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Biomedical subjects

M E Selzer

Publications and source records attributed to M E Selzer.

At least 37 records · Page 2Linked to original sources
PubMed1993

Cytoarchitecture of spinal-projecting neurons in the brain of the larval sea lamprey.

The descending spinal projecting system of the lamprey is of interest because it includes axons that activate swimming pattern generators and because regeneration of this system is involved in the behavioral recovery of lampreys following spinal transection. However, little is known about the true size of this projection and of the distribution of its terminations along the spinal cord. Brain neurons with spinal projections were studied in larval sea lampreys by using wholemount preparations labeled retrogradely with horseradish peroxidase (HRP) from spinal injections at 10%, 15%, 25%, 50%, 70%, and 75% of body length from the anterior end. Neurons projecting to different levels of the spinal cord were mapped. A large number of descending axons terminated within nine segments caudal to the last gill. The spinal projection system was divided into 10 bilateral groups based on cytoarchitectural landmarks. All of the lateral nuclear groups had contralateral spinal projections. In addition to the 12 pairs of Müller cells, the pair of Mauthner cells, and the pair of auxiliary Mauthner cells described by previous authors, the study revealed four pairs of smaller neurons that were individually identifiable.

Animals↗
PubMed1992

Neurological rehabilitation.

Increasingly, neurologists are participating in the rehabilitation of disorders of the nervous system. Compelling reasons why neurologists, especially those with academic interests, should become involved in rehabilitation include the opportunity to observe patients in the recovery phases of their illnesses and to study issues relating to functional recovery, exposure to patients (such as those with spinal cord injury) who are often not seen by neurologists in the acute phase, and the opportunity to help establish a scientific base for rehabilitation medicine. Many areas of investigation can contribute to the scientific basis of neurological rehabilitation. Among the most promising are regeneration in the central (CNS) and peripheral nervous systems, adaptive mechanisms following CNS injury, computational neuroscience, neuromuscular physiology of chronic denervating conditions (e.g., the post-polio syndrome), and outcome studies of both physical and pharmacological therapeutic modalities. While there may be financial advantages to involvement in neurological rehabilitation, these are probably overestimated and interest in this field would continue to grow without them. There is a need for enhanced training in this subspecialty, including the development of dual certification programs in neurology and rehabilitation medicine.

Certification↗
PubMed1991

Preferential regeneration of spinal axons through the scar in hemisected lamprey spinal cord.

Axons of lamprey spinal cord can regenerate across a complete spinal transection. Thus, unlike the scar of injured mammalian spinal cords, the scar in the lamprey is not an absolute impediment to regeneration. However, it is still not known whether the scar is a relative impediment or whether it provides a favorable environment for regeneration compared to the spinal cord parenchyma. In order to answer this question, the cords of 12 large larval sea lampreys (4-5 years old) were hemisected at the level of the third gill and the animals allowed to recover for 10 weeks. The large reticulospinal neurons (Müller and Mauthner cells) or their giant axons were injected intracellularly with HRP and their regenerating neurites visualized in central nervous system (CNS) wholemounts. Forty-five of seventy-one regenerating neurites (64%) grew beyond the level of the hemisection. Of these, 36 (82%) regenerated through the scar and remained on the same side of the cord as their parent axons, while only 8 (18%) crossed the midline and grew around the scar. Thus, regenerating neurites of giant reticulospinal axons tended to grow through the hemisection scar rather than around it. Once they passed the level of injury, they continued to elongate in their appropriate paths. It is possible that this tendency for axons to regenerate through the scar reflects the greater amount of empty spaces on the hemisected side. In order to rule this out, 13 animals received contralateral simultaneous hemisections at the level of the 3rd and 7th gills. This procedure created large numbers of degenerating axons and potential empty spaces both rostral and caudal to the scars within both hemicords; 92 of 158 neurites (58%) regenerated beyond the level of their respective hemisections. All of these grew through the scar and none crossed to the contralateral side. Distal to either hemisection, neurites remained on their correct side regardless of whether the contralateral cord contained normal CNS parenchyma or axonal debris and empty spaces produced by Wallerian degeneration. Moreover, in hemisected and double hemisected animals, as well as in completely transected control animals, neurites regenerating in their correct direction grew further than those that were misrouted. Because lamprey spinal axons grow preferentially through a scar rather than around it, the scar may play a positive role in supporting axonal regeneration.

Animals↗
PubMed1991

Axonal regeneration in the adult lamprey spinal cord.

Larval sea lampreys recover from complete spinal transection by a process involving directionally specific axonal regeneration. In order to determine whether this is also true of adults, 14 adult lampreys were transected at the level of the 5th gill and allowed to recover for 10 weeks. Müller and Mauthner cells and their giant reticulospinal axons (GRAs) were impaled with microelectrodes and injected with horseradish peroxidase (HRP). The tissue was processed for HRP histochemistry and wholemounts of brain and spinal cord were prepared. All animals recovered coordinated swimming; 61 of 121 (50%) neurites emanating from 30 axons regenerated caudal to the scar into the distal stump. Of the neurites which had grown beyond the scar, 92% were correctly oriented, i.e., caudalward and ipsilateral to the parent axon. Retransection in two additional animals eliminated the recovered swimming. Thus, behavioral recovery in adult sea lampreys is accompanied by directionally specific axonal regeneration.

Animals↗
PubMed1991

The need for cellular elements during axonal regeneration in the sea lamprey spinal cord.

Spinal axons in the larval sea lamprey regenerate following a complete spinal transection. It is not known whether regenerating growth cones require contact with cellular elements or whether the basement membrane and collagenous meninx primitiva which surround the spinal cord are sufficient for neurite out-growth. To determine this, a freeze lesion was made which severed axons, destroyed neuronal perikarya, and greatly reduced the number of glial cells. After at least 10 weeks of recovery, 50 neurites from 31 Müller and Mauthner axons were labeled by intracellular injection of HRP. Eighty-six percent of these neurites did not regenerate into the lesion site. No neurites grew through the lesion. No animals recovered coordinated swimming. These results suggest that glial and/or neuronal surfaces are required for axonal regeneration. Moreover, a monolayer of glial cells appears to be suboptimal and a three-dimensional matrix of cells may be necessary to promote regeneration in the lamprey spinal cord.

Animals↗
PubMed1989

Lamprey neurofilaments combine in one subunit the features of each mammalian NF triplet protein but are highly phosphorylated only in large axons.

Compared with heteropolymeric assemblies of neurofilament (NF) triplet proteins in mammalian NFs, lamprey (Petromyzon marinus) NFs are homopolymers of 180 kDa subunits (NF180). We describe unique features of lamprey NF180 that distinguish it as a prototype of vertebrate NF subunits. These features may underlie key functions subserved by the earliest vertebrate NFs. Lamprey NF180 displays properties common to all intermediate filament (IF) proteins, but it also exhibits features that distinguish the mammalian triplet of NF subunits from all other IF proteins. For example, digestion of lamprey NF180 with chymotrypsin produces an insoluble 40 kDa core unit and releases a soluble fragment intermediate in size (140 kDa) to the carboxy-terminal (sidearm) extensions of the 2 high-molecular-weight (Mr) mammalian NF subunits. The core unit contains epitopes similar to those in the core of each mammalian NF triplet protein, while the soluble fragment contains other determinants similar to those in the sidearms of the 2 high-Mr mammalian NF polypeptides. Like these polypeptides, the immunological properties of some NF180 peripheral determinants were strongly affected by their phosphorylation state. Indeed, NF180 shares immunological similarities with the multiphosphorylation repeat domains in the high-Mr mammalian NF subunits. Further similarities with mammalian NF proteins include the preferential expression of poorly phosphorylated NF180 isoforms and of phosphate-dependent NF180 epitopes in axons of all sizes, and the restriction of nonphosphorylated NF180 isoforms to neuronal perikarya. In marked contrast to mammals, however, the most heavily phosphorylated isoforms of NF180 were expressed exclusively in large-diameter axons. We conclude that the single subunit forming lamprey NFs exhibits the essential features of mammalian NFs, i.e., a filament-forming core and a carboxy-terminal extension with a multiphosphorylation site. Further, the sharp restriction of heavily phosphorylated NF180 to large axons suggests that multiphosphorylation domains were acquired during evolution to permit larger axon diameters and faster conduction velocities.

Alkaline Phosphatase↗
PubMed1988

Direct extracellular electrical stimulation influences density dependent aggregation of fetal rat cerebrocortical neurons in vitro.

Cells isolated from fetal (E17) rat cerebral cortex form aggregates in a density-dependent manner. Direct current electrical stimulation influences the formation of neuronal aggregates by promoting neuronal survival at a calculated current density of 15 nA/cm2 (with an average calculated field strength of 1 microV/cm), and inhibiting neuronal survival at calculated current densities of both 1 nA/cm2 and 150 nA/cm2. Electrical stimulation had no observable effect on neuronal aggregation independent of its effect on cell survival.

Animals↗
PubMed1987

The axon reaction of lamprey spinal interneurons.

Axotomy and partial denervation of giant interneurons (GIs) and lateral cells (LCs) were produced by complete spinal transection in the larval lamprey spinal cord. Both cell types demonstrated a reduction in cytoplasmic basophilia, increase in cell size, nuclear eccentricity, and formation of a chromophilic nuclear cap. This was quantified in the case of cell diameter. During the first 8 weeks of recovery, the GIs with the largest diameters were found progressively further from the scar and this peak change moved at approximately 0.5 mm/day. The increase in size of GIs remained up to 20 weeks post-transection, long after the time required for their axons to regenerate across the scar and form functioning synapses. GIs injected intracellularly with horseradish peroxidase (HRP) also showed this increase in diameter as well as a simplification of their dendritic trees. Intracellular recordings from GIs revealed changes in the frequency and amplitude of spontaneous synaptic input. In the first two weeks after transection, spontaneous excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) were less frequent than in control cells. After 6 weeks of recovery they became more frequent than in control cells. EPSPs predominated in axotomized GIs, while in control cells they constituted only 36% of the total of spontaneous potentials. A reversible increase in the amplitude of these EPSPs occurred at 3-4 weeks of recovery time. The resting membrane potential was significantly reduced by the 6th week after transection and returned to normal after the 22nd week.

Animals↗
PubMed1987

Specificity of synaptic regeneration in the spinal cord of the larval sea lamprey.

1. Pairs of central neurones in large larval sea lampreys were impaled with micro-electrodes and studied for synaptic connexions in both unoperated control animals and animals which had recovered from complete spinal transection. Two identified classes of neurones served as post-synaptic targets: giant interneurones (g.i.s) and lateral cells (l.c.s). Several identified neurone types were tested as potential sources of presynaptic input. 2. When synaptic potentials had short, fixed latencies they also persisted during activation of the presynaptic cell at 3.3-33.3 Hz and were not eliminated after addition of lamprey saline containing high (20 mM) Ca2+. These presumably represented monosynaptic connexions. Variable-latency responses were eliminated by faster rates of stimulation of the presynaptic cell and were mediated via polysynaptic pathways. 3. In control animals, g.i.s received monosynaptic input from more caudal g.i.s in fourteen of thirty-two tested cell pairs. These excitatory post-synaptic potentials (e.p.s.p.s) were composite electrochemical responses. The amplitudes of the earlier electrical component averaged 1.66 +/- 0.24 mV (mean +/- S.E. of mean) and the amplitude of the later chemical component averaged 0.79 +/- 0.05 mV. 4. In operated larvae, eight of forty-seven g.i.-g.i. pairs separated by the transection scar were connected by monosynaptic composite e.p.s.p.s. In these pairs the electrical component averaged 0.84 +/- 0.17 mV (P less than 0.05 vs. control) and the chemical component averaged 1.56 +/- 0.40 mV. The average conduction velocity between these cells was less than that in control g.i.-g.i. pairs (0.93 +/- 0.11 vs. 1.61 +/- 0.25 m/s; P less than 0.01). 5. The l.c.s showed monosynaptic e.p.s.p.s after activation of a subset of the bulbar Müller neurones (B2-4) in seven of twelve pairs. In behaviourally recovered larvae three of twenty-two similar pairs separated by the transection scar were also connected via monosynaptic e.p.s.p.s. The average conduction velocity between these experimental neurones was also less than that in control bulbar-l.c. pairs (1.03 +/- 0.03 vs. 1.58 +/- 0.09 m/s; P less than 0.001). 6. Several types of neurones were either infrequently linked or never connected to g.i.s or to l.c.s in control larvae. In animals which had recovered from a spinal transection, no synaptic connexions were found from such neurones on to g.i.s or l.c.s respectively, in 124 tested cell pairs. In addition, dorsal cells (intraspinal primary sensory neurones) received no synaptic input upon stimulation of the spinal cord before or after transection.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Enhanced survival of rat neonatal cerebral cortical neurons at subatmospheric oxygen tensions in vitro.

In vitro tissue culture experiments are routinely performed at atmospheric oxygen tension (21%), although most cells experience lower oxygen tensions in vivo. The optimal oxygen tension for the survival of neurons and synthesis of neurofilament (NF) was determined using dissociated neonatal rat cerebral cortex and monoclonal antibodies to the 68 kDa and 200 kDa subunits of NF. Maximum production of each subunit determined by Enzyme-Linked Immunosorbant Assay occurred at 9% O2. Neuronal survival determined by immunohistochemistry was also maximal at 9% O2. CNS neurons are highly sensitive to oxygen tension and grow best at levels approximating capillary rather than atmospheric pO2.

Animals↗
PubMed1986

Activity-dependent depression of nerve action potential by phenytoin.

The action of the anticonvulsant drug phenytoin was investigated on the responsiveness of isolated amphibian and human nerves to repetitive stimulation. At low frequencies of stimulation (0.5-25 Hz) the drug (at a concentration of 0.1 mM) had no notable effect on the compound nerve action potential. By contrast, at higher rates of stimulation (50-300 Hz), it produced a progressive decrease in amplitude and integral of the compound action potential. This effect was positively correlated with the frequency of nerve activation and was markedly enhanced by elevating the extracellular K+ concentration. Thus, phenytoin induces a use- and frequency-dependent depression of axon conduction, which may contribute to its preferential suppression of the spread of high-frequency seizure discharge in the brain.

Action Potentials↗
PubMed1986

Frequency-dependent action of phenytoin on lamprey spinal axons.

The effect of the antiepileptic drug phenytoin (diphenylhydantoin, DPH) was tested on the conduction of intracellularly recorded action potentials in lamprey giant reticulospinal axons. When the isolated spinal cord was exposed to 80 microM DPH for up to 4 h, no significant effect was seen on the amplitude or conduction velocity of the action potential, although the maximum rate of rise was reduced from 247.8 to 149.6 V/s after 1 h. However, at higher stimulus frequencies both the amplitude and conduction velocity of the action potential were reduced progressively during a 500 stimulus train. The reduction was greater the higher the stimulus frequency, and was reversed upon return to 1 Hz stimulation. At frequencies greater than 40 Hz an all-or-none block developed. This also developed sooner the higher the stimulus frequency. Axons bathed in drug-free solutions did not show this effect at stimulus frequencies up to 100 Hz. Similar effects were seen in 16 microM DPH when the spinal cord was exposed to the drug overnight. This is close to the human therapeutic CSF level. The frequency-dependent depression of the action potential was greatly potentiated by increasing the extracellular potassium concentration from 2.1 to 5 mM. Under these conditions the axons rapidly developed block at stimulus frequencies as low as 2 Hz, and this was not reversible during a 5 h wash. In the absence of DPH, 5 mM potassium produced a 4-5 mV depolarization, but did not induce a frequency-dependent block. This effect of potassium may be important to the therapeutic effect of DPH because during epileptiform activity the extracellular K+ increases several fold.

Action Potentials↗
PubMed1986

Phenytoin: mechanisms of its anticonvulsant action.

Phenytoin is a major anticonvulsant drug that is very effective in controlling a wide variety of seizure disorders while impairing neurological function little, if at all. Early work suggested the hypothesis that the drug's effects were due to a selective block of high-frequency neuronal activity. This theory is reevaluated in the light of accumulated observations on the effects of phenytoin in many neuronal and synaptic preparations. Most of these observations can be explained by a use- and frequency-dependent suppression of the sodium action potential by phenytoin, with a consequent filtering out of sustained high-frequency neuronal discharges and synaptic activity. The molecular mechanism for this is a voltage-dependent blockade of membrane sodium channels responsible for the action potential. Through this action, phenytoin obstructs the positive feedback that underlies the development of maximal seizure activity, while normal brain activity, proceeding at lower neuronal firing rates, is spared its depressant action. Other mechanisms of action that may contribute to the drug's efficacy and selectivity are also discussed.

Action Potentials↗
PubMed1986

Functional regeneration following spinal transection demonstrated in the isolated spinal cord of the larval sea lamprey.

Axons in the larval sea lamprey can regenerate across the site of a spinal cord transection and form functioning synapses with some of their normal target neurons. The animals recover normal-appearing locomotion, but whether the regenerating axons and their synaptic connections are capable of playing a functional role during this behavior is unknown. To test this, "fictive" swimming was induced in the isolated spinal cord by the addition of D-glutamate to the bathing solution. Ventral root discharges of segments above and below a healed transection showed a high degree of phase-locking. This strongly suggests that the behavioral recovery is mediated by regenerated functional synaptic connections subserving intersegmental coordination of the central pattern generator for locomotion.

Action Potentials↗