Transneuronal Degeneration Research Articles

Nigral degeneration following striato-pallidal lesion in tissue type plasminogen activator deficient mice

Tissue type plasminogen activator (tPA) has been suggested as a key factor in excitotoxic neuronal death in the hippocampus. Transneuronal degeneration of the substantia nigra pars reticulata (SNR) neurons after striato-pallidal lesions is attributable to excess excitatory glutamatergic inputs into the SNR following inhibitory GABAergic deafferentation and tPA may contribute to the mechanism of transneuronal degeneration of the SNR. To examine this possibility, we studied pathological changes in the SNR following striato-pallidal lesions produced by electrocoagulation in tPA-deficient mice. There was no difference in the degree of SNR degeneration, or in microglial activation and proliferation in the degenerating SNR of tPA-deficient and control mice. Our results indicate that tPA does not contribute to transneuronal degeneration in the SNR following striato-pallidal lesions in mice.

Dizocilpine maleate, MK-801, but not 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline, NBQX, prevents transneuronal degeneration of nigral neurons after neurotoxic striatal–pallidal lesion

Unilateral neurotoxin lesion of rat caudate–putamen and globus pallidus resulted in delayed, transneuronal degeneration of GABAergic substantia nigra pars reticulata neurons. To explore whether the disinhibition of endogenous glutamate excitatory input played a role in the degeneration of substantia nigra pars reticulata neurons, animals with unilateral striatal–pallidal lesions received three daily intraperitoneal injections of either dizocilpine maleate (MK-801, 1 or 10 mg/kg), an N-methyl- d-aspartate glutamate receptor blocker, or 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX, 30 mg/kg), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor blocker, that began 24 h after the striatal–pallidal neurotoxin lesion. Drug treatment affected neither the volume of the initial lesion nor the volume of striatal–pallidal glial fibrillary acidic protein immunoreactivity. Neuron number in the substantia nigra pars reticulata ipsilateral to the lesioned striatopallidum was reduced on average by 37% in untreated control rats, in low dose MK-801, and NBQX-treated rats ( P<0.0001). However, in animals treated with high doses of MK-801 there was no difference in the number of neurons in the substantia nigra pars reticulata ipsilateral or contralateral to the neurotoxin lesion. These data demonstrate that dose-related treatment with N-methyl- d-aspartate glutamate receptor blockers protects substantia nigra pars reticulata neurons, and suggests that glutamatergic mechanisms play a role in delayed transneuronal degeneration.

Fimbria–fornix transection and excitotoxicity produce similar neurodegeneration in the septum

Fimbria–fornix transection produces neuronal injury in the septum. This cellular pathology is characterized by somatodendritic vacuolar abnormalities in neurons. Because these cellular changes are reminiscent of some of the morphological abnormalities seen with glutamate receptor-mediated excitoxicity, we tested whether excitotoxic injury to the septal complex of adult rats mimics the degeneration observed within the dorsolateral septal nucleus and medial septal nucleus following fimbria–fornix transection. The septal complex was evaluated at various time-points (6 h to 14 days) by light and electron microscopy following unilateral injection of the N-methyl- d-aspartate receptor agonist quinolinate or the non- N-methyl- d-aspartate receptor agonist kainate, and the morphological changes observed were compared to those abnormalities in the medial septal nucleus and dorsolateral septal nucleus at three to 14 days after fimbria–fornix transection. The patterns of cytoplasmic abnormalities and vacuolar injury were morphologically similar in the somatodendritic compartment of neurons following excitotoxicity and axotomy paradigms. These similarities were most evident when comparing the persistently injured neurons in the penumbral regions of the excitotoxic lesions at one to 14 days recovery to neurons in the medial septal nucleus and dorsolateral septal nucleus at seven and 14 days after fimbria–fornix transection. Pretreatment with the N-methyl- d-aspartate receptor antagonist dizocilpine maleate prior to unilateral fimbria–fornix transection attenuated the somatodentritic vacuolar damage found within the ipsilateral dorsolateral and medial septal nuclei at 14 days recovery. Because glutamate is the principal transmitter of hippocampal efferents within the fimbria–fornix, we conclude that postsynaptic glutamate receptor activation participates in the evolution of septal neuron injury following fimbria–fornix transection. Thus, excitotoxicity is a possible mechanism for transneuronal degeneration following central nervous system axotomy.

Cerebellar atrophy in Alzheimer's disease—clinicopathological correlations

Morphometry of the cerebellum of 11 subjects who died in the severe, final stage of Alzheimer's disease (AD) and of five age-matched subjects without dementia revealed significant atrophy in the AD group, with a decrease in the volume of the molecular layer by 24% and of the granular layer by 22% in comparison with controls. The 32% decrease in the total number of Purkinje cells that was observed correlates with the atrophy of the molecular layer, whereas the 30% reduction in the total number of granule cells correlates with the atrophy of the molecular and granular layers. A unique pattern of Alzheimer-type pathology was observed in the cerebellum: (1) there were no neurofibrillary changes in the cerebellum of either the control or the AD subjects, (2) there was almost the same extent of leptomeningeal and cortical amyloid angiopathy in the normal aged subjects and in the AD patients, and (3) the presence of plaques was noted in the AD group, but not in the control group. This pattern of pathology suggests that two factors might be considered in the etiopathogenesis of cerebellar atrophy: (1) transneuronal degeneration and neuronal loss resulting from primary pathologic changes in cerebral structures and (2) parenchymal cerebellar ß-amyloidosis. The correlation between the temporal duration of AD and both the decrease of the total number of granule cells ( r=0.86, p<0.01) and the volumetric loss of the molecular ( r=0.73, p<0.05) and granular ( r=0.93, p<0.001) layers of the cerebellar cortex indicates that these cerebellar atrophic changes are likely to be related to the basic pathologic process of AD. Similarly, the correlation between the most complex parameter the atrophy of the cerebellar cortex and the Functional Assessment Staging (FAST) measure of the clinical severity of AD at the time of demise ( r=0.63, p<0.05) as well as with the duration of AD ( r=0.78, p<0.01) indicates that cerebellar pathology, when viewed holistically, evolves continuously in association with clinical changes throughout the clinically manifest course of AD.

Olivary degeneration after intracranial haemorrhage or trauma: follow-up MRI.

We studied serial MRI appearances of transneuronal degeneration in the inferior olives, retrospectively analysing follow-up images of five patients, three with head injury and two with brain stem haemorrhage. We performed 13 MRI studies 4 days to 2 years 7 months after the accident. All but one of the patients exhibited bilateral olivary high signal on T2-weighted images. The interval between causal event and appearance of olivary changes was 2-4 months, images 4 days to 1.5 months after the accidents revealing no changes. Olivary enlargement was observed in four patients 2-4 months after ictus.

Transplanted neurons alter the course of neurodegenerative disease in Lurcher mutant mice.

Embryonic cerebellar, neocortical, and striatal tissues derived from NSE-LacZ transgenic mice were transplanted into the right cerebellar hemisphere of 8- to 10-day-old Lurcher or wild-type mice. Host mice survived for 30-90 days and the transplanted tissue was examined by light microscopy using Nissl staining, X-gal histochemistry, and immunohistochemistry for calcium binding protein and glutamic acid decarboxylase. Transplantation of cerebellar tissue, but not neocortical or striatal progenitors, resulted in robust infiltration of the lurcher mutant host cerebellar cortex by transgenic Purkinje neurons. Deep to the infiltrated molecular layer, the host granular layer was thicker and denser than the mutant granular layer, but transgenic cells did not contribute to the spared granular layer. The host inferior olivary complex consistently exhibited a noticeable bilateral asymmetry in Nissl-stained sections. A quantitative analysis of the olivary complex was performed in 10 90-day-old host mice. The results indicate that the left inferior olivary complex of 90-day-old host mice contained more neurons than the right inferior olive of the host mice and contained more neurons than was observed in 90-day-old Lurcher control mice. Analysis by olivary subdivision indicates that increased neuron numbers were present in all subdivisions of the host left inferior olive. These studies confirm the specific attractive effect of the mutant cerebellar cortex on transplanted Purkinje neuron progenitors and indicate that neural transplants may survive the neurodegenerative period to interact with developing host neural systems. The unilateral rescue of Lurcher inferior olivary neurons in cerebellar transplant hosts indicates that transplanted neurons may interact with diseased host neural circuits to reduce transneuronal degeneration in the course of a neurodegenerative disease.

Monocular enucleation prevents retinal ganglion-cell loss following neonatal visual cortex damage in cats.

Damage to primary visual cortex (VC) in young cats leads to severe retrograde degeneration of the dorsal lateral geniculate nucleus (dLGN) and selective transneuronal retrograde degeneration of a class of retinal ganglion cells (RGCs) that have a medium-size soma. Previous studies have shown that "programmed" RGC death associated with normal development in one eye can be attenuated by removal of the other eye, suggesting that binocular interactions can influence developmental RGC death. The present study investigated whether removal of one eye also attenuates the ganglion cell loss that accompanies an early VC lesion. Five one-week-old cats received a unilateral VC lesion (areas 17, 18, and 19), and three of these cats also underwent monocular enucleation at the same time. Two normal control animals also were examined. RGC measurements were made from flat-mounted retinae when the animals were 5 weeks old. Sampling was restricted to a retinal area corresponding to the retinotopic representation included in the VC lesion. Results indicate that there is a marked loss of medium-size RGCs in the hemiretinae projecting to the damaged hemisphere in cats that received a VC lesion alone. However, there is no such loss in VC-lesion animals that also have a monocular enucleation. These results indicate that the transneuronal RGC loss that occurs after an early visual cortex lesion can be influenced by binocular interactions.

ADC and Diffusion Anisotropy Indices in Wallerian Degeneration

We compared the sensitivity of diffusion MRI to T2SI for early detection of Wallerian degeneration secondary to cerebral infarction. Serial full tensor DWI of 15 acute stroke patients with B=1221. ROI analysis of ADC, T2, DWI, eigenvalues, and anisotropy indices in bilateral intracerebral corticospinal tracts. 5/16 patients developed DWI hyperintensity and/or ADC/FA reduction, prior to T2 prolongation, during initial two weeks in ipsilateral corticospinal tracts. Mean FA and ADC reductions were 12% and 24% respectively. All were subsequently confirmed to be Wallerian degeneration on follow up MRI.Another 6/15 patients without observable DWI signal changes demonstrated ipsilateral ADC and FA reductions at one or more levels in CS tracts without subsequent demonstration of Wallerian. Antegrade thalamic transneuronal degeneration was noted in 2/15. Changes in diffusion parameters precede T2 signal abnormalities in the evolution of Wallerian degeneration.

Unilateral enucleation of adult rats does not effect the synapse-to-neuron ratio within the stratum griseum superficiale of the superior colliculi.

Ninety-day-old hooded male rats were anaesthetised with an intraperitoneal injection of a mixture of xylazine and ketamine and had their right eyes removed. Groups of non-enucleated control and enucleated rats were killed at either 150 or 390 days of age by intracardiac perfusion with fixatives. Stereological methods were used to estimate the synapse-to-neuron ratios within the stratum griseum superficiale (SGS) layers of both the ipsi- and contra-lateral superior colliculi. The enucleation had no significant effects on this ratio irrespective of the side or age of the brains examined. This experiment shows that a constant synapse-to-neuron ratio may be maintained within the SGS layer of the rat superior colliculus despite the inevitable loss of synaptic contacts due to the anterograde transneuronal degeneration initiated by the enucleation.

MR imaging of CNS tractopathy: wallerian and transneuronal degeneration.

MR imaging of CNS tractopathy: wallerian and transneuronal degeneration.

Histological and temporal characteristics of nigral transneuronal degeneration after striatal injury

Neurotoxic injury of the caudate-putamen and lateral globus pallidus unilaterally initiated transneuronal degeneration of neurons in the ipsilateral substantia nigra reticulata (SNR). Quantification of SNR neurons using unbiased stereology demonstrated that neuron loss began 4 days after the initial striatal lesion, followed by significant loss (50%) at 6 days and a plateau at 8 days. Analysis at the light and ultrastructural levels revealed morphological changes consistent with a type of programmed cell death. These temporal and histological results refine an in vivo model in which to explore mechanisms of delayed neuronal degeneration.

Brain-derived neurotrophic factor prevents the loss of nigral neurons induced by excitotoxic striatal-pallidal lesions

GABAergic neurons in the rat substantia nigra die after inhibitory inputs to the nigra have been killed, and glutamatergic inputs disinhibited, by striatal-pallidal injections of ibotenic acid. This delayed transneuronal injury model imitates the neuron loss observed in Huntington's disease, and may also imitate neuron loss distant from the primary injury in stroke and Parkinson's disease. Because the neurotrophins brain-derived neurotrophic factor and neurotrophin-3 can prevent excitotoxic killing of cultured GABA neurons, we tested whether either factor could protect nigral neurons from transneuronal degeneration. A continuous, three week supranigral infusion of brain-derived neurotrophic factor completely prevented the loss of nigral neurons caused by the ibotenic acid-induced destruction of the caudate–putamen and globus pallidus, and brain-derived neurotrophic factor increased nigral neuron size by 25%. These effects were specific to the TrkB tyrosine kinase receptor that mediates brain-derived neurotrophic factor actions, since supranigral infusions of saline or the TrkC preferring neurotrophin-3, did not prevent nigral neuron loss or induce a hypertrophic response. Neither trophic factor influenced the ibotenic acid destruction of striatal or pallidal neurons. These results demonstrate that exogenously supplied brain-derived neurotrophic factor can prevent delayed, transneuronal loss, and implicate decreased excitatory amino acid transmission or diminished nigral neuron susceptibility to glutamate inputs in the protective effect of brain-derived neurotrophic factor.

Upper Motor Neuron Lesions in Stroke Patients Do Not Induce Anterograde Transneuronal Degeneration in Spinal Anterior Horn Cells

To determine whether upper motor neuron lesions in stroke can cause transneuronal degeneration of lower motor neurons, we assessed spinal anterior horn cells in patients dying with poststroke hemiplegia. Subjects were four stroke patients with severe left hemiplegia and four age-matched control subjects who died of nonneurological disease. After histological processing and staining, cytoarchitectonic assessment was made of all neurons in the ventral horns of the 4th lumbar segment of the spinal cord according to cell diameter and topography. In the four stroke patients, no differences were seen in anterior horn cell populations or diameter and size distribution patterns between affected and unaffected sides or between these patients and the control subjects. The present quantitative analysis provides no evidence of anterograde transneuronal degeneration of lower motor neurons after upper motor neuron damage in stroke patients.

Transneuronal retrograde degeneration of retinal ganglion cells following cerebral hemispherectomy in cats

We have assessed the extent of transneuronal retrograde degeneration of retinal ganglion cells (RGCs) following the removal of a whole cerebral hemisphere at postnatal age 16 and 25 days. In the P16 animal, the nasal retina contralateral to the lesion suffered a 41% cell loss, whereas cell loss in the temporal retina ipsilateral to the lesion was 33%. Cell loss was greater in nasal retina and mainly included medium sized cells (200–600 μm2). In the P25 animal overall there was no evidence for ganglion cell loss.

Spinal Cord Transection—No Loss of Distal Ventral Horn Neurons

Anterograde transneuronal degeneration is caused by the loss of afferent input to the nerve cells and may occur in a number of neuronal systems. Transection of the adult spinal cord, causing anterograde transneuronal degeneration in ventral horn neurons, distal to the lesion, has been reported by some authors, while others contend that no such changes take place. The present study was undertaken in order to investigate whether transection of adult mouse thoracic spinal cord induces neuronal death in the ventral horns distal to the lesion. By means of modern stereological techniques such as the optical disector, the total number of cells in the lumbar ventral horns was estimated 7 weeks after transection. The mean numbers of neurons and glial and endothelial cells were 82,000 versus 89,000, 259,000 versus 301,000, and 129,000 versus 144,000 in the transected (n = 6) and sham-operated animals (n = 5), respectively. These differences were not statistically significant. Furthermore, neuronal soma volume was estimated by another stereological method, the vertical rotator. Mean neuronal soma volume was not significantly different between transected (2762 &mgr;m3) and sham-operated (2617 &mgr;m3) mice. Although no reduction in cell number or neuronal soma volume was observed, the mean volume of the ventral horns in the lumbar segments was significantly less in transected than in sham-operated animals, 2.49 mm3 versus 3.05 mm3 (P < 0.05). In conclusion, the transection of adult mouse thoracic spinal cord does not induce neuronal degeneration in the lumbar ventral horns. Copyright 1997 Academic Press. Copyright 1997 Academic Press

Continuous intraventricular drug infusion for the in vivo study of transneuronal degeneration in the striatonigral system of the rat

Injuries to certain parts of the brain may induce neuronal death in distant areas innervated by the sites of the primary lesion. Such characteristic pathological changes, known as anterograde transneuronal degeneration, may occur at the next and more distant synaptic levels and play a part in the slow progression of some types of system degeneration [1]. Delayed transneuronal degeneration of the substantia nigra pars reticulata (SNr) is one example of this form of cell death, and it occurs as a consequence of a neostriatal lesion caused by focal ischemia [2, 9, 18], Huntington's disease [13], or experimental axon-sparing injections of neurotoxin [7, 16, 17]. Ever since the demonstration by Saji and Reis [16]that the administration of GABA receptor agonist effectively prevented delayed transneuronal degeneration of the SNr, the degeneration of nigral reticulata cells has been attributed to the loss of striatal inhibition ( Fig. 1A). The latter process severely upset the balance of membrane potential of nigral reticulata cells, producing an effect resembling excitotoxicity [10, 16, 18]. In this report, we describe a continuous intraventricular MK-801 infusion technique that is useful in clarifying the role of glutamatergic action via N-methyl- d-aspartate (NMDA) receptor subclasses involved in exo-focal postischemic death of the SNr.

GABA receptor agonist promotes reformation of the striatonigral pathway by transplant derived from fetal striatal primordia in the lesioned striatum.

Striatal lesions are known to cause the anterograde transneuronal degeneration of the substantia nigra pars reticulata (SNr) neurons in consequence to loss of GABAergic inhibitory striatonigral efferents. The present study was undertaken to examine whether long-term intraventricular administration of the GABA agonist muscimol could promote reformation of the striatonigral pathway arising from transplants by rescuing host SNr neurons from transneuronal death in rats with striatal ischemic lesions. Compared to nongrafted rats with striatal lesions, (i) a prominent axonal projection from the transplants to the ipsilateral substantia nigra, (ii) a significant increase in number of survived neurons in the ipsilateral SNr, and (iii) a significant reduction in number of apomorphine-induced turning behaviors were found in grafted animals with muscimol infusion, but not in those without muscimol administration. These findings suggest that preservation of the host target neurons for grafted cells may increase an efficacy of cerebral implants in establishment of the host-graft fiber connections, possibly, leading to functional restoration.

3-Acetylpyridine-induced degeneration and regeneration in the adult lizard brain: a qualitative and quantitative analysis

The neurotoxin 3-acetylpyridine (3AP) produces highly selective neuronal damage in specific areas of the lizard brain. Following 3AP intoxication, proliferation and migration of replacement neurons born in the ventricular walls lead to regeneration of the lesioned areas. Earlier studies established the time course of 3AP-induced degeneration and subsequent regeneration in the medial cerebral cortex of adult lizards (Font, E., Garcı́a-Verdugo, J.M., Alcántara, S. and López-Garcı́a, C., Neuron regeneration reverses 3-acetylpyridine-induced cell loss in the cerebral cortex of adult lizards, Brain Res., 551 (1991) 230–235 [13]). Complementary to our previous studies, we now provide a qualitative and quantitative account of the extent and distribution of neurotoxic damage in the brain as a whole of lizards treated with 3AP using Nissl and Golgi stains, a degeneration-sensitive reduced-silver method, and electron microscopy. Additionally, [ 3H]thymidine autoradiography was used to assess changes in the rate of neurogenesis caused by the 3AP treatment. Single doses of 3AP caused degenerative changes in all the cortical areas, anterior dorsal ventricular ridge, deep layers of the lateral cortex, lateral amygdaloid nucleus, and nucleus sphericus, while sparing other brain areas. The most frequent neuropathic change after 3AP treatment was clumping of the nuclear chromatin with formation of pyknotic nuclei. Occasionally, a second type of injury was observed in neurons of the cell layer of the dorsomedial cortex (DMC). 3AP also caused a conspicuous loss of dendritic spines in bipyramidal neurons of the dorsomedial and dorsal cortices possibly representing transneuronal degeneration. Numbers of [ 3H]thymidine-labeled cells were higher in lizards previously treated with 3AP than in controls. These results demonstrate that the neurotoxic lesion is capable of inducing an increase in the normal rate of adult neurogenesis. Whereas regeneration in the remaining areas was morphologically and histologically complete, in some animals, cell proliferation in the DMC resulted in formation of an abnormal cell plate.

Behavioral correlates of transneuronal degeneration of substantia nigra reticulata neurons are reversed by ablation of the subthalamic nucleus

In rats, acute injury of neurons in the caudate nucleus (CN) and globus pallidus (GP) by local injection of ibotenic acid (IA) or by transient forebrain ischemia has caused transneuronal cell death of neurons in the substantia nigra reticulata (SNr) weeks after the initial injury. Recently transient expression of an immediate early gene c-fos was induced specifically in neurons of the subthalamic nucleus (STN) and SNr at 36–48 h after the IA-lesions, prior to the delayed degeneration of SNr neurons. These cellular and molecular events may alter the level of inhibitory output from the basal ganglia and lead to movement disorders. To test (i) whether movement disorders occur in the early period after unilateral lesions of the CN and GP by IA-injection, and (ii) whether ablation of the STN reverses the early movement disorders, we used a modified version of Porsolt forced swim test in which the lesion-induced asymmetry of motor function becomes apparent as rotation when the animals are forced to swim. Following unilateral IA-lesions of the right CN and GP in rats, rapid contraversive rotation appeared transiently 36–48 h after the lesions, and, in turn, slow ipsiversive rotation appeared at 3–5 days postlesion. Prior ablation of the ipsilateral STN reversed these early movement disorders produced by the unilateral IA-lesions of the CN and GP and instead created persistent contraversive rotation 7–10 days after the lesions. Each phase of the dominant rotation behavior was dependent on asymmetrical limb motor activity; decreased left limb activity caused contraversive rotation, and increased left limb activity caused ipsiversive rotation. Reversal of these early movement disorders suggests that ablatin of the STN prevents the transneuronal degeneration of the SNr.

The effects of lesions to thalamic lateral internal medullary lamina and posterior nuclei on learning, memory and habituation in the rat

The behavioral effects of radiofrequency lesions to the lateral internal medullary lamina region (IML) or the posterior region (Po: containing the parafascicular and posterior nuclei) of the thalamus were compared to sham operated controls. Subjects were pre-operatively trained and then tested for post-operative retention of a NMTP task. Whereas the Po-lesion group was impaired only on long delays (60, 90 s), the IML-lesion group was impaired on retention and re-acquisition and demonstrated lower performance at all delays (5–90 s) of the NMTP task. Post-operative training and testing was conducted on three additional tasks: Morris water maze, acoustic startle, and passive avoidance. The IML-lesion group was impaired in finding a hidden and visual platform in the Morris water maze, demonstrated a blunted response but normal habituation to an acoustic startle stimulus, and showed normal retention of a passive avoidance task. On those three tasks, the performance of the Po-lesion group was similar to controls. In the IML-lesion group, neuronal loss resulting from axotomy and/or transneuronal degeneration was observed within nuclei of the midline and anterior thalamus and the mammillary body. These results suggest that lesions to the IML region disrupt a range of cognitive functions and produce pathological destruction in distant brain regions; whereas damage to the posterior thalamus causes spatial delay-sensitive deficits.