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Results for “induced neurons”

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At least 19 recordsLinked to original sources
PubMed1976

Metabolic control of respiratory neuronal activity and the accompanying changes in breathing movements of the rabbit. III. Phase shifts in respiratory neurons induced by inflation and collapse of the lung, hyperventilation, or metabolic modifiers.

Phase shifts between inspiratory-related and expiratory-related discharge patterns can be reversibly induced in respiratory neurons following volume changes of the lung, hypocapnic apnea as a result of hyperventilation, or superfusion with certain metabolic modifiers. Phase-spanning expiratory-inspiratory or inspiratory-expiratory discharges are frequently induced in those neurons which are activated either by pulmonary stretch receptors or collapse afferents. The same is true for regulatory effectors which activate key steps of the neuronal metabolism such as ADP, 3-phosphoglycerate, L-glutamine, fructose-6-phosphate and fructose-1,6-diphosphate. In contrast, inhibitory vagal inputs or superfusion with citrate, an inhibitory metabolic modifier, revert preexisting expiratory-inspiratory discharges into a phase-coupled inspiratory pattern. It is postulated that the respiratory neuronal networks represents a time-optimal control system which strives to adjust to a new equilibrium value in a minimum of time, following a given mechanical or chemical perturbation. Following the hypothesis advanced by Cohen (1974) that the phase-spanning units modulate the activity of the in-phase neurons, it is suggested that the additional recruitment of expiratory-inspiratory and inspiratory-expiratory units provides a measure of the quality of time-optimal control and hence a performance index of the system.

Animals↗
PubMed2024

A Transcriptional Signature of Induced Neurons Differentiates Virologically Suppressed People Living With HIV from People Without HIV.

Neurocognitive impairment is a prevalent and important co-morbidity in virologically suppressed people living with HIV (PLWH), yet the underlying mechanisms remain elusive and treatments lacking. Here, we explored for the first time, use of participant-derived directly induced neurons (iNs) to model neuronal biology and injury in PLWH. iNs retain age- and disease-related features of the donors, providing unique opportunities to reveal novel aspects of neurological disorders. We obtained primary dermal fibroblasts from six virologically suppressed PLWH (range: 27 - 64 years, median: 53); 83% Male; 50% White) and seven matched people without HIV (PWOH) (range: 27 - 66, median: 55); 71% Male; 57% White). iNs were generated using transcription factors NGN2 and ASCL1, and validated by immunocytochemistry and single-cell-RNAseq. Transcriptomic analysis using bulk-RNAseq identified 29 significantly differentially expressed genes between iNs from PLWH and PWOH. Of these, 16 genes were downregulated and 13 upregulated in PLWH iNs. Protein-protein interaction network mapping indicates that iNs from PLWH exhibit differences in extracellular matrix organization and synaptic transmission. IFI27 was upregulated in iNs from PLWH, which complements independent post-mortem studies demonstrating elevated IFI27 expression in PLWH-derived brain tissue, indicating that iN generation reconstitutes this pathway. Finally, we observed that expression of the FOXL2NB-FOXL2-LINC01391 genome locus is reduced in iNs from PLWH and negatively correlates with neurocognitive impairment. Thus, we have identified an iN gene signature of HIV through direct reprogramming of skin fibroblasts into neurons revealing novel mechanisms of neurocognitive impairment in PLWH.

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PubMed1979

Analysis of fast axoplasmic transport in nerve ligation and adriamycin-induced neuronal perikaryon lesions.

Fast axoplasmic transport was examined in experimental nerve ligation and adriamycin-induced neuronal perikaryon lesions. Animals were sacrificed at precisely 3 and 4 h following the injection of [3H]leucine. In single ligated nerves, the 3 and 4 h down-flow rates, which include the time for neuronal processing of labelled material, were 379.2 +/- 23.51 and 370.8 +/- 26.93 mm/day, respectively, compared to the calculated rate of fast axoplasmic transport of 345.6 +/- 25.22 mm/day. In double-ligated nerves the down-flow rates were 364.8 +/- 40.32 and 342 +/- 32.2 mm/day, respectively, while the fast axoplasmic transport rate was 273.6 +/- 36.16 mm/day. In contrast, in adriamycin toxicity the down-flow rates were 363.9 +/- 21.54 and 378 +/- 14.69 mm/day with a normal calculated rate of fast axoplasmic transport of 420 +/- 18 mm/day. These studies illustrate that evaluation of two (or more) different time intervals can be used to assess the site of impaired delivery of labelled materials to the peripheral portions of the nerve. Furthermore, a single time interval examination of transport should not be equated with axoplasmic transport especially under pathological conditions.

Animals↗
PubMed2025

Transcriptional signature of induced neurons differentiates virologically suppressed people with HIV from people without HIV.

Neurocognitive impairment is a prevalent comorbidity in virologically suppressed people living with HIV (PLWH), yet the underlying mechanisms remain elusive and treatments lacking. We explored use of participant-derived directly induced neurons (iNs) to model neuronal biology and injury in PLWH. iNs retain age- and disease-related donor features, providing unique opportunities to reveal important aspects of neurological disorders. We obtained primary dermal fibroblasts from 6 virologically suppressed PLWH and 7 matched people without HIV (PWOH). iNs were generated using transcription factors NGN2 and ASCL1 and validated by immunocytochemistry, single-cell RNA-Seq, and electrophysiological recordings. Transcriptomic aging analyses confirmed retention of donor age-related signatures. Bulk RNA-Seq identified 29 significantly differentially expressed genes between PLWH and PWOH iNs. Of these, 16 were downregulated and 13 upregulated in PLWH iNs. Protein-protein interaction network mapping indicated iNs from PLWH exhibited differences in extracellular matrix organization and synaptic transmission. IFI27 was upregulated in PLWH iNs, complementing independent postmortem studies demonstrating elevated IFI27 expression in PLWH-derived brain tissue. FOXL2NB-FOXL2-LINC01391 expression was reduced in PLWH iNs and negatively correlated with neurocognitive impairment. Thus, we identified an iN gene signature of HIV revealing mechanisms of neurocognitive impairment in PLWH.

Humans↗
PubMed2026

A human lysosomal storage disorder toolkit for decoding proteome landscapes in cortical-like and dopaminergic-like induced neurons.

Lysosomes maintain cellular homeostasis by degrading proteins delivered via endocytosis and autophagy and by recycling building blocks for organelle biogenesis. Lysosomal storage disorders (LSDs) comprise a group of diseases affecting diverse lysosomal functions. To facilitate molecular phenotyping across diverse LSD gene classes, we are developing a library of human embryonic stem cells engineered to lack individual LSD genes as a resource for the field. Here, we report our initial stem cell toolkit lacking one of 23 LSD genes, including the majority of genes associated with sphingolipidoses and neuronal ceroid lipofuscinoses, and its use in the generation of a proteomic resource for induced cortical-like and midbrain dopaminergic-like neurons. In-depth abundance and correlation profiling across organelles and suborganelle components revealed potential vulnerabilities that reflect distinct patterns of proteome alterations across both genotypes and neuronal cell types. We characterize alterations in the mitochondrial proteome associated with GBA1 and ASAH1 deficiency and identify synaptic and mitochondrial defects in ASAH1-/- induced neurons that correlate with defects in neuronal firing rates. Moreover, we developed an informatic pipeline for proteome-wide identification of individual protein-protein interactions and protein complexes that may be disrupted as a result of LSD gene deficiency. Finally, we visualized structural alterations of ASAH1-deficient endolysosomes in situ using cryoelectron tomography, revealing swollen organelles that were largely devoid of dense internal membranes characteristic of wild-type cells, but containing numerous intralumenal vesicle compartments. This toolkit and associated proteomic landscapes provide a resource for defining molecular signatures associated with LSD gene dysfunction and organelle vulnerability.

Humans↗
PubMed1978

Selective degeneration of chemosensitive primary sensory neurones induced by capsaicin: glial changes.

Capsaicin treatment of newborn rats results in the degeneration of primary sensory neurones involved in the mediation of chemogenic pain. In the present study glial changes following the pharmacologically-induced degeneration of unmyelinated primary afferent fibres terminating in Rexed's laminae I and II of the spinal cord were investigated. Light microscopy revealed an increase in the number of phagocytic glial cells in this area, reaching a maximum at 24 h after the administration of capsaicin; they had almost completely disappeared by 72 h. At the ultrastructural level these cells were characterized by their elongate or irregular nuclei with a pronounced heterochromatin pattern, a moderately dense cytoplasmic matrix, hour-glass shaped mitochondria and very large numbers of heterogeneous dense bodies and lipid droplets. On the basis of these observations, these cells were considered to represent reactive microglial cells engaged in the phagocytosis of degenerated neuronal debris. The possible origin and mode of elimination of these elements from the central nervous tissue is briefly discussed.

Animals↗
PubMedDate not supplied

[Effect of precursors and cofactors of nucleic acid and protein synthesis on the response of cortical neurons induced by polarization].

Injection of K-orotate and folic acid in different proportions and of vitamine B12 produces changes in the S35-methionine inclusion in the proteins of the sensorimotor cortex, basal ganglia, hypothalamus and hippocampus depending on the proportions of the injected agents. In animals with activation of the synthesis in the brain, surface anode polarization increased the mean frequency of spike activity of the neurones in the sensorimotor cortex and reduced the relative number of units, which responded to polarization by inhibition, as compared with the control animals and those in which no activation of protein synthesis was observed. The characteristics of cortical unit responses to surface anode polarization in experimental rats are apparently due to changes in the chemoreactive properties of their membranes, which set in under the influence of changes in the nucleic acid and protein synthesis in these neurones.

Animals↗
PubMed1979

Ibotenic acid-induced neuronal degeneration: a morphological and neurochemical study.

Possible neurotoxic actions of intracerebral injections of ibotenic acid, a conformationally restricted analogue of glutamic acid, have been evaluated in rat brain and compared with those of kainic acid. Light microscopical analysis revealed that ibotenic acid produced a marked disappearance of nerve cells in all areas studied, namely striatum, the hippocampal formation, substantia nigra and piriform cortex. Lesions in areas distant to the injection site were not seen. Axons of passage and nerve terminals of extrinsic origin did not seem to be damaged, since, e.g., no apparent degeneration of the dopaminergic terminals in the neostriatum was observed except for a small area surrounding the cannula. In the neostriatum, enkephalin immunoreactive neuronal cell bodies as well as nerve terminals disappeared after injection of ibotenic acid into this nucleus. After injection into the substantia nigra tyrosine hydroxylase immunoreactive cell bodies in the zona compacta disappeared, whereas no certain effect could be seen on the enkephalin immunoreactive nerve fibers. In vitro experiments, conducted with striatal synaptosomal and membrane preparations, showed that ibotenic acid differed from kainic acid by being devoid of a significant inhibitory effect on high affinity glutamate uptake and by having a low affinity for 3H-kainic acid binding sites. Furthermore, ibotenic acid did not interfere with the binding of a number of radioligands for other transmitter receptors. As compared to kainic acid, ibotenic acid has the advantage of being less toxic to the animals and of producing more discrete lesions, possibly due to faster metabolism and/or other fundamental biochemical differences. Because of these special features, ibotenic acid seems to represent a valuable new tool in the morphological and functional analysis of central neuronal systems.

Animals↗
PubMed1979

Neuronal degeneration induced by stereotaxic injection of beta-bungarotoxin into rat brain.

The presynaptic protein neurotoxin beta-bungarotoxin (beta-bgt) caused degeneration of neurons, following stereotaxic administration into rat brain. Focal lesions were induced with as little as 0.1 ng (5 fmol) of beta-bgt; indicating that the toxin is over 10(6) times more potent than kainic acid. More extensive studies in the septo-hippocampal system showed beta-bgt lesions affected both cell bodies and nerve terminals and were not neurotransmitter-specific. The endogenous phospholipase A2 activity of beta-bgt did not simply account for the creation of lesions since an acidic phospholipase A isoenzyme from Vipera russellii was virtually inactive in causing neuronal damage.

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