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PubMed1980

Ultrastructure of degenerating cerebellothalamic terminals in the ventral medial nucleus of the cat.

Terminal degeneration of cerebellar afferents in the ventral medial thalamic nucleus (VM) was studied in cats at the ultrastructural level after uni- or bilateral lesions in the brachium conjunctivum (BC). To achieve discrete lesions within the BC, a new very accurate stereotaxic technique was used. Numerous large terminals belonging to a population of so-called LR boutons were observed degenerating in the VM. The boutons displayed a wide variety of degenerative changes. Some revealed the features of the classical neurofilamentous type of degeneration. Others, although containing a slightly increased number of neurofilaments, featured much more prominently large numbers of coated vesicle shells and heavy accumulations of a flocculent electron-dense material. Degeneration in a third group of boutons similar to some extent to the light type of degeneration was characterized by tight clumping of enormously swollen or distorted synaptic vesicles within a light matrix. At later stages, however, all these boutons were believed to become shrunken and electron-dense since intermediate stages between the light- and dark-appearing boutons were observed. The degenerating cerebellar boutons formed asymmetrical synaptic contacts. Groups of 3 or 4 boutons terminated upon dendrites of projection neurons synapsing more frequently on spines than on dendritic stems. The synaptic contacts between cerebellar boutons and the vesicle-containing dendrites of local circuit neurons were encountered as often if not more than the contacts on projection neuron dendrites. Triads consisting of cerebellar boutons and dendrites of both types of neurons were observed very regularly. This synaptic arrangement provides the anatomical basis for the modification of cerebellar input in the VM by interneurons.

Afferent Pathways↗

PubMed1995

Evidence for transneuronal degeneration in the spinal cord in man: a quantitative investigation of neurons in the intermediate zone after long-term amputation of the unilateral upper arm.

Does transneuronal degeneration occur in the neurons of the spinal intermediate zone following degeneration of the anterior horn cells in man? To investigate this possibility, we carried out a quantitative examination of neurons in the cervical intermediate zone of a 56-year-old man who had suffered accidental amputation of the right upper arm 38 years prior to death. Recently, we reported that the cervical anterior horn cells of this patient were reduced in number not only on the amputation side but also on the spared side. The present study revealed that medium-sized neurons in the cervical intermediate zone, which were considered to be internuncial neurons, were decreased in number on both the amputation and the spared sides, but less so on the spared side. These findings indicate that retrograde transneuronal degeneration occurs in the internuncial neurons following degeneration of the anterior horn cells caused by amputation. Sequentially to this, degeneration of the commissural neurons in the intermediate zone secondary to that of the internuncial neurons may induce degeneration of the neurons in the intermediate zone and the anterior horn cells on the spared side.

Amputation, Traumatic↗

PubMed1985

Degeneration patterns of postganglionic fibers following sympathectomy.

In cats the time course of degeneration following lumbal sympathectomy was studied in the ramus communicans griseus (rcg) and in the nerves to the triceps surae muscle using light and electron microscopic methods. The left lumbar sympathetic trunk including its rami communicantes was removed from L2 to S1 using a lateral approach. The animals were sacrificed between 2 and 48 days after the sympathectomy. Tissue samples were taken (a) one cm proximal to the entrance of the rcg into the spinal nerve, and (b) one cm proximal to the entrance of the nerve into the muscle belly. In the rcg signs of degeneration can already be recognized in the myelinated as well as in the unmyelinated axons 48 h after sympathectomy. The degenerative processes in the axons reach their peak activity at about 4 days p.o. They end a week later. Signs of the reactions of the Schwann cells and of the endoneural cells can first be seen 2 days p.o. They are most pronounced around the 8th day p.o., and last at least up to the third week. Thereafter the cicatrization processes settled to a rather steady state (total observation period 7 weeks). In the muscle nerves the first signs of an axonal degeneration of the sympathetic fibers can be recognized 4 days after surgery. The signs of axonal degeneration are most striking about 8 days p.o. They have more or less disappeared another week later. The reactions of the Schwann cells also start on the fourth day but outlast the degenerative processes by some 8 days. Thus the degenerative and reactive processes in the rcg precede those in the muscle nerves by 2 days early after surgery and by 6 days 3 weeks later. Seven weeks after surgery, fragments of folded basement lamella and Remak bundles with condensed cytoplasm and numerous flat processes are persisting signs of the degeneration. In addition to the differences in time course between the proximal and the distal site of observation, it was also noted that both the axonal degeneration and the reactions of the Schwann cells are more pronounced in the rcg than in the muscle nerve. For example there was abundant mitotic activity in the central endoneural and Schwann cells whereas we could not detect such activity in the periphery.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1988

A study of cerebellar and cerebral cortical degeneration in miniature poodle pups with emphasis on the ultrastructure of Purkinje cell changes.

In a litter of three Miniature Poodles, a normal female pup contrasted with two males which displayed severe equilibrium and postural disturbances soon after birth. In the male pups diffuse cerebral cortical degeneration accompanied cerebellar cortical atrophy, which was characterized by extensive loss and degeneration of Purkinje neurons. As in some prior histological descriptions of canine cerebellar atrophies, degenerating Purkinje cells appeared either pale, swollen and vacuolated or shrunken and hyperchromatic. Swollen vacuolated cell bodies and condensed necrotic neurons were scattered through the cerebral cortex. Ultrastructural studies revealed that the vacuolar degeneration in Purkinje and cerebral neurons was referable to marked dilation of endoplasmic reticulum and loss of ribosomes. In shrunken Purkinje neurons, increased cytoplasmic eosinophilia was associated with a decline in Nissl bodies and accumulations of mitochondria and especially lamellar bodies. The latter, stacked derivatives of endoplasmic reticulum, were not encountered in shrunken cerebral perikarya. Lamellar bodies reached giant proportions in the dendritic stems of degenerating Purkinje neurons. In Purkinje axons, however, these bodies often were overshadowed by aggregates of axoplasmic tubules. The cytological changes in these Poodle pups were notably different from those reported in earlier ultrastructural studies of canine inherited cerebellar degenerations.

Animals↗

PubMed1993

Different rates of axonal degeneration in the crossed and uncrossed retinofugal pathways of Monodelphis domestica.

The uncrossed retinofugal fibres in the marsupial Monodelphis domestica form a separate bundle as they pass through the optic chiasm. The uncrossed fibres segregate from the crossed fibres a short distance before they reach the chiasm, gathering as an essentially exclusive bundle in the ventral part of the optic nerve. This bundle then passes laterally through the optic chiasm and into the optic tract. The distinctive position of the uncrossed fibres has allowed us to recognise that, surprisingly, the uncrossed fibres degenerate more rapidly than the rest. Seven days after a monocular enucleation approximately 60-80% of the fibres of the crossed component in the main part of the optic nerve near the chiasm have a normal cross sectional appearance in electron micrographs whereas less than 20% of the fibres in the uncrossed bundle look normal. The rapid degeneration of the uncrossed fibres cannot be related to any morphological parameter of the axons. Their fibre diameters are mainly medium to thick, lying within the range of axon diameters found in the rest of the nerve. The axon-myelin ratios of the uncrossed fibres are also no different from those of the crossed optic fibres. There are no structural peculiarities identifiable with light or electron microscopical methods in either the axons or in the glia of the uncrossed bundle that might account for the more rapid degeneration. There is evidence that the degenerative change in the main part of the optic nerve progresses from the lesion towards the chiasm, and that for the crossed fibres it may progress slightly faster for the thicker than for the thinner fibres. The degeneration in the uncrossed bundle does not fit any of the rules that have been proposed for relating rate of degeneration to fibre diameter. We conclude that the rate of Wallerian degeneration is determined by factors that yet remain to be defined.

Animals↗

PubMed1994

The proximo-distal spread of axonal degeneration in the dorsal columns of the rat.

The pivotal event in Wallerian degeneration is the breakdown of the axon. Establishing the pathophysiology of axonal degeneration has implications for the understanding of the pathogenesis of other types of nerve degenerations. A key aspect of the pathophysiology is the spatiotemporal pattern of spread after transection, an issue that has remained controversial. We have studied the progression of axonal degeneration in the dorsal columns of the rat following L4L5L6 dorsal radiculotomy. Axonal degeneration proceeds in a proximo-distal fashion, beginning near the site of transection and spreading up the dorsal columns at a net rate of about 3 mm h-1. In addition, there was early degeneration of the preterminal axons in the gracile nuclei. This pattern suggests that the 'clearing' of axonally transported materials from the distal stump by continued anterograde transport may underlie axonal breakdown after transection.

Animals↗

PubMed1989

Intestinal neuronal degeneration in a patient with chronic idiopathic intestinal pseudoobstruction.

Neuropathological examination of the gut in a patient with chronic idiopathic intestinal pseudoobstruction and temporal lobe epilepsy showed a degeneration of Auerbach's and of Meissner's plexus. The extent of generative changes increased in an aboral to oral direction. Neuronal degeneration was characterized by ballooning of the cytoplasm of the ganglial cells, by a hyperargyrophilia, a shortening and dilation of cell processes, and a progressive fragmentation and loss of axons. In rectal biopsies, a PAS-positive granular material was detected in the cytoplasm of ballooned ganglial cells. A severe peripheral neuropathy with fiber degeneration in the posterior columns and axonal lesions within ventral nerve roots and a more recent fiber degeneration in the lateral columns corresponding to the picture of subacute combined degeneration of the spinal cord and a symmetrical Ammon's horn sclerosis was present. This case of progressive intestinal neuronal degeneration of unknown origin is a newly described condition leading to chronic idiopathic intestinal pseudoobstruction.

Adolescent↗

PubMed1996

[Incidence of posterior vitreous detachment in eyes with and without age-related macular degeneration. An ultrasonic study].

Data in the literature differ widely regarding the incidence and age at which posterior vitreous detachment occurs. We investigated the incidence of posterior vitreous detachment in elderly patients and whether this varied between eyes with and without age-related macular degeneration (AMD). Patients ranged in age from 51 to 89 years (median: with AMD 74 years, without AMD 70 years). A total of 251 eyes were examined by B-mode ultrasonography for the presence of posterior vitreous detachment. In 119 eyes no pathological changes were found in the macular region. The other 132 eyes exhibited either exudative or non-exudative age-related macular degeneration. Ultrasonography revealed complete posterior vitreous detachment in only 19% of eyes without and 15% of eyes with macular degeneration. Eyes with macular degeneration, though, had a significantly higher (p = 0.0059) incidence of incomplete vitreous detachment than eyes without macular degeneration. Whether this represents a cause or a consequence of the macular degeneration remains unclear. Our results show that complete posterior vitreous detachment is rarer in the elderly than hitherto assumed.

Aged↗

PubMed1998

Histopathological and ultrastructural features of feline hereditary cerebellar cortical atrophy: a novel animal model of human spinocerebellar degeneration.

Human spinocerebellar degeneration is one of the intractable diseases. We studied the detailed neuropathology of cats with hereditary cerebellar degeneration obtained from the experimental breeding. The findings included almost total loss of Purkinje cells with an increase in Bergmann's glia in the cerebellar hemisphere, preservation of some Purkinje cells in the vermis and moderate neuronal depletion of the olive nucleus. Cerebellar and pontine nuclei were normal. The cerebrum and spinal cord as well as the peripheral nervous system appeared normal. Electron microscopic examination revealed swelling of the distal dendrites of Purkinje cells in the less-affected nodule of the vermis, and clusters of presynaptic boutons without any synaptic contact in the severely affected folia where Purkinje cell bodies and dendrites disappeared. Prolonged existence of presynapses in the molecular and Purkinje cell layers was confirmed by positive immunoreactivity to anti-synaptophysin. Quantitative analysis using electron microscopy demonstrated an apparent increase in the density and mean size of presynapses in the molecular layer of the severely affected folia. These findings indicate that degeneration of Purkinje cells started at the most distal part of the dendrite in this animal model of cerebellar degeneration, and that presynapses, axon terminals of the granular cells and basket cells can exist for a long time even after complete degeneration of the Purkinje cells. Further investigation of this novel animal model may promote a better understanding of pathogenesis of human hereditary cerebellar degeneration.

Animals↗

PubMed1999

Axonal degeneration with tympanal nerve of Schistocerca gregaria.

This study describes time course and ultrastructural changes during axonal degeneration of different neurones within the tympanal nerve of the locust Schistocerca gregaria. The tympanal nerve innervates the tergit and pleurit of the first abdominal segment and contains the axons of both sensory and motor neurones. The majority of axons (approx. 97%) belong to several types of sensory neurones: mechano- and chemosensitive hair sensilla, multipolar neurones, campaniform sensilla and sensory cells of a scolopidial organ, the auditory organ. Axons of campaniform sensilla, of auditory sensory cells and of motor neurones are wrapped by glial cell processes. In contrast, the very small and numerous axons (diameter <1 microm) of multipolar neurones and hair sensilla are not separated individually by glia sheets. Distal parts of sensory and motor axons show different reactions to axotomy: 1 week after separation from their somata, distal parts of motor axons are invaded by glial cell processes. This results in fascicles of small axon bundles. In contrast, distal parts of most sensory axons degenerate rapidly after being lesioned. The time to onset of degeneration depends on distance from the lesion site and on the type of sensory neurone. In axons of auditory sensory neurones, ultrastructural signs of degeneration can be found as soon as 2 days after lesion. After complete lysis of distal parts of axons, glial cell processes invade the space formerly occupied by sensory axons. The rapid degeneration of distal auditory axon parts allows it to be excluded that they provide a structure that leads regenerating axons to their targets. Proximal parts of severed axons do not degenerate.

Animals↗

PubMed2003

Familial early onset macular degeneration in cynomolgus monkeys (Macaca fascicularis).

The mode of inheritance of macular degeneration was determined with 45 cynomolgus monkeys (18 females and 27 males) who were the offspring of one breeding male with typical macular degeneration. In the first generation, 27 offspring (10 females and 17 males) were born from mating between the macular degeneration-affected founder male and 5 normal female breeders. Among them, 18 monkeys (9 females and 9 males) were judged as having macular degeneration (affected). Next, the distribution of affected offspring was examined with 18 offspring who were born from 3 different mating pairs, normal vs normal, affected vs normal and affected vs affected, when they became 2 years old. All of the 9 monkeys (4 females and 5 males) obtained from the 2 pairs of normal vs normal were normal. On the other hand, 6 affected monkeys (3 females and 3 males) were detected in 8 offspring from the mating pair of affected vs normal, and the single offspring produced by the mating pair of affected vs affected was affected. These results showed that this degeneration must be early onset familial macular degeneration controlled by autosomal dominant gene(s).

Age of Onset↗

PubMed1981

A possible relationship between lattice and snail track degenerations of the retina.

We studied 1,000 eyes of 500 subjects in an attempt to discover a relationship between lattice and snail track degenerations of the peripheral retina. Because of the clinical similarities between these two degeneration lesions, we suggest that snail track degeneration is either a variant of or an early stage of lattice degeneration. Long-term follow-up of eyes with snail track degeneration is essential to detect any morphologic alteration in the lesions suggesting lattice degeneration.

Adolescent↗

PubMed1989

Electron-lucent degenerating geniculate terminals in cat striate cortex.

Degenerating geniculate axon terminals in cat striate cortex have been previously described as electron-dense. After electrolytic lesion of the lateral geniculate nucleus, we observed degenerating terminals in layer 4 of striate cortex which were electron-lucent. The lucent terminals --which co-exist with the dense terminals--are characterized by a pale matrix, large size, distorted mitochondria, and a paucity of synaptic vesicles. They preferentially (82.5%) contact dendritic spines. Lucent terminals were common in layer 4, rare in layer 6, and absent from layers 1 through 3 and layer 5. This distribution is consistent with the projection of the lateral geniculate nucleus to the striate cortex. Thus, geniculate terminals undergo both the electron-lucent and electron-dense degeneration reactions in cat striate cortex, and the lucent terminals make a significant contribution to the amount of degeneration present. The relationship of lucent degeneration to other forms of degeneration is discussed.

Animals↗

PubMed1991

The role of complement in myelin phagocytosis during PNS wallerian degeneration.

Myelin removal in nerves undergoing wallerian degeneration mainly depends on invading, non-resident macrophages. The present study clarifies the role of serum complement components in this process in vitro and in vivo. Macrophages cocultured with degenerating nerves in vitro were unable to invade these nerves in the presence of C3-deficient serum. Application of C3-deficient serum subsequent to cellular invasion abolished the myelin phagocytic capacity of the invaded macrophages. This indicates that opsonization of myelin by complement components is necessary in myelin ingestion via macrophage receptors. In vivo, a monoclonal antibody to the macrophage complement receptor type 3 (CR3) significantly reduced myelin phagocytosis. Immunohistochemistry with anti-C3 antibodies showed a marked reaction in degenerating nerves. Immunoelectron microscopy localized C3 particles at the degenerating myelin sheaths. Haematogenous cells, invading the degenerating nerves, also showed a strong reaction for C3 in their cytoplasm. These results indicate that complement components play a critical role both in macrophage invasion of degenerating nerves and in the ingestion of myelin by these cells.

Animals↗

PubMed1989

Transneuronal retrograde degeneration of retinal ganglion cells after damage to striate cortex in macaque monkeys: selective loss of P beta cells.

We examined the retinae of two monkeys whose left striate cortex had been removed eight years previously and compared the transneuronally degenerated hemiretina of each eye with the normal hemiretina, and with the retinae of normal monkeys. All retinae were prepared as whole mounts. One from each pair was stained with Cresyl Violet; the other was reacted for horseradish peroxidase two days after placing pellets of the enzyme in the optic nerve. Measurements of ganglion cell density in the Nissl-stained retina of the contralateral right eye showed that approximately 80% of retinal ganglion cells were missing in the central 30 degrees of the degenerated hemiretinae. More peripherally the percentage loss was less extensive. Measurements of cell soma size and dendritic field size of peroxidase-labelled classified surviving cells in the degenerated temporal hemiretina of the ipsilateral eye showed them to be morphologically normal. In comparison with the normal hemiretina, however, the mean soma size at three selected eccentricities was larger than normal, suggesting selective loss of smaller ganglion cells. Classification of peroxidase-labelled ganglion cells in the normal and degenerated hemiretinae revealed that the population of P beta cells was reduced by as much as 85% in the degenerated region. There was comparable change in the density of P alpha or P gamma cells. The degeneration of the great majority of P beta cells, which are believed to be the morphological substrate of ganglion cells with small and colour-opponent receptive fields, must set limits on the visual sensitivity and discrimination that survive damage to striate cortex.

Animals↗

PubMed1990

The pattern of axonal degeneration in the peripheral nervous system varies with different types of lesion.

Degeneration of axons in the mouse sciatic nerve was examined using conventional silver staining and by noting the presence or absence of a compound action potential on stimulating the nerve distal to the point of crush or cut. The presence of myeloperoxidase-positive cells was also examined in frozen sections of the nerve. In all experiments the distal, disconnected segment was studied. Degeneration after crushing with fine watchmakers forceps always began in the most distal part of the nerve and proceeded in a distoproximal direction, from the nerve entry point into a muscle back to the crush site. Myeloperoxidase-positive cells were also recruited into the nerve starting at the distal rather than proximal (the originally injured) end. This result favours the view that degeneration is triggered by lack of trophic support from the cell body rather than entry of deleterious substances at the site of the injury, for the terminals furthest from both the source of supply and the injury are affected first. Degeneration following nerve section was always more rapid than after crushing. The rate of axonal sealing at the injury was, however, no slower than after crushing, so it does not seem likely that greater entry of possible degeneration-triggering material at the injury site is the explanation for this. Crush lesions in which the perineurium was also cut open and the blood supply at the site was damaged, degenerated at the slower rate characteristic of simple crushes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Degeneration of Purkinje cells in parasagittal zones of the cerebellar vermis after treatment with ibogaine or harmaline.

The indole alkaloids ibogaine and harmaline are beta-carboline derivatives that cause both hallucinations and tremor. Reports that ibogaine may have potent anti-addictive properties have led to initiatives that it be tested for the treatment of opiate and cocaine addiction. In this study, ibogaine-treated rats were analysed for evidence of neurotoxic effects because human clinical trials of ibogaine have been proposed. We recently found that ibogaine induces a marked glial reaction in the cerebellum with activated astrocytes and microglia aligned in parasagittal stripes within the vermis. Based on those findings, the present study was conducted to investigate whether ibogaine may cause neuronal injury or degeneration. The results demonstrate that, after treatment with ibogaine or harmaline, a subset of Purkinje cells in the vermis degenerates. We observed a loss of the neuronal proteins microtubule-associated protein 2 and calbindin co-extensive with loss of Nissl-stained Purkinje cell bodies. Argyrophilic staining of Purkinje cell bodies, dendrites and axons was obtained with the Gallyas reduced silver method for degenerating neurons. Degenerating neurons were confined to narrow parasagittal stripes within the vermis. We conclude that both ibogaine and harmaline have selective neurotoxic effects which lead to degeneration of Purkinje cells in the cerebellar vermis. The longitudinal stripes of neuronal damage may be related to the parasagittal organization of the olivocerebellar climbing fiber projection. Since these drugs produce sustained activation of inferior olivary neurons, we hypothesize that release of an excitatory amino acid from climbing fiber synaptic terminals may lead to excitotoxic degeneration of Purkinje cells.

Animals↗

PubMed1996

Transneuronal degeneration in substantia nigra pars reticulata following striatal excitotoxic injury in adult rat: time-course, distribution, and morphology of cell death.

Previous studies have demonstrated neuronal loss in the substantia nigra pars reticulata following excitotoxic injury to the striatum of adult rats, and have considered this to be an anterograde transneuronal effect. However, the mode and temporal pattern of cell death in this model are unknown. We injected ibotenate into the striatum of adult rats and performed Nissl and silver staining of the substantial nigra, the globus pallidus and the entopeduncular nucleus at multiple times up to postlesion day 28. Silver-stained degenerating cells were identified in the substantia nigra pars reticulata at days 3-14 after the lesion, with maximal occurrence at day 3. Degenerating cells and fibers were preferentially distributed in the central region of the substantia nigra pars reticulata. At the cellular level, degenerating cells, frequently demonstrating morphological characteristics of neurons, showed intense silver staining of the nucleus and punctate staining of the cytoplasm. Apoptosis was not observed. In situ end-labeling confirmed the non-apoptotic nature of the cell death. There was no secondary cellular degeneration in other striatal targets, including the globus pallidus, substantia nigra pars compacta or entopeduncular nucleus. Double staining with silver and tyrosine hydroxylase immunohistochemistry disclosed degenerating cells within the tyrosine hydroxylase-positive ventral tier in the substantia nigra pars reticulata, but in no instance was there double staining within a single cell. Our results demonstrate that secondary neuronal degeneration occurs within the substantia nigra pars reticulata within a few days following excitotoxic injury to the striatum of adult rats. The cell death is non-apoptotic, unlike that occurring in the substantia nigra of neonatal rats following similar striatal lesion. This mode of transneuronal cell death may be relevant to human diseases, such as Huntington's disease and the multiple system atrophies, in which, in addition to the major striatal neuronal loss, there is considerable loss of neurons in the substantia nigra pars reticulata.

Animals↗