Retrograde Transneuronal Degeneration Research Articles

Transsynaptic Degeneration of Retinal Ganglion Cells Following Lesions to Primary Visual Cortex in Marmosets.

A lesion to primary visual cortex (V1) in primates can produce retrograde transneuronal degeneration in the dorsal lateral geniculate nucleus (LGN) and retina. We investigated the effect of age at time of lesion on LGN volume and retinal ganglion cell (RGC) density in marmoset monkeys. Retinas and LGNs were obtained about 2years after a unilateral left-sided V1 lesion as infants (n = 7) or young adult (n = 1). Antibodies against RBPMS were used to label all RGCs, and antibodies against CaMKII or GABAA receptors were used to label nonmidget RGCs. Cell densities were compared in the left and right hemiretina of each eye. The LGNs were stained with the nuclear marker NeuN or for Nissl substance. In three animals lesioned within the first 2 postnatal weeks, the proportion of RGCs lost within 5mm of the fovea was ∼twofold higher than after lesions at 4 or 6 weeks. There was negligible loss in the animal lesioned at 2years of age. A positive correlation between RGC loss and LGN volume reduction was evident. No loss of CaMKII-positive or GABAA receptor-positive RGCs was apparent within 2mm of the fovea in any of the retinas investigated. Susceptibility of marmoset RGCs to transneuronal degeneration is high at birth and declines over the first 6 postnatal weeks. High survival rates of CaMKII and GABAA receptor-positive RGCs implies that widefield and parasol cells are less affected by neonatal cortical lesions than are midget-pathway cells.

Novel Findings in Obstetric Brachial Plexus Palsy: A Study of Corpus Callosum Volumetry and Resting-State Functional Magnetic Resonance Imaging of Sensorimotor Network.

The response of the brain to obstetric brachial plexus palsy (OBPP) is not clearly understood. We propose that even a peripheral insult at the developmental stage may result in changes in the volume of white matter of the brain, which we studied using corpus callosum volumetry and resting-state functional magnetic resonance imaging (rsfMRI) of sensorimotor network. To study the central neural effects in OBPP. We performed an MRI study on a cohort of 14 children who had OBPP and 14 healthy controls. The mean age of the test subjects was 10.07±1.22 yr (95% confidence interval). Corpus callosum volumetry was compared with that of age-matched healthy subjects. Hofer and Frahm segmentation was used. Resting-state fMRI data were analyzed using the FSL software (FMRIB Software Library v5.0, Oxford, United Kingdom), and group analysis of the sensorimotor network was performed. Statistical analysis of corpus callosum volume revealed significant differences between the OBPP cohort and healthy controls, especially in the motor association areas. Independent t-test revealed statistically significant volume loss in segments I (prefrontal), II (premotor), and IV (primary sensory area). rsfMRI of sensorimotor network showed decreased activation in the test hemisphere (the side contralateral to the injured brachial plexus) and also decreased activation in the ipsilateral hemisphere, when compared with healthy controls. OBPP occurs in an immature brain and causes central cortical changes. There is secondary corpus callosum atrophy which may be due to retrograde transneuronal degeneration. This in turn may result in disruption of interhemispheric coactivation and consequent reduction in activation of sensorimotor network even in the ipsilateral hemisphere.

Progression of retinal ganglion cell loss in multiple sclerosis is associated with new lesions in the optic radiations.

The mechanism of retinal ganglion cell and retinal nerve fiber layer loss in multiple sclerosis (MS) remains unknown. This study aimed to investigate the association between temporal retinal nerve fiber layer (tRNFL) thinning and disease activity in the brain determined by T2 lesions on magnetic resonance imaging (MRI). Fifty-five consecutive patients with relapsing-remitting MS and 25 controls were enrolled. All patients underwent annual optical coherence tomography and high-resolution MRI scans for tRNFL thickness and brain lesion volume analysis, respectively. Significant tRNFL thickness reduction was observed over the 3-year follow-up period at a relatively constant rate (1.02 μm/year). Thinning of tRNFL fibers was more prominent in younger patients (P = 0.01). The tRNFL loss was associated with new MRI lesions in the optic radiations (ORs). There was significantly greater tRNFL thinning in patients with new lesional activity in the ORs compared with patients with new lesions outside the ORs (P = 0.009). This study supports the notion that retrograde transneuronal degeneration caused by OR lesions might play a role in progressive retinal nerve fiber layer loss. In addition, the results of the study also indicate that the disease-related neurodegenerative changes in the retina start much earlier than the clinical diagnosis of MS.

Retrograde transneuronal degeneration in the retina and lateral geniculate nucleus of the V1-lesioned marmoset monkey

Retrograde transneuronal degeneration (RTD) of retinal ganglion cells and dorsal lateral geniculate (LGN) neurons are well described following a lesion of the primary visual cortex (V1) in both Old World monkeys and humans. Based on previous studies of New World monkeys and prosimians, it was suggested that these species displayed no RTD following a lesion of V1. In this study of the New World marmoset monkey, 1 year after a unilateral V1 lesion either in adults or at 14 days after birth, we observed ~20 % ganglion cell (GC) loss in adult but ~70 % in infants. This finding is similar to the RTD previously described for Old World Macaca monkeys. Furthermore, in infants we find a similar amount of RTD at 3 weeks and 1 year following lesion, demonstrating that RTD is very rapid in neonates. This highlights the importance of trying to prevent the rapid onset of RTD following a lesion of V1 in early life as a strategy for improved functional recovery. Despite differences in GC loss, there was little difference between LGN degeneration in infant versus adult lesions. A wedge on the horizontal meridian corresponding to the LGN foveal representation revealed extensive neuronal loss. Retinal afferent input was labeled by cholera toxin B subunit. Input to the degenerated parvocellular layers was difficult to detect, while input to magnocellular and koniocellular layers was reduced but still apparent. Our demonstration that the New World marmoset monkey shares many of the features of neuroplasticity with Old World Macaca monkeys and humans emphasizes the opportunity and benefit of marmosets as models of visual cortical injury.

Spinal cord surgery after root avulsion injury in man results in motor and sensory recovery

Event Abstract Back to Event Spinal cord surgery after root avulsion injury in man results in motor and sensory recovery Thomas Carlstedt1* 1 Karolinska Institutet, Hand surgery, Sweden Spinal nerve root avulsion is a longitudinal spinal cord injury that affects mainly the final common motor pathway and the primary sensory medullary trajectories. In humans this occurs most frequently in traction injuries to the brachial plexus but also in trauma to the lumbosacral plexus and cauda equina as well as conus medullaris. This injury has serious effects on the pertinent spinal cord segment with the breakdown of connections and networks, death of motor, autonomic and sensory neurons and the development of a spinal cord scar. This injury often occurs as a result of road traffic accidents or violent acts. About 1000 patients are affected annually in the UK. The functional consequence of such injury is lower motoneuron syndromes, associated with autonomic paralysis including dysfunctional internal organs, limb muscle atrophy, sensory impairment and chronic pain. Spinal nerve root injury has been associated with an overall poor clinical outcome as a successful surgical repair would require axonal regrowth within the central nervous system as spinal cord regeneration. A surgical technique for the repair of this spinal cord injury was developed from basic science experiments and successfully translated to humans. Today, the reimplantation of avulsed ventral roots to the spinal cord in total brachial plexus avulsion injury restores useful proximal limb function and is the method of choice in the treatment of such devastating injuries. Even hand function can be restored by this technique. By means of functional magnetic resonance imaging (fMRI) it was established that the restored hand function relayed on pre-injury established cortical sensory program. Sensory roots are not possible to replant with functional recovery. Sensory recovery is therefore not occurring. In some cases as an expression of plasticity there are phenomenona observed as referrals of sensation to the denervated limb as well as hypersensitivity at border zones between normal and denervated dermatomes. When nerve graft has been implanted into the dorsal part of the spinal cord it has been possible to record return of some aspects of sensation. There was in such a case possible to elicit a biceps reflex and also record by means of electrophysiology a H-reflex proving that by this surgical technique it has been possible to restore a sensory-motor spinal cord reflex. However, neither quantitative sensory testing (QST), nor contact heat evoked potential stimulation (CHEPs) could demonstrate any exteroceptive sensory qualities. Pain, which is most severe and excruciating in most cases of brachial plexus avulsion injuries were found to be alleviated in conjunction with motor recovery after motor (but not sensory) root replantation. The mechanisms behind this are elusive but recent observations have indicated that there is retrograde transneuronal degeneration into the spinal cord dorsal horn following ventral root avulsion. This is reversed by ventral root replantation. These observation achieved by spinal cord surgery will serve as baseline data when assessing the effects of future application of adjuvant therapies Keywords: avulsion, Pain, Regeneration, Spinal Cord, spinal nerve root Conference: Karolinska Institutet 200 years anniversary Symposium on Traumatic Injuries in the Nervous System, Stockholm, Sweden, 15 Sep - 16 Sep, 2010. Presentation Type: Presentation Topic: Traumatic Injuries in the Nervous System Citation: Carlstedt T (2010). Spinal cord surgery after root avulsion injury in man results in motor and sensory recovery. Front. Neurol. Conference Abstract: Karolinska Institutet 200 years anniversary Symposium on Traumatic Injuries in the Nervous System. doi: 10.3389/conf.fneur.2010.56.00020 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 03 Sep 2010; Published Online: 21 Sep 2010. * Correspondence: Prof. Thomas Carlstedt, Karolinska Institutet, Hand surgery, Stockholm, Sweden, carlstedt.thomas@googlemail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Thomas Carlstedt Google Thomas Carlstedt Google Scholar Thomas Carlstedt PubMed Thomas Carlstedt Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. 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Quantitative morphological analysis of the cerebellar nuclei in normal and lurcher mutant mice. I. Morphology and cell number

The present study indicates that the cerebellar nuclei of the mouse are essentially identical in structure with those described in the rat, and that the atrophic cerebellar nuclei in lurcher mutant mice exhibit a comparable anatomical organization. A quantitative estimate of the atrophy observed in the cerebellar nuclei of the adult lurcher mutant mouse reveals an overall 60% decrease in volume. Cell counts in the wild-type cerebellar nuclei reveal a total of 8,528 principal neurons and 10,203 small neurons. The ratio of small/principal neurons is 0.5 in the fastigial nucleus and between 1 and 1.5 in other subdivisions. In lurcher, the principal neurons are slightly reduced in number (-20%) in the nuclear complex, while the population of small neurons is reduced by 37% in the interposed and dentate nuclei, but is unchanged in the fastigial nucleus. These results suggest that the massive deafferentation of the cerebellar nuclei that occurs between 10 and 30 days of age in lurcher mutants has a relatively mild effect on the principal cerebellar nuclear neurons. In the population of small neurons, however, the effect of deafferentation may be exacerbated by a secondary retrograde transneuronal degeneration brought on by the severe degeneration of inferior olivary neurons and cerebellar cortex in this mutant.

The effects of the loss of target cells upon photoreceptor inputs in the fly's optic lobe.

The sensitivity of sensory neurons to target cell denervation varies in the CNS. We have examined the effects of surgically interrupting the output axons of the first optic neuropil, or lamina, in the optic lobe of the fly (Musca domestica), upon the receptor terminal inputs to the lamina. Two of the output interneurons are the monopolar cells L1 and L2, which are found as a pair in each of the unit modules or cartridges of the lamina neuropil. The lamina axons of L1 and L2 degenerate rapidly (within 0.5 h) in a retrograde direction from their lesion site, but there is no sign of retrograde transneuronal degeneration to the receptor terminals, across the input synapse. At each of these synaptic sites, L1 and L2 are invariable contributors to two of the four elements of a postsynaptic tetrad. Not only do the receptor terminals persist, but the presynaptic ribbons at the tetrad sites do also, opposite the degenerated spines of L1 and L2, indicating their lack of target dependence at least over the longest period of post-lesion recovery (48 h) examined. The areal density of presynaptic sites was conserved in the face of the degenerative loss of L1 and L2, as were the numbers of capitate projections (glial invaginations into receptor terminals). The stability of both synaptic density and capitate projection number indicates that they are predominantly influenced by the receptor terminals, which are still intact. A reduction in the number of mitochondrial profiles was one of the few observed changes in the receptor terminals. The results reflect the autonomy which the terminals have, during development, from their interneurons; they especially reflect the role of the terminals in the adult, in maintaining the presynaptic site of their afferent synapses, the tetrads.

Retinal ganglion cell death during regeneration of the frog optic nerve is not accompanied by appreciable cell loss from the inner nuclear layer

We estimated cell numbers in the ganglion cell and inner nuclear layers of adult frog (Hyla moorei) retinae, examining normal animals and those with regenerated optic nerves. Analysis of sections stained with cresyl violet showed that cell numbers in a nasotemporal strip, which included the area centralis and visual streak, were comparable between sides for both these cellular layers in normal animals. In line with our previous observations, after optic nerve regeneration cell numbers in the ganglion cell layer had fallen by 35-43% compared to the unoperated sides. By contrast cell numbers remained similar for the inner nuclear layers on the two sides. We conclude that retrograde transneuronal degeneration had not taken place in the inner nuclear layer in response to ganglion cell death.

The effects of unilateral cortical and tectal lesions on retinal ganglion cells in rats

The ganglion cell layer of the retina was examined for retrograde transneuronal degeneration after removing the striate cortex unilaterally in infant or adult rats. No significant degeneration occurred, even after a survival time of 15 months, and the rat is therefore unlike other mammals in which the phenomenon has been studied. A possible explanation that most optic axons bifurcate in rats and that the tectal branch can sustain the ganglion cell after the branch to the dorsal lateral geniculate nucleus has degenerated following removal of striate cortex was ruled out by the demonstration that combined unilateral removal of striate cortex and superior colliculus in adults was similarly ineffective. Unilateral removal of the superior colliculus alone also failed to affect ganglion cells of adult rats but produced conspicuous degeneration in infants. The greater vulnerability of the infantile developing visual system casts doubt on the common assumption that the effects of brain damage are less severe in infants than adults.

Cell death of motoneurons in the chick embryo spinal cord. III. The differentiation of motoneurons prior to their induced degeneration following limb-bud removal.

AbstractThe differentiation of motoneurons following early limb‐bud ablation was studied in chick embryos from four days to hatching. Following the removal of the normal targets of these cells about 90% of the neurons in the lateral motor column (LMC) of segments 23–29 (lumbar) were found to disappear. By counting degenerating cells it was shown that virtually all of the cell loss could be accounted for by cell death, rather than impaired proliferation or enhanced migration away from the LMC. Quantitative comparisons of cell death between the peripherally deprived and the control, non‐deprived side demonstrated that limb‐bud removal not only enhanced the 50% natural cell death known to occur in this system, but also greatly accelerated the whole process. By stage 30 (6.5‐7 days) 75% of the final cell loss had occurred on the deprived side, whereas only 40% of the final cell loss had occurred on the control side. In both cases, however, cell death was confined to the period of limb innervation. Axon counts of the peripherally deprived ventral root showed that all the deprived neurons initially had sent an axon out of the spinal cord. Most of these, however, became caught in a neuroma before reaching the site of limb attachment. Though no synapses were found in the neuroma the axons were shown to be able to transport HRP back to the spinal cord. Before they began to degenerate, the deprived LMC motoneurons developed dendritic processes and these were able to form synapses with axons in the prospective lateral white matter. In early stages, frequent axo‐glial “synapses” were observed in the prospective lateral white matter of both deprived and control sides of the spinal cord. Since by stage 36 (day 10) these had virtually all disappeared, it was suggested that synapse formation in this region of the spinal cord may initially be under few constraints. In late stages (i.e., after day 8) it was noted that there were frequently signs of axonal degeneration in the lateral white matter on both sides of the spinal cord, suggesting a retrograde transneuronal degeneration initiated by the earlier cell death of motoneurons. Electron microscopic examination of the deprived LMC cells at different stages prior to degeneration failed to uncover any obvious differences between them and control cells on the non‐deprived side of the spinal cord.By histochemical and neurochemical methods the cholinergic enzymes acetylcholinesterase and choline acetyltransferase were found to develop normally up until the onset of frank degeneration in the deprived motoneurons, on day 5 or 6. After this the enzymes decreased at a rate comparableto the morphological loss of motoneurons by cell death.On the basis of these various lines of evidence, it is argued that all the motoneurons in the LMC have a remarkable intrinsic capacity to initiate differentiation and that neurons experimentallydeprived of their normal target are no different in this respect.

Retrograde transneuronal degeneration of optic fibers and their terminals in lateral geniculate nucleus of rhesus monkey.

Abstract In Rhesus monkey, the optic nerve fibers and their boutons were studied at 5, 14, 49, 79 and 180 days following ablation of the occipital lobe. Retrograde transneuronal degeneration in optic nerve terminals appeared as early as 14 days but lacked a uniform pattern. In some terminals, mitochondrial changes and/or smooth membranous proliferation were common. In others, depletion of synaptic vesicles was more pronounced. Rarely, these terminals were seen to undergo bulbous enlargement and to contain stacks of neurofilaments. Lamellated osmiophilic profiles and dense bodies together with glycogen particles were often encountered in late stages of degeneration. This irregular pattern of degeneration contrasted with the uniform filamentous change that the terminals are known to undergo when the optic nerves are severed. The reason for the lack of a consistent and synchronous degenerative pattern was attributed, mainly, to the difference in rate and severity of axonal reaction in geniculate neurons. Six months after the occipital lobectomy, swollen nerve fibers larger than the largest normal fibers were present, both in the geniculate nucleus and in the optic nerves proper. They displayed diverse changes and contained complex structures. They were similar to the altered fibers described in certain toxic neuropathies. The pathomechanism of retrograde transneuronal degeneration in retinal fibers was not clear; however, the phenomenon of ‘dying-back’ was invoked to explain this type of degeneration.

Degeneration in the nucleus of origin of the preganglionic fibers to the chick ciliary ganglion following early removal of the optic vesicle.

AbstractExtirpation of the optic vesicle in chick embryos towards the end of the second day of incubation leads to a progressive hypoplasia in the ciliary ganglion and to a secondary, or retrograde transneuronal degeneration, in the accessory oculomotor nucleus from which the preganglionic fibers to the ciliary ganglion are derived. The primary changes in the ciliary ganglion are first observed at about the eighth day of incubation and the resulting cell loss proceeds over the next three or four days to include almost all of the ganglion cells. At the tenth day of incubation (when the volume of the ciliary ganglion is reduced by just over 70%) early signs of cell degeneration can be recognized in both the medial and lateral divisions of the accessory oculomotor nucleus in the form of cell shrinkage, loss of Nissl material and some cell loss. By the fourteenth day of incubation (Stage 40) the nucleus is virtually depleted of neurons with only an occasional shrunken cell persisting in the medial accessory nucleus. After even longer survival periods complete cell loss may occur in the nucleus, but in many of the experiments a small number of cells survive: these are probably related to ciliary ganglion cells which have established aberrant peripheral connections, or in those cases in which the lesion of the optic vesicle was incomplete, to the cells which innervate the surviving ocular tissue.

An experimental study of the relation between the medial mamillary nucleus and the cingulate cortex.

The cellular changes in the mamillary nuclei following lesions of the cingulate cortex, the anterior thalamic radiation and the anterior thalamic nuclei have been studied in rabbits varying in age from 10 days to young adults. Distinct cellular degeneration ranging in severity from slight cell shrinkage to complete cell loss occurs in the medial and supra-mamillary nuclei subsequent to the retrograde changes in the anterior thalamic nuclei. The severity of this ‘retrograde transneuronal degeneration’ is a function of the age of the animal at the time of operation and of the post-operative survival period. With the aid of this technique, it has been shown that the caudal part of the pars anterior and the ventro-lateral two-thirds of the pars medialis of the medial mamillary nucleus project to the antero-medial nucleus of the thalamus, the pars basalis to the antero-dorsal nucleus and the pars posterior to the antero-ventral nucleus. No changes were observed in the lateral mamillary nucleus in any of the experiments.