabbit polyclonal antibody raised against the amino acids 91-105 mapping to the amino terminal domain of mouse c-Jun p39 (c-Jun/sc45) transiently immunostained the cytoplasm of dying spinal cord motoneurons at a time coincident with naturally occurring motoneuron death. Late apoptotic bodies were devoid of c-Jun/sc45 immunoreactivity. A monoclonal antibody directed against a region corresponding to the amino acids 26-175 of c-Jun p39 (c-Jun/mAB) did not specifically immunostain dying neurons, but, rather, showed nuclear immunolabeling in almost all healthy motoneurons. Experimentally induced programmed death of motoneurons by means of early limb bud ablation, axotomy, or in ovo injection of the neurotoxin beta-bungarotoxin increased the number of dying cells showing positive c-Jun/sc45 immunoreactivity. Immunoelectron microscopy with c-Jun/sc45 antibody showed that the signal was present in the cytoplasm without a specific association with organelles, and was also present in large lysosome-like dense bodies inside neuritic profiles. Similar findings were obtained in different types of cells undergoing normal or experimentally induced PCD. These include dorsal root ganglion neurons, Schwann cells, muscle cells, neural tube and neural crest cells during the earliest stages of spinal cord development, and interdigital mesenchymal cells of hindlimbs. In all these cases, cells showed morphological and histochemical characteristics of apoptotic-like PCD. By contrast, motoneurons undergoing necrotic cell death induced by the excitotoxin N-methyl-D-aspartate did not show detectable c-Jun/sc45 immunoreactivity, although they displayed an increase in nuclear c-Jun/mAB immunostaining. In Western blot analysis of spinal cord extracts, c-Jun/sc45 antibody weakly detected a 39-kD band, corresponding to c-Jun, and more strongly detected two additional bands of 66 and 45 kD which followed developmental changes coincident with naturally occurring or experimentally stimulated apoptotic motoneuron death. By contrast, c-Jun/mAB only recognized a single p39 band as expected for c-Jun, and did not display changes associated with neuronal apoptosis. From these data, we conclude that the c-Jun/sc45 antibody recognizes apoptosis-related proteins associated with the early stages of morphological PCD in a variety of neuronal and non-neuronal cells, and that c-Jun/sc45 is a reliable marker for a variety of developing cells undergoing programmed cell death.  相似文献   

17.
Developmental motoneuron cell death and neurotrophic factors   总被引:5,自引:0,他引:5  
During the development of higher vertebrates, motoneurons are generated in excess. In the lumbar spinal cord of the developing rat, about 6000 motoneurons are present at embryonic day 14. These neurons grow out axons which make contact with their target tissue, the skeletal muscle, and about 50% of the motoneurons are lost during a critical period from embryonic day 14 until postnatal day 3. This process, which is called physiological motoneuron cell death, has been the focus of research aiming to identify neurotrophic factors which regulate motoneuron survival during this developmental period. Motoneuron cell death can also be observed in vitro when the motoneurons are isolated from the embryonic avian or rodent spinal cord. These isolated motoneurons and other types of primary neurons have been a useful tool for studying basic mechanisms underlying neuronal degeneration during development and under pathophysiological conditions in neurodegenerative disorders. Accumulating evidence from such studies suggests that some specific requirements of motoneurons for survival and proper function may change during development. The focus of this review is a synopsis of recent data on such specific mechanisms.  相似文献   

18.
The molecular cues that generate spinal motoneurons in early embryonic development are well defined. Motoneurons are generated in excess and consequently undergo a natural period of programmed cell death. Although it is not known exactly how motoneurons compete for survival in embryonic development, it is hypothesized that they rely on the ability to access limited amounts of trophic factors from peripheral tissues, a process that is tightly regulated by skeletal muscle activity. Attempts to elucidate the molecular mechanisms that underlie motoneuron generation and programmed cell death in embryos have led to various effective strategies for treating injury and disease in animal models. Such studies provide great hope for the amelioration of human amyotrophic lateral sclerosis (ALS), a devastating progressive motoneuron degenerative disease. Here we review the clinical relevance of studying motoneuron specification and death during embryonic development.  相似文献   

19.
The functional status of brachially innervated hindlimbs, produced by transplanting hindlimb buds of chick embryos in place of forelimb buds, was quantified by analyzing the number and temporal distribution of spontaneous limb movements. Brachially innervated hindlimbs exhibited normal motility until E10 but thereafter became significantly less active than normal limbs and the limb movements were more randomly distributed. Contrary to the findings with axolotls and frogs, functional interaction between brachial motoneurons and hindlimb muscles cannot be sustained in the chick embryo. Dysfunction is first detectable at E10 and progresses to near total immobility by E20 and is associated with joint ankylosis and muscular atrophy. Although brachially innervated hindlimbs were virtually immobile by the time of hatching (E21), they produced strong movements in response to electrical stimulation of their spinal nerves, suggesting a central rather than peripheral defect in the motor system. The extent of motoneuron death in the brachial spinal cord was not significantly altered by the substitution of the forelimb bud with the hindlimb bud, but the timing of motoneuron loss was appropriate for the lumbar rather than brachial spinal cord, indicating that the rate of motoneuron death was dictated by the limb. Measurements of nuclear area indicated that motoneuron size was normal during the motoneuron death period (E6-E10) but the nuclei of motoneurons innervating grafted hindlimbs subsequently became significantly larger than those of normal brachial motoneurons. Although the muscle mass of the grafted hindlimb at E18 was significantly less than that of the normal hindlimb (and similar to that of a normal forelimb), electronmicroscopic examination of the grafted hindlimbs and brachial spinal cords of E20 embryos revealed normal myofiber and neuromuscular junction ultrastructure and a small increase in the number of axosomatic synapses on cross-sections of motoneurons innervating grafted hindlimbs compared to motoneurons innervating normal forelimbs. The anatomical data indicate that, rather than being associated with degenerative changes, the motor system of the brachial hindlimb of late-stage embryos is intact, but inactive. © 1993 John Wiley & Sons, Inc.  相似文献   

20.
On a preparation of isolated spinal cord of the frog Rana ridibunda, using intracellular recording from lumbar motoneurons, there were compared effects of GABA and Gly on membrane potentials, membrane resistance, and EPSP evoked by activation of dorsal root fibers or of brainstem reticular formation. All parameters were compared in the same cell. At the same concentration (10 mM), Gly evoked membrane depolarization by 20–50% greater than GABA. Response of application of a mixture of GABA and Gly was by 20% lower than the arithmetic sum of responses to the GABA application and the Gly application. The late components and the semiwidth both of complex and of simpler DR and RF EPSP decreased significantly (to 95%) on the background of application of GABA and Gly. The late components of the both EPSP were inhibited stronger by GABA than by Gly. The early mono- and disynaptic EPSP components were inhibited to the essentially lesser degree than the late components. Gly always inhibited the early DR EPSP more markedly than GABA did. In the greater part of motoneurons the early RF EPSP were stronger inhibited by Gly, in their smaller part, by GABA. In many motoneurons the early components did not decrease at all. The motoneuron membrane resistance decreased under effect of GABA and Gly to the approximately equal extent (by 10–30%). Not in all neurons there was revealed the correspondence between a decrease of the membrane resistance (RM) and a decrease of the early EPSP components. Based on the obtained data, it is suggested that the inhibitory influences in frogs is mediated by both Gly- and GABA-receptors. On the membrane of motoneuron the inhibition is mediated to the relatively greater degree by Gly-receptors, whereas on the membrane of interneurons, by GABA-receptors. During inhibition of DR EPSP the predominance of Gly-receptors is observed in the greater number of motoneurons than during inhibition of RF EPSP. Between individual motoneurons there are significant quantitative differences of all parameters.  相似文献   

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