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Results for “selective vulnerability”

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PubMed2005

Increased sensitivity of striatal dopamine release to H2O2 upon chronic rotenone treatment.

It is believed that both mitochondrial dysfunction and oxidative stress play important roles in the pathogenesis of Parkinson's disease (PD). We studied the effect of chronic systemic exposure to the mitochondrial inhibitor rotenone on the uptake, content, and release of striatal neurotransmitters upon neuronal activity and oxidative stress, the latter simulated by H(2)O(2) perfusion. The dopamine content in the rat striatum is decreased simultaneously with the progressive loss of tyrosine hydroxylase (TH) immunoreactivity in response to chronic intravenous rotenone infusion. However, surviving dopaminergic neurons take up and release only a slightly lower amount of dopamine (DA) in response to electrical stimulation. Striatal dopaminergic neurons showed increased susceptibility to oxidative stress by H(2)O(2), responding with enhanced release of DA and with formation of an unidentified metabolite, which is most likely the toxic dopamine quinone (DAQ). In contrast, the uptake of [(3)H]choline and the electrically induced release of acetylcholine increased, in coincidence with a decline in its D(2) receptor-mediated dopaminergic control. Thus, oxidative stress-induced dysregulation of DA release/uptake based on a mitochondrial deficit might underlie the selective vulnerability of dopaminergic transmission in PD, causing a self-amplifying production of reactive oxygen species, and thereby contributing to the progressive degeneration of dopaminergic neurons.

Acetylcholine↗

PubMed2026

Transcriptomic landscape of microglia in mouse models of social dysfunction and oxytocin-mediated recovery.

Atypical sociability is a hallmark of neurodevelopmental disorders arising from genetic susceptibility and prenatal environmental perturbations that can affect diverse brain cell types. Using single-cell transcriptomics, we previously identified selective vulnerability of parvocellular oxytocin (OT) neurons in the paraventricular hypothalamus (PVH) following embryonic exposure to valproic acid (VPA), a teratogen that induces social deficits. Neonatal chemogenetic activation of OT neurons rescued these behavioral abnormalities and partially restored dysregulated gene expression. However, the effects of VPA exposure and OT neuron stimulation on non-neuronal PVH cells remained unclear. Here, we show that VPA induces transcriptional abnormalities in PVH microglia. Spatial transcriptomics revealed altered distributions of PVH microglial subtypes. Notably, neonatal OT neuron stimulation reversed a subset of VPA-induced microglial gene downregulation, while pharmacological manipulation of microglia normalized aberrant OT gene expression in putative parvocellular OT neurons. These findings support bidirectional OT neuron-microglia interactions that may underlie social dysfunction following embryonic VPA exposure.

autism spectrum disorder↗

PubMed2003

Cytology of human dorsal midcingulate and supplementary motor cortices.

Human dorsal midcingulate cortex (MCC) is activated during many cognitive tasks and its role in skeletomotor functions is reflected in the size, density, and neurofilament proteins (NFP) expressed by neurons in this region. The present study used antibodies for neuron-specific nuclear binding protein and NFP in three postmortem cases to assess the cytology of the dorsal midcingulate areas 24c', 24d, and 32' and supplementary motor cortex. Area 24c' has a thin layer Va and a Vb with large and NFP+ neurons not present on the gyral surface. Area 24d has two divisions; area 24dv on the ventral bank has layer Vb neurons that form aggregates, while area 24dd on the dorsal bank has large and solitary layer Vb pyramids. Co-registration of each case to standardized coordinates showed that the rostral area 24d border is at the vertical plane of the anterior commissure and its caudal border with area 23c is -2+/-0.21cm in the y-axis. The transition to supplementary motor areas is characterized by significant increases in the density of large, NFP expressing neurons in layer IIIc and a substantial reduction in the size and density of such neurons in layer V. Since many acute pain studies activate dorsal MCC, understanding the architecture of this region will help explain its selective vulnerability to chronic pain and stress syndromes.

Female↗

PubMed2005

The experimental toxicology of metallic mercury on the murine peripheral motor system: a novel method of assessing axon calibre spectra using the phrenic nerve.

The toxicology of metallic mercury on motor neurons and their processes requires further work to resolve controversial implications in the aetiology of human motor neuron disease (MND). The assessment of experimental neurotoxicity in the peripheral motor system is, however, technically problematic and difficult to interpret. The mean number of axons in a nerve can vary considerably due to a high degree of biological variation. Atrophy of large axons can appear as loss when, in fact, their numbers appear in smaller diameter axonal categories. We addressed these quantitative problems using the murine phrenic nerve (MPN), a mono-fascicular, predominantly motor nerve as a model system. One micrometer transverse sections of gluteraldehyde/osmium tetroxide fixed MPNs were stained for myelin using a silver technique. Axon areas were measured from digital images of the nerve in cross-section (ImagePro Plus software) and transformed to circular diameter equivalents, then displayed as frequency distributions. We found a high biological variation in the mean axon number between paired nerves within experimental groups. Therefore, axon diameter data within individuals group was pooled. Theoretical simulation of axonal degeneration, atrophy and hypertrophy of larger myelinated axons (also affected in MND) were modelled by manipulating the original data set. With this model, by comparing normal distributions, it is possible to distinguish axonal atrophy, degenerative loss, and hypertrophy as distinct pathological processes in the large calibre axon subgroup that are selectively vulnerable to metallic toxins such as mercury.

Animals↗

PubMed2004

Immunophilin expression in the HIV-infected brain.

Immunophilins (IP) are receptors for immunosuppressive drugs and also aid protein folding, assembly, and trafficking. This autopsy study analyses the levels of FKBP12 in the brain of patients with HIV encephalitis. We show that the expression of FKBP12 is increased in the deep gray matter and frontal cortex where it colocalizes with markers of pathology. Changes in FKBP12 levels may be linked to the abnormal protein folding and axonal transport that characterize the neurodegenerative process and could also explain the selective vulnerability of the basal ganglia to HIV infection.

Adult↗

PubMed2004

Early vestibular dysfunction in Machado-Joseph disease detected by caloric test.

The selective vulnerability of distinct neuronal structures is a major feature of Machado-Joseph disease (MJD), also known as spinocerebellar ataxia 3 (SCA3). Vestibular dysfunction is known to be a symptom of MJD, but little is known about precisely when the vestibular system becomes impaired. Using a caloric test, we evaluated vestibular function in 2 MJD patients. One developed the initial symptom 1 year before evaluation, and the other 3 years before evaluation. Neither demonstrated a bilateral response in electronystagmography using ice-cold water irrigation, indicating severe vestibular disturbance. These results suggest that vestibular dysfunction is a symptom that develops very early in MJD and may contribute to unsteady gait as the initial symptom. The vestibular system thus appears to be one of the structures most vulnerable to MJD.

Adult↗

PubMed2005

Separating functional and structural damage in persistent vegetative state using combined voxel-based analysis of 3-D MRI and FDG-PET.

Functional and structural damage in postanoxic persistent vegetative state (PVS) was analysed using 18fluorodeoxyglucose PET (FDG-PET) coregistered to 3-D MRI in combination with morphometric 3-D MRI analysis (voxel-based morphometry, VBM). In five patients in late stages of non-traumatic PVS, combined analysis using statistical parametric mapping (SPM2) was performed to compare metabolic impairment and structural loss. FDG-PET showed widespread hypometabolism at p<0.001 (corrected) in the parietal, parietooccipital and frontotemporal cortices, cingulum, frontal medial and precentral gyrus, and within the bilateral thalamus. VBM revealed multilocal structural loss at p<0.001 (corrected) in the inferior parietal and superior/medial frontal cortices, insula and operculum, superior and medial temporal lobes, cingulum and fusiform gyrus, caudate, midbrain, dorsal pons, and the cerebellum, but to a lesser extent in the thalamus. The selective vulnerability of the brain in a sample of PVS patients could be mapped in vivo, indicating that a complex structural and functional lesion pattern of the cerebral networks seems to be associated with this condition.

Adult↗

PubMed2005

Distribution of brain atrophy in behavioral variant frontotemporal dementia.

Marked brain atrophy occurs in frontotemporal dementia (FTD) yet substantial variation between cases is seen. Recently, a four-level staging scheme which reflects increasing disease duration, severity of dementia and degree of neurodegeneration was described. In the present study, the extent and magnitude of atrophy in behavioral variant FTD and its relationship to disease duration and pathological subtype was further evaluated by quantifying the volume of 30 anatomically-defined regions. A validated point count technique was applied to 17 patients with FTD (9 Pick's disease, 6 dementia lacking distinctive histology, 2 FTD with motor neuron disease) and 21 controls. Atrophy was seen in all brain regions except the inferior frontal cortex and area 37. As might be expected, increasing severity of atrophy occurred with increasing disease duration and stage however measurable atrophy was more widespread than indicated by the staging scheme. Furthermore, severity of atrophy was not related to pathological subtype. Frontal, limbic and temporal regions appeared to be severely affected early in the disease process with temporal lobe atrophy the best predictor of disease duration. White matter, more posterior regions and the subcortex were affected later in the disease. These findings demonstrate a pattern of selective vulnerability which progresses over time. Furthermore, they demonstrate that although patients with a similar clinical subtype may have differing underlying histopathology, the pattern, severity and progression of brain atrophy is the same. This suggests that the regional pattern of neurodegeneration, rather than the type of histopathology influences the clinical syndrome in FTD.

Aged↗

PubMed2005

ALS syndrome in patients with HIV-1 infection.

BACKGROUND: A viral etiology of amyotrophic lateral sclerosis (ALS) has been proposed because of the selective vulnerability of motor neurons to certain viruses. During the last 20 years, at least 19 cases of ALS or ALS-like disease have been reported in HIV-1 (HIV) seropositive individuals. OBJECTIVE: To describe two cases of clinically definite ALS in patients with HIV infection and to review the previously reported cases of HIV-associated ALS syndrome. SETTING: A multidisciplinary ALS center and Neuro-AIDS clinic at a tertiary care university hospital. PATIENTS/DESIGN: We investigated and prospectively monitored two patients who had developed clinically definite ALS by El Escorial criteria several years after acquiring the HIV infection. The previously reported cases of ALS or ALS-like disease in patients with HIV infection were reviewed for comparison and contrast with the characteristics of sporadic ALS. RESULTS: The clinical course of ALS in our two HIV seropositive individuals mirrored that of classical sporadic ALS. A review of previously described 19 patients with ALS syndrome revealed clinically definite ALS in 4 cases and clinically probable or possible ALS in 15. ALS commenced at different stages of the HIV disease; in 7 patients, HIV infection was discovered contemporaneously with diagnosis of ALS. CD4+ T cell count ranged from 2 to 560 cells/mm3. Three (1 definite ALS) of the fatal cases were studied at autopsy and all exhibited pathology outside the motor neuron pool. Unlike our patients, 7 of 8 patients with HIV-associated ALS syndrome receiving HAART demonstrated at least partial recovery of their motor deficit. CONCLUSIONS: ALS-like syndrome can occur in association with HIV infection; however, the causal relationship remains uncertain. Patients with ALS syndrome related to HIV infection are generally younger in age and often demonstrate pathology outside the motor neuron system. Patients with HIV-associated ALS syndrome may improve following antiretroviral therapy. An aggressive HAART regimen to reduce viral load should be pursued in all such cases.

Adult↗

PubMed2007

Role of the activated extracellular signal-regulated kinase pathway on histological and behavioral outcome after traumatic brain injury in rats.

The extracellular signal-regulated kinase (ERK) pathway, which modulates the activity of many transcriptional factors leading to the proliferation of various cells, is activated in lesions in regions of selective vulnerability after traumatic brain injury (TBI). In the present study, using the ERK inhibitor U0126, we investigated the role of the ERK pathway in histopathological and behavioral outcomes after TBI. Adult male Sprague-Dawley rats, weighing 300-400 g were subjected to lateral fluid percussion brain injury. The ERK inhibitor U0126 was injected intravenously before injury at 100, 200 and 400 microg/kg. The severity of CA3 neuronal damage was evaluated by the number of surviving CA3 neurons 7 days after injury. The contusional lesion volume 72 h after injury was analysed using a computer-assisted analysis system. Three different motor skill tasks were measured on days 1-5, 7, 14 and 21 after injury. Pretreatment with U0126 significantly reduced both CA3 neuronal damage and contusional lesion volume after injury. In addition, administration of U0126 ameliorated motor function recovery on days 3, 4 and 5 after injury. Therefore, inhibition of ERK phosphorylation could be a potentially effective therapeutic target after TBI.

Animals↗

PubMed2005

Mechanisms of hypoxic tolerance in presymptomatic APP23 transgenic mice.

In the B6-Tg (ThylAPP)23Sdz (APP23tg) transgenic mouse model of Alzheimer's disease hypoxic tolerance is impaired prior to amyloid deposition. We therefore investigated mechanisms known to mediate resistance to hypoxic episodes in presymptomatic APP23tg and appropriate control strains. The mRNA expression levels in the hippocampus of adenosine receptor subtypes A1 and A3, estrogen receptors alpha and beta, progesterone receptor, and neuronal and endothelial nitric oxide synthase were investigated with semi-quantitative RT-PCR. Mice were pretreated in vivo with a low dose of 3-nitropropionate, an inhibitor of succinic dehydrogenase, known to mediate hypoxic tolerance within 1h. We found increased expression levels in presymptomatic, untreated APP23tg animals of adenosine A3 receptor mRNA and estrogen receptor alpha mRNA. In addition, we observed an increase in nNOS expression levels upon mild cellular hypoxia induced by 3-NP in transgenic but not in wild-type animals. We conclude that overexpression of human APP results in differential expression of receptors conferring hypoxic tolerance prior to amyloid deposition. Up-regulation of nNOS expression levels upon hypoxic challenge in APP23tg transgenic animals may therefore reflect a selective vulnerability in these animals even before amyloid deposition.

Alzheimer Disease↗

PubMed2005

Neuro-modulation, aminergic neuro-disinhibition and neuro-degeneration. Draft of a comprehensive theory for Alzheimer disease.

A comprehensive theory for Alzheimer disease (AD) which can provide a clue to the neuronal selective vulnerability (pathoklisis) is still missing. Based upon evidence from the current literature, the present work is aimed at proposing such a theory, namely the 'aminergic disinhibition theory' of AD. It includes data-based hypotheses as to the pathoklisis, mechanisms of neuro-degeneration and dementia as well as the aetiology of the disease. Alzheimer disease is regarded as a disorder of neural input modulation caused by the degeneration of four modulatory amine transmitter (MAT) systems, namely the serotoninergic, the noradrenergic, the histaminergic, and the cholinergic systems with ascending projections. MATs modulate cognitive processing including arousal, attention, and synaptic plasticity in learning and memory, not only through direct, mostly inhibitory impact on principal neurones but also partially through interaction with local networks of GABA-ergic inter-neurones. The distribution and magnitude of the pathology in AD roughly correlate with the distribution and magnitude of MAT modulation: Regions more densely innervated by ascending MAT projections are, as a rule, more severely affected than areas receiving less MAT innervation. Because the global effect of MATs in the forebrain is inhibition, the degeneration of four MAT systems, some related peptidergic systems and a secondary alleviation of the GABA-ergic transmission means a fundamental loss of inhibitory impact in the neuronal circuitry resulting in neuronal (aminergic) disinhibition. Clearly, the basic mechanism promoting neuronal death in AD is thought to be a chronic disturbance of the inhibition-excitation balance to the advantage of excitation. Chronic over-excitation is conceived to result in Ca2+ dependent cellular excito-toxicity leading to neuro-degeneration including amyloid-beta production and NFT formation. Disinhibited neurons will degenerate while less excited (relatively over-inhibited) neurones will survive. Because the decline of aminergic transmission in AD is likely to start at the receptor level, it is hypothesized that early impairment by a molecular 'hit' to an MAT receptor (or a group of receptors) initiates a pathogenetic cascade that develops in an avalanche-like manner. Based on experimental evidence from the literature, the 'hit' might be the attachment of a targeted pathogen like a small roaming amino acid sequence to the receptor(s), e.g., the serotoninergic 5-HT2A-R. Referential sequence analysis could be a means to identify such a small pathogen hidden in a large receptor molecule.

Alzheimer Disease↗

PubMed2004

Neonatal mice lacking functional Fas death receptors are resistant to hypoxic-ischemic brain injury.

Neonatal hypoxia-ischemia (HI) upregulates Fas death receptor expression in the brain, and alterations in expression and activity of Fas signaling intermediates occur in neonatal brain injury. B6.MRL-Tnfrsf6(lpr) mice lacking functional Fas death receptors are protected from HI brain damage in cortex, striatum, and thalamus compared to wild-type mice. Expression of Fas death receptor and active caspases increase in the cortex after HI. In wild-type mice, the hippocampus is most severely injured, and the hippocampus is the only region not protected in the B6.MRL-Tnfrsf6(lpr) mice. The selective vulnerability of the hippocampus to injury correlates with (1) lower basal expression of [Fas-associated death-domain-like IL-1beta-converting enzyme]-inhibitory protein (FLIP), (2) increased degradation of spectrin to its 145 or 150 kDa breakdown product, and (3) a higher percentage of non-apoptotic cell death following neonatal HI. We conclude that Fas signaling via both extrinsic and intrinsic caspase cascades causes brain injury following neonatal HI in a region-dependent manner. Basal levels of endogenous decoy proteins may modulate the response to Fas death receptor signaling and provide a novel approach to understanding mechanisms of neonatal brain injury.

Animals↗

PubMed2005

Accelerated amyloid deposition, neurofibrillary degeneration and neuronal loss in double mutant APP/tau transgenic mice.

Even though the idea that amyloid beta peptide accumulation is the primary event in the pathogenesis of Alzheimer's disease has become the leading hypothesis, the causal link between aberrant amyloid precursor protein processing and tau alterations in this type of dementia remains controversial. We further investigated the role of beta-amyloid production/deposition in tau pathology and neuronal cell death in the mouse brain by crossing Tg2576 and VLW lines expressing human mutant amyloid precursor protein and human mutant tau, respectively. The resulting double transgenic mice showed enhanced amyloid deposition accompanied by neurofibrillary degeneration and overt neuronal loss in selectively vulnerable brain limbic areas. These findings challenge the idea that tau pathology in Alzheimer's disease is merely a downstream effect of amyloid production/deposition and suggest that reciprocal interactions between beta-amyloid and tau alterations may take place in vivo.

Alzheimer Disease↗

PubMed2005

Toxin-induced movement disorders.

Toxins can be cited as a cause of several movement disorders, but this association is rare and the resultant syndromes usually include additional signs that are not typical for the idiopathic movement disorders. Most instances of confirmed toxin-induced movement disorders show lesions on CT and MRI scans of cortical or subcortical structures. A common underlying element in these toxin-induced syndromes is the development of lesions primarily in the pallidum and striatum. Because many toxins result in lesions affecting these structures, a selective vulnerability to hypoxic or metabolic insults has long been postulated. The susceptibility of these structures may relate to a number of factors, including the pattern of oxidative metabolism, heavy metal concentration, vascular perfusion, and neuronal innervation. Finally, in addition to causing disability, certain neurotoxins have led to a better understanding of human disease through the development of research models. As an example, the MPTP model has not only provided an animal model to study therapeutic strategies in PD but has also contributed important insights into the mechanism of neuronal degeneration.

Animals↗

PubMedDate not supplied

Changes in cPKC isoform-specific membrane translocation and protein expression in the brain of hypoxic preconditioned mice.

Previous studies have shown that the level of total conventional protein kinase C (cPKC) membrane translocation (activation) was increased in the brain of hypoxic preconditioned mice. In order to find out which isoform of cPKC may participate in the development of cerebral hypoxic preconditioning (HPC), we used Western bolt and immunohistochemistry to observe the effects of repetitive hypoxic exposure (H1-H6, n = 6 for each group) on the level of cPKC isoform-specific protein expression and its membrane translocation in the cortex and hippocampus of mice. We found that the levels of cPKC betaII and gamma membrane translocation were increased significantly (p < 0.05 versus normoxic H0 group, n = 6) in response to repetitive hypoxic exposure (H1-H4) at an early phase of hypoxic preconditioning, but no significant changes of cPKC alpha and betaI membrane translocation were found during cPKC alpha, betaI, betaII and gamma protein expression both in hippocampus and cortex. In addition, an extensive subcellular redistribution of cPKC betaII and gamma was detected by immunohistochemistry staining in the cortex after repetitive hypoxic exposures (H3). However, a significant decrease in the expression of cPKC gamma protein (p < 0.05 versus H0 group) was found only in the cortex of delayed hypoxic preconditioned mice (H5-H6). These results suggest that the activation of cPKC betaII and gamma may be involved in the early phase of cerebral hypoxic preconditioning and the changes in cPKC gamma protein expression may participate in the development of the late phase of cerebral hypoxic preconditioning as well as selective vulnerability to hypoxia both in cortex and hippocampus.

Animals↗

PubMed2006

Effects of food restriction on synthesis and expression of brain-derived neurotrophic factor and tyrosine kinase B in dentate gyrus granule cells of adult rats.

We have previously found that the dendritic trees of dentate gyrus granule cells are selectively vulnerable to food restriction but there are reorganizational morphological events that minimize functional impairments. As the neurotrophin brain-derived neurotrophic factor (BDNF) and the cognate receptor tyrosine kinase B (TrkB) are involved in the maintenance of the structure of dendritic trees, we thought of interest to verify if there are alterations in its synthesis and expression in granule cells. To investigate this issue, 2-month-old rats were submitted to 40% caloric restriction for 6 months and compared to controls fed ad libitum. The numbers of granule cells containing BDNF and TrkB proteins were estimated from immunostained sections and the respective mRNA levels of individual neurons evaluated using nonradioactive in situ hybridization. After dietary treatment there was a 15% reduction of BDNF-immunoreactive granule cells with no changes of the number of TrkB-immunostained neurons. No alterations were found in the levels of BDNF and TrkB mRNAs of individual granule cells. As caloric restriction extends the lifespan of animals, the restrictive dietary regimens are generally regarded as beneficial to the organisms, but the present results suggest that caution is needed when extrapolating to some neuronal populations.

Animals↗

PubMed2006

Activation of leukocyte-endothelial interactions and reduction of selective neuronal death after global cerebral ischemia.

The role of leukocyte-endothelial interactions (LEI) as part of the inflammatory response after global cerebral ischemia (GCI) is hardly understood and may be detrimental as well as beneficial. Objective of the current study was to investigate the cause-effect relationship of activated leukocytes for the development of ischemic brain damage. Mongolian gerbils were subjected to 15 min of global cerebral ischemia. A cranial window was implanted for quantitative analysis of the pial microcirculation focusing on leukocyte-endothelium interactions by intravital fluorescence microscopy up to 3 h of reperfusion. Subsequently the animals were daily screened for neurological deficits and the evolving brain damage was assessed histologically after 4 days. After global cerebral ischemia the number of rolling and adherent leukocytes increased 20- and >23-fold, respectively upon 3 h of reperfusion as compared to controls (P<0.05). Ischemic animals developed neurological deficits and showed a significant loss of neurons in selective vulnerable areas of the brain. The extent of leukocyte activation, i.e. the maximum number of rollers and stickers directly correlated to the number of viable neurons on day 4 in hippocampus, cortex, and striatum. We conclude that there is a relationship between activation of leukocyte-endothelium interactions and the reduction of ischemic brain damage after global cerebral ischemia. Activation of leukocytes may have neuroprotective potential or indicate regenerative processes.

Animals↗