Biomedical subjects
Publications and source records attributed to J K Jansen.
Fridtjof Nansen (1861-1930) started his four-year research carrier in neurobiology at the Museum in Bergen in 1882. His PhD thesis from 1886 describes the structure of the nervous system in selected groups of invertebrates and in Amphioxus and the hagfish. For his time, he was a firm antireticularist and is still recognised as a forerunner of the emerging neurone doctrine of contiguity and no continuity between neurons in neural pathways.
During metamorphosis of flatfish larvae, eye migration leads to a 90 degrees misalignment of the visual and vestibular frames of reference. In order to maintain vestibular eye stabilization, the vestibulo-ocular (V-O) pathways have to be radically reorganized. Here, we have examined the vestibular projections in turbot larvae and juveniles by means of conventional neurohistological techniques using horseradish peroxidase and fluorescent dextranamines as tracers. We have found that the vestibular projections to the rostral eye motor nuclei consist of five densely clustered groups of neurons projecting to the rostral eye motor nuclei, some through the ipsilateral, others through the contralateral medial longitudinal fascicle (MLF). In addition, there are three groups of vestibulo-spinal neurons. The most prominent of these gives rise to the ipsilateral vestibulo-spinal tract. The other two project contralaterally, one descending in the MLF, the other more laterally in the anterior funiculus of the spinal cord. These subnuclei of the vestibular complex are easily identifiable in larvae before metamorphosis, as well as in juvenile turbots. The number of projection neurons in each of the subnuclei is approximately doubled over the period of metamorphosis. Applying different tracers to rostrally and caudally projecting pathways, we found no double-labeled neurons, indicating that the V-O and vestibulo-spinal groups are distinct entities. However, by applying the two tracers ipsi- and contralaterally in the terminal fields in the rostral eye motor nuclei after metamorphosis, we found many double-labeled neurons in all the V-O subgroups. In contrast, we found only a small fraction of double-labeled vestibular neurons when the same strategy was applied to larval preparations. We conclude that 1) the basic organization of the vestibular nuclei of the turbot is similar to that of other teleosts, in larvae as well as juveniles; 2) there is a substantial increase in projection neurons over the period of metamorphosis in all the subgroups of the vestibular nuclear complex; and 3) many more of the V-O neurons project bilaterally to the rostral eye motor nuclei in juvenile than in larval turbots.
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The article briefly reviews current views on the formation of neural pathways and appropriate connectivity between neurons during the development of the nervous system. The importance of axonal guidance and neurotrophic factors is pointed out. The relevance of these processes to clinical applications is illustrated by a few examples of recent attempts to develop new strategies for the treatment of certain neurological disorders. The prediction is that appreciable progress can be expected in the foreseeable future.
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The vestibulo-ocular pathways have been examined in embryonic chicks using horseradish peroxidase or diI as retrograde and anterograde tracers. The vestibular neurons project to the rostral, external eye motor nuclei over one or the other of three separate pathways; the ipsilateral and contralateral medial longitudinal fascicle and the contralateral brachium conjunctivum. The brachium conjunctivum component originates dorsally in the superior vestibular region and projects to the contralateral inferior oblique and superior rectus motor nuclei. An ipsilateral component of the medial longitudinal fascicle is labeled from more ventral sites in the vestibulo-cerebellar process and terminates in the ipsilateral superior oblique and inferior rectus nuclei. The contralateral medial longitudinal fascicle component originates still more ventrally and terminates in the contralateral superior oblique and inferior rectus motor nuclei. Accordingly, the vestibulo-ocular pathways in chickens operate predominantly on synergistic pairs of external eye muscles. These selective terminal fields are established within a day or two after the first terminals invade the eye motor nuclei during embryogenesis.
(1) The perinatal reorganization of muscle innervation is executed in a setting established by the earlier embryonic developmental processes. Prominent among these is the generation of a stereotyped set of skeletal muscles, each innervated in an orderly fashion from an appropriate pool of spinal motoneurons. The muscles contain functionally specialized types of fibers which differentiate in patterns characteristic for each muscle even without innervation. (2) Cholinergic motoneurons are required for functional innervation of skeletal muscles. In addition the muscle fibers must be in a receptive state. Denervation or paralysis recreates the receptive state. Chemically the receptive state is not well defined. It is associated with an immature distribution of AChRs and NCAM. (3) Nmjs are located in an orderly fashion on muscle fibers. Their normal distribution can be disrupted by paralysis during development. When junctions are first formed the nerve terminal induces local aggregation, stabilization and mature ionophore kinetics of the AChRs, as well as appearance of junctional specific AChE. Some of the effects require muscle activity. Terminal-derived substances like agrin and CGRP may normally contribute to these processes, as may other not yet identified agents. (4) Numerically, motoneuronal pools are regulated according to the available target. At the same time, the generation of secondary myotubes requires innervation by active motoneurons, and may also be quantitatively regulated by the number of innervating motoneurons. The generation of the primary generation of myotubes is independent of innervation. (5) Soon after the muscle fiber is first innervated additional terminals from other axons form junctions at the same site. The extent of polyneuronal innervation differs between muscles and between fiber types in the same muscle. Following a delay of several days after birth the individual terminals increase their contact area by arborization. The postsynaptic differentiation with redistribution of AChR, AChE and formation of subsynaptic folds is initiated. The complete maturation of the endplate requires several weeks. (6) Around birth or a few days later processes which eliminate redundant terminals are initiated. The rate of elimination appears to be aimed at nearly synchronous completion of the process in muscles with related functions. (7) There are two types of processes involved in the elimination of supernumerary terminals. The one gives rise to a competitive interaction between terminals innervating the same muscle fiber. The second is related to the reduction in the number of terminals which a motoneuron can maintain in the muscle. The two normally act in concert to determine the mature pattern of innervation of a muscle.(ABSTRACT TRUNCATED AT 400 WORDS)
We studied the fiber type composition and contractile properties of mouse soleus motor units at 2 days, 5 days and 2 weeks of age. We used Lucifer Yellow injection to mark muscle fibers belonging to the same motor unit in the two youngest age groups, and the traditional method of glycogen depletion in the oldest. The age groups were chosen because 2 days is at the end of muscle fiber production; 5 days is at the start of synapse elimination in the muscle and 2 weeks is at the end. Muscle fibers were classified as fast (F) or slow (S) on the basis of their myosin heavy chain (MHC) content, as determined by different monoclonal antibodies. Motor units are already dominated by either F- or S-fibers at 2 days, suggesting an early preferential innervation of the two types of fibers. A substantial part of the remaining refinement of the innervation takes place during the next 3 days, while the total number of terminals in the muscle remains constant. This is most easily explained by an exchange of aberrant for correct synapses during this period. A smaller part of the refinement of the innervation occurs during the subsequent period of synapse elimination.
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The present work aims to distinguish between processes that lead to neonatal synapse elimination. We have partially denervated the mouse soleus muscle just after birth by cutting one (L5) of the two (L4 and L5) spinal nerves which supply its innervation. After 4-6 weeks' survival times, we determined the number of remaining motor units (MUs) and the number of innervated fibres in the muscle by conventional physiological and histological techniques. There was no significant overlap between the remaining MUs. Their average size was reduced from about 230 muscle fibres at birth to about 80 after 4-6 weeks, compared to only 30 in normal animals of the same age. We conclude that two processes are required to explain synapse elimination in the muscle: a non-competitive process, inherent to the immature motor neurons and leading to a substantial reduction in their field of innervation; a competitive process between axon terminals innervating the same muscle fibre.
We have used recently developed fluorescein- and rhodamine-conjugated dextran-amines as axonal tracers in in vitro preparations of the nervous system of the chicken embryo. These substances are efficiently taken up by injured axons and transported rapidly to the cell bodies. They are also, albeit to a lesser degree, taken up by intact nerve terminals in skeletal muscle. They reveal the dendritic and axonal structure of labelled neurons, and are well suited for use in double-labelling experiments.
Chicken embryos were treated with partially paralysing doses of d-tubocurarine (dtc) from embryonic (E) days 6 to 10. The pattern of innervation of the lateral gastrocnemius (GL) muscle was examined both morphologically and physiologically just before hatching on day E20 or E21. There was a 70% increase in number of surviving motor neurons in the lateral motor column and a 50% increase in the number of myelinated axons in the nerve to GL. The GL muscle was significantly atrophic, with an average weight of 40% of normal. The atrophy was largely due to the reduced size of the muscle fibres. The mean size of the motor units was essentially unchanged or perhaps slightly increased. There was a striking increase in the level of polyneuronal innervation of the muscle fibres, both in terms of number of synaptic sites per fibre and number of axons innervating each site. Spontaneous miniature endplate potentials (mepps) indicated focal innervation of the fibres in the normal muscle. Most fibres in the dtc-treated muscles had mepps of widely varying time courses, and there was no simple relation between amplitude and rise time. Many of the slow mepps were not represented in the endplate potentials evoked by nerve stimulation. The quantal content of the endplate potential (epp) was generally increased in the dtc-treated muscles. The findings are discussed in terms of a retrograde signal from muscle to nerve and its dependence on muscle activity.
The elimination of the polyneuronal innervation was reinvestigated in normal rats from the tenth day after birth. The extent of polyneuronal innervation was measured by intracellular recordings in cut muscle fibre preparations. (Barstad 1962). This preparation has the advantage that it favours the recording of small signals. With this increased nerve terminal function in the course of elimination. These small potentials were always observed in fibres with an additional large end-plate potential and were occasionally present even in one-month old rats.
The polyneuronal innervation of skeletal muscles of newborn rats was eliminated completely in spite of virtually complete destruction of the sympathetic nervous system with 6-OH dopamine (6-OHDA). There was, however, a moderate delay in the elimination of redundant nerve terminals which is probably a secondary effect of the treatment.
1. The pattern of synaptic activity in lateral gastrocnemius (l.g.) motoneurones in the lumbar spinal cord of chick embryos (Stage 44-45, 19-21 d of incubation) has been examined using intracellular recording. In the motoneurones of normal chick embryos, stimulation of different peripheral, sciatic nerve branches gave rise to characteristic synaptic responses. Stimulation of the lateral gastrocnemius nerve caused a monosynaptic e.p.s.p. which was graded by the intensity of nerve stimulation. Stimulation of synergistic muscle afferents also caused a brief latency e.p.s.p., followed by longer latency excitatory and inhibitory synaptic potentials. Stimulation of antagonistic muscle afferents or cutaneous afferents gave rise to longer latency inhibitory and excitatory synaptic potentials respectively.2. The synaptic activity of l.g. motoneurones was also recorded in embryos in which short segments of the lumbar neural crest had been destroyed by microcautery at 3 d of incubation (Stage 18). The embryos developed without sensory ganglia and dorsal roots in the corresponding region.3. At 19-21 d of incubation, the amplitude of the l.g. e.p.s.p. of l.g. motoneurones in deafferented segments was on the average only a half to a third of the amplitude seen in motoneurones of intact spinal segments. However, both the l.g. and synergist e.p.s.p.s were larger than those seen in acutely deafferented segments of normal embryos.4. In spite of the weak monosynaptic input from l.g. and synergistic afferents, the pattern of synaptic activity evoked by antagonistic muscle afferent or cutaneous afferent stimulation was not different from normal. This was even the case for gastrocnemius motoneurones in which no early e.p.s.p. could be evoked by stimulating the l.g. or synergistic muscle nerves.5. No muscle spindles could be seen in sections of l.g. muscles from embryos with extensive lesions of the lumbosacral neural crest. Incomplete lesions of l.g. segments reduced the number of spindles in the muscle.6. These results suggest that when motoneurones are deprived of part of their normal synaptic input before the formation of peripheral connexions, the identity of the motoneurones (in terms of the origin of their synaptic input) is preserved. Missing synaptic inputs are either replaced by appropriate afferent fibres, if they are available, or not at all. The chick sensory ganglion cells with monosynaptic connexions to motoneurones appear to be unable to compensate significantly for peripheral or central defects in the innervation of the hind limb. They behave as if their developmental possibilities were quite rigidly determined at an early embryonic stage.
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After transplantation of the superficial fibular and the medial plantar nerve to neighbouring sites in the proximal region of adult rat soleus muscles many muscle fibres were initially innervated by axons in both foreign nerves after resection of the original soleus nerve. The foreign endplates were formed at ectopic sites and were often separately located on individual muscle fibres. After 3-4 weeks many endplates had been eliminated and most muscle fibres were innervated by only a single foreign axon. Many muscle fibres still had multiple esterase-staining endplate sites in the region innervated by the foreign nerve. On examination by electronmicroscopy, some of these sites were seen to have lost their presynaptic terminal while the postsynaptic structure of the endplate remained intact. Other sites were only partially occupied by motor axon terminals. On each muscle fibre there was always at least one fully occupied endplate region. In some instances separate endplate sites on the same muscle fibre were innervated by branches of the same motor axon. We conclude that the elimination of endplates is due to a competitive interaction between motor axons innervating the same muscle fibre. Morphologically, the elimination of functional endplates is caused by a retraction of nerve terminals from the postsynaptic site.