Early phrenic motor neuron loss and transient respiratory abnormalities following unilateral cervical spinal cord contusion

Contusion-type cervical spinal cord injury (SCI) is one of the most common forms of SCI observed in patients. In particular, injuries targeting the C3-C5 region affect the pool of phrenic motor neurons (PhMNs) that innervates the diaphragm, resulting in significant and often chronic respiratory dysfunction. Using a previously described rat model of unilateral midcervical C4 contusion with the Infinite Horizon Impactor, we have characterized the early time course of PhMN degeneration and consequent respiratory deficits following injury, as this knowledge is important for designing relevant treatment strategies targeting protection and plasticity of PhMN circuitry. PhMN loss (48% of the ipsilateral pool) occurred almost entirely during the first 24 h post-injury, resulting in persistent phrenic nerve axonal degeneration and denervation at the diaphragm neuromuscular junction (NMJ). Reduced diaphragm compound muscle action potential amplitudes following phrenic nerve stimulation were observed as early as the first day post-injury (30% of pre-injury maximum amplitude), with slow functional improvement over time that was associated with partial reinnervation at the diaphragm NMJ. Consistent with ipsilateral diaphragmatic compromise, the injury resulted in rapid, yet only transient, changes in overall ventilatory parameters measured via whole-body plethysmography, including increased respiratory rate, decreased tidal volume, and decreased peak inspiratory flow. Despite significant ipsilateral PhMN loss, the respiratory system has the capacity to quickly compensate for partially impaired hemidiaphragm function, suggesting that C4 hemicontusion in rats is a model of SCI that manifests subacute respiratory abnormalities. Collectively, these findings demonstrate significant and persistent diaphragm compromise in a clinically relevant model of midcervical contusion SCI; however, the therapeutic window for PhMN protection is restricted to early time points post-injury. On the contrary, preventing loss of innervation by PhMNs and/or inducing plasticity in spared PhMN axons at the diaphragm NMJ are relevant long-term targets

Age-related cell cycle kinetics in the stimulated mouse vaginal epithelium

The cell cycle of the vaginal epithelium of castrated mice after an estrogenic stimulation has been investigated in adult and in aged animals. In aged animals, some cells (at least the first entering S-phase in response to the stimulus) remain able to react and to complete the prereplicative phase as fast as in younger animals. The dose of the stimulus has an all-or-nothing effect on the triggering of the response, and the critical dose value does not change with age. The only age effect suggested here is a lower proportion of cells synthesizing DNA in response to the stimulus, indicating an enhanced variability in the responding times of the individual cells.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Effect of aging on the morphology and function of the thyroid gland of the cream hamster - Further evidence for two different mechanisms of hormone secretion

The effect of aging on the morphology and function of the thyroid gland of the cream hamster was studied by light and electron microscopy coupled with autoradiography or histochemistry. Morphologically, aging induces an accumulation of lysosomal dense bodies and a loss of the phagocytosis of colloid droplets after stimulation with TSH. Iodine uptake and organification occur normally and thyroglobulin synthesis, estimated by autoradiography with 3H-leucine, is not different from that observed in young animals. The basal T4 and T3 plasma levels are lower in the old animals. A low iodine diet administered for several months prevents the age related accumulation of lysosomal dense bodies. Hormone secretion seems to proceed by two different mechanisms; phagocytosis of colloid droplets, the classical mechanism that decreases with age, and an additional mechanism, probably micropinocytosis, that is maintained during the whole lifespan. © 1981 Springer-Verlag.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Effect of aging on the proliferative activity of renewing cell populations after a specific stimulus

In adult organisms, specific stimuli of the proliferative activity of most renewing cell populations produce a burst of cells passing from G1-phase into S-phase (or from G2 into the mitotic phase for some cell types). As aging modifies some cell kinetic parameters, we investigated whether the timing and/or the magnitude of the response to specific stimuli is also changed. Our results suggest that, when exposed to a proper stimulus, the germinative cell population of the vaginal epithelium of castrated mice is able to increase its proliferative activity after the same time-lag and apparently to the same extent in old as in adult animals. This suggests that the capacity of renewing cell populations to respond to regulatory signals of their proliferative activity can be preserved with aging.SCOPUS: NotDefined.jinfo:eu-repo/semantics/publishe

Glycogen synthase kinase-3beta and the p25 activator of cyclin dependent kinase 5 increase pausing of mitochondria in neurons.

The complex bi-directional axoplasmic transport of mitochondria is essential for proper metabolic functioning of neurons and is controlled by phosphorylation. We have investigated by time-lapse imaging the effects of increased expression of glycogen synthase kinase-3beta (GSK-3beta) and of the p25 activator of cyclin dependent kinase 5 on mitochondria movements in mammalian cortical neurons and in PC12 cells. Both GSK-3beta and p25 increased the stationary behaviour of mitochondria in PC12 and in neurons, decreased their anterograde transport but did not affect the intrinsic velocities of mitochondria. The microtubule-associated tau proteins were more phosphorylated in GSK-3beta and p25 transfected neurons, but ultrastructural observation showed that these cells still contained microtubules and nocodazole treatment further reduced residual mitochondria movements in GSK-3beta or p25 transfected neurons, indicating that microtubule disruption was not the primary cause of increased mitochondrial stationary behaviour in GSK-3beta or p25 transfected neurons. Our results suggest that increased expression of GSK-3beta and p25 acted rather by decreasing the frequency of mitochondrial movements driven by molecular motors and that GSK-3beta and p25 might regulate these transports by controlling the time that mitochondria spend pausing, rather than their velocities.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Systemic effects of N,N-dimethyl-paraphenylenediamine hydrochloride on phosphate metabolism in innervated and denervated, slow and fast muscles of the rat

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Glande thyroïde et vieillissement: répercussion sur la fonction sécrétoire.

English AbstractJournal Articleinfo:eu-repo/semantics/publishe

Age delays thyroglobulin progression towards dense lysosomes in the cream hamster thyroid

We have shown that large lysosomes appear in thyroids of aging male cream hamsters. To investigate the role of this lysosomal change in the age-dependent reduction in hormone secretion, thyroids of young ( 22 months of age) male and female hamsters were labeled with 125I at near isotopic equilibrium. Changes in thyroid morphology were analyzed by light- and electron-microscopic morphometry. Changes in thyroglobulin processing were analyzed by subcellular fractionation and identification of 125I-compounds by sucrose gradients and reverse-phase high-pressure liquid chromatography (HPLC). Sexual dimorphism present in thyroids of young animals became more marked upon aging. The parallel increase in thyroid weight and thyroglobulin content was more conspicuous in old females than in old males. Two morphological observations were specific to old females: (1) large follicles with flat epithelium and evenly labeled colloid and (2) deposits of amyloid material (possibly immunoglobulin light chain-related) between follicles. Although lysosomes were enlarged in female and male aged thyroids, they did not accumulate iodine. However, after isopycnic centrifugation of crude lysosomal fractions in Percoll gradients, 125I in old thyroids was not distributed mainly in the dense fraction L1 (lysosomes) as in young thyroids, but partly in particles of lower density (light L2 and buoyant fractions). 125I in the lighter particles was mostly found in intact thyroglobulin and in large iodopeptides. This 125I shift towards less dense particles was more marked in females than in males. These results indicate that age delays thyroglobulin progression towards dense lysosomes and suggest that the slower traffic of thyroglobulin in the endocytic pathway contributes to the reduction in thyroid hormone secretion in the aged cream hamster.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

The active form of glycogen synthase kinase-3beta is associated with granulovacuolar degeneration in neurons in Alzheimer's disease.

Glycogen synthase kinase-3beta (GSK-3beta) is a physiological kinase for tau and is a candidate protein kinase involved in the hyperphosphorylation of tau present in paired helical filament (PHF)-tau of neurofibrillary tangles (NFT) in Alzheimer's disease (AD). GSK-3beta is also a key element of several signaling cascades (including cell death cascades). We have investigated the immunocytochemical localization of GSK-3 immunoreactivity in AD. Neurons exhibiting strongly GSK-3-immunoreactive granules were observed in AD, with a much higher frequency than in control subjects. This immunoreactivity was found to co-localize with the granulovacuolar degeneration (GVD) and to be associated with the granules of the granulovacuolar bodies. The GVD granules showed a strong GSK-3alpha and GSK-3beta immunoreactivity, and this immunoreactivity was abolished by preabsorption with recombinant GSK-3. In addition, the GVD immunoreactivity was observed with an antibody against the tyrosine-phosphorylated and active form of GSK-3. Some granules of the granulovacuolar degeneration were also intensely labeled with an antibody specific for tau isoforms containing insert 1 (exon 2) and with antibodies specific for tau phosphorylated on Ser262 and for tau phosphorylated on Thr212/Ser214, two phosphorylation sites generated in vitro by GSK-3alpha and beta. GSK-3beta was expressed in neurons containing NFT but only a small proportion of intracellular NFT were observed to be GSK-3beta immunoreactive. Immunoblotting analysis of fractions enriched in PHF-tau did not reveal any GSK-3beta immunoreactivity in these fractions, indicating that GSK-3beta was only loosely associated to NFT. These results suggest that neurons developing GVD sequester an active, potentially deleterious, form of GSK-3 in this compartment and that increased GSK-3 immunoreactivity in a subset of neurons quantitatively differentiates normal aging from AD.In VitroJournal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

C9 Tau et toxicité de l’amyloïde Aß dans les modèles transgéniques APP

info:eu-repo/semantics/publishe