Browse
Submit Data
Databases
API
Help

Dataset Information

23 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Transient Stimulation with Psychoplastogens Is Sufficient to Initiate Neuronal Growth.

ABSTRACT: Cortical neuron atrophy is a hallmark of depression and includes neurite retraction, dendritic spine loss, and decreased synaptic density. Psychoplastogens, small molecules capable of rapidly promoting cortical neuron growth, have been hypothesized to produce long-lasting positive effects on behavior by rectifying these deleterious structural and functional changes. Here we demonstrate that ketamine and LSD, psychoplastogens from two structurally distinct chemical classes, promote sustained growth of cortical neurons after only short periods of stimulation. Furthermore, we show that psychoplastogen-induced cortical neuron growth can be divided into two distinct epochs: an initial stimulation phase requiring TrkB activation and a growth period involving sustained mTOR and AMPA receptor activation. Our results provide important temporal details concerning the molecular mechanisms by which next-generation antidepressants produce persistent changes in cortical neuron structure, and they suggest that rapidly excreted psychoplastogens might still be effective neurotherapeutics with unique advantages over compounds like ketamine and LSD.

SUBMITTER: Ly C

PROVIDER: S-EPMC8033616 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Mutant IDH is sufficient to initiate enchondromatosis in mice.

Project description:Enchondromas are benign cartilage tumors and precursors to malignant chondrosarcomas. Somatic mutations in the isocitrate dehydrogenase genes (IDH1 and IDH2) are present in the majority of these tumor types. How these mutations cause enchondromas is unclear. Here, we identified the spectrum of IDH mutations in human enchondromas and chondrosarcomas and studied their effects in mice. A broad range of mutations was identified, including the previously unreported IDH1-R132Q mutation. These mutations harbored enzymatic activity to catalyze ?-ketoglutarate to d-2-hydroxyglutarate (d-2HG). Mice expressing Idh1-R132Q in one allele in cells expressing type 2 collagen showed a disordered growth plate, with persistence of type X-expressing chondrocytes. Chondrocyte cell cultures from these animals or controls showed that there was an increase in proliferation and expression of genes characteristic of hypertrophic chondrocytes with expression of Idh1-R132Q or 2HG treatment. Col2a1-Cre;Idh1-R132Q mutant knock-in mice (mutant allele expressed in chondrocytes) did not survive after the neonatal stage. Col2a1-Cre/ERT2;Idh1-R132 mutant conditional knock-in mice, in which Cre was induced by tamoxifen after weaning, developed multiple enchondroma-like lesions. Taken together, these data show that mutant IDH or d-2HG causes persistence of chondrocytes, giving rise to rests of growth-plate cells that persist in the bone as enchondromas.

| S-EPMC4352794 | biostudies-literature

Efferocytosis of apoptotic alveolar epithelial cells is sufficient to initiate lung fibrosis.

Project description:Type II alveolar epithelial cell (AEC) apoptosis is a prominent feature of fibrotic lung diseases and animal models of pulmonary fibrosis. While there is growing recognition of the importance of AEC injury and apoptosis as a causal factor in fibrosis, the underlying mechanisms that link these processes remain unknown. We have previously shown that targeting the type II alveolar epithelium for injury by repetitively administering diphtheria toxin to transgenic mice expressing the diphtheria toxin receptor off of the surfactant protein C promoter (SPC-DTR) develop lung fibrosis, confirming that AEC injury is sufficient to cause fibrosis. In the present study, we find that SPC-DTR mice develop increased activation of caspase 3/7 after initiation of diphtheria toxin treatment consistent with apoptosis within AECs. We also find evidence of efferocytosis, the uptake of apoptotic cells, by alveolar macrophages in this model. To determine the importance of efferocytosis in lung fibrosis, we treated cultured alveolar macrophages with apoptotic type II AECs and found that the uptake induced pro-fibrotic gene expression. We also found that the repetitive intrapulmonary administration of apoptotic type II AEC or MLE-12 cells induces lung fibrosis. Finally, mice lacking a key efferocytosis receptor, CD36, developed attenuated fibrosis in response to apoptotic MLE-12 cells. Collectively, these studies support a novel mechanism linking AEC apoptosis with macrophage pro-fibrotic activation via efferocytosis and reveal previously unrecognized therapeutic targets.

| S-EPMC6193049 | biostudies-literature

Recurrently connected and localized neuronal communities initiate coordinated spontaneous activity in neuronal networks.

Project description:Developing neuronal systems intrinsically generate coordinated spontaneous activity that propagates by involving a large number of synchronously firing neurons. In vivo, waves of spikes transiently characterize the activity of developing brain circuits and are fundamental for activity-dependent circuit formation. In vitro, coordinated spontaneous spiking activity, or network bursts (NBs), interleaved within periods of asynchronous spikes emerge during the development of 2D and 3D neuronal cultures. Several studies have investigated this type of activity and its dynamics, but how a neuronal system generates these coordinated events remains unclear. Here, we investigate at a cellular level the generation of network bursts in spontaneously active neuronal cultures by exploiting high-resolution multielectrode array recordings and computational network modelling. Our analysis reveals that NBs are generated in specialized regions of the network (functional neuronal communities) that feature neuronal links with high cross-correlation peak values, sub-millisecond lags and that share very similar structural connectivity motifs providing recurrent interactions. We show that the particular properties of these local structures enable locally amplifying spontaneous asynchronous spikes and that this mechanism can lead to the initiation of NBs. Through the analysis of simulated and experimental data, we also show that AMPA currents drive the coordinated activity, while NMDA and GABA currents are only involved in shaping the dynamics of NBs. Overall, our results suggest that the presence of functional neuronal communities with recurrent local connections allows a neuronal system to generate spontaneous coordinated spiking activity events. As suggested by the rules used for implementing our computational model, such functional communities might naturally emerge during network development by following simple constraints on distance-based connectivity.

| S-EPMC5549760 | biostudies-literature

One lyn molecule is sufficient to initiate phosphorylation of aggregated high-affinity IgE receptors.

Project description:In response to antigenic stimuli, the multisubunit immune recognition receptors become aggregated and then phosphorylated on their cytoplasmic tyrosines. For the clonotypic receptors of B and T cells and for Fc receptors such as the high-affinity receptor for IgE (FcepsilonRI), a Src family kinase initiates this phosphorylation. We ask whether aggregation of the initiating kinase itself is required for signal transduction or whether, alternatively, a single associated kinase molecule can phosphorylate the receptors in an aggregate. We formulate the alternative molecular mechanisms mathematically and compare predictions with experimental findings on FcepsilonRI-bearing cells expressing varying amounts of the transfected Src family kinase Lyn. The data are consistent with the requirement of only a single Lyn molecule per FcepsilonRI aggregate to initiate signaling and are inconsistent with a mechanism requiring more than one Lyn molecule.

| S-EPMC17565 | biostudies-literature

Stromal epigenetic dysregulation is sufficient to initiate mouse prostate cancer via paracrine Wnt signaling.

Project description:Carcinomas most often result from the stepwise acquisition of genetic alterations within the epithelial compartment. The surrounding stroma can also play an important role in cancer initiation and progression. Given the rare frequencies of genetic events identified in cancer-associated stroma, it is likely that epigenetic changes in the tumor microenvironment could contribute to its tumor-promoting activity. We use Hmga2 (High-mobility group AT-hook 2) an epigenetic regulator, to modify prostate stromal cells, and demonstrate that perturbation of the microenvironment by stromal-specific overexpression of this chromatin remodeling protein alone is sufficient to induce dramatic hyperplasia and multifocal prostatic intraepithelial neoplasia lesions from adjacent naïve epithelial cells. Importantly, we find that this effect is predominantly mediated by increased Wnt/?-catenin signaling. Enhancement of Hmga2-induced paracrine signaling by overexpression of androgen receptor in the stroma drives frank murine prostate adenocarcinoma in the adjacent epithelial tissues. Our findings provide compelling evidence for the critical contribution of epigenetic changes in stromal cells to multifocal tumorigenesis.

| S-EPMC3528570 | biostudies-literature

CD45 is sufficient to initiate EndMT in human endothelial cells

Project description:Bulk RNA-Seq revealed that activation of the endogenous CD45 promoter induced expression of several genes implicated in EndMT. CD45-positive endothelial cells showed significantly increased migration, a hallmark of EndMT, increased collagen gel contraction, a hallmark of mesenchymal cells, and decreased cell-cell barrier integrity, indicating reduced endothelial function.

2023-05-03 | GSE207837 | GEO

Rare individual amyloid-? oligomers act on astrocytes to initiate neuronal damage.

Project description:Oligomers of the amyloid-? (A?) peptide have been implicated in the neurotoxicity associated with Alzheimer's disease. We have used single-molecule techniques to examine quantitatively the cellular effects of adding well characterized A? oligomers to primary hippocampal cells and hence determine the initial pathway of damage. We found that even picomolar concentrations of A? (1-40) and A? (1-42) oligomers can, within minutes of addition, increase the levels of intracellular calcium in astrocytes but not in neurons, and this effect is saturated at a concentration of about 10 nM of oligomers. Both A? (1-40) and A? (1-42) oligomers have comparable effects. The rise in intracellular calcium is followed by an increase in the rate of ROS production by NADPH oxidase in both neurons and astrocytes. The increase in ROS production then triggers caspase-3 activation resulting in the inhibition of long-term potentiation. Our quantitative approach also reveals that only a small fraction of the oligomers are damaging and that an individual rare oligomer binding to an astrocyte can initiate the aforementioned cascade of responses, making it unlikely to be due to any specific interaction. Preincubating the A? oligomers with an extracellular chaperone, clusterin, sequesters the oligomers in long-lived complexes and inhibits all of the physiological damage, even at a ratio of 100:1, total A? to clusterin. To explain how A? oligomers are so damaging but that it takes decades to develop Alzheimer's disease, we suggest a model for disease progression where small amounts of neuronal damage from individual unsequestered oligomers can accumulate over time leading to widespread tissue-level dysfunction.

| S-EPMC4004235 | biostudies-literature

An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice.

Project description:Mutations in the gene encoding the p110? subunit of PI3K (PIK3CA) that result in enhanced PI3K activity are frequently observed in human cancers. To better understand the role of mutant PIK3CA in the initiation or progression of tumorigenesis, we generated mice in which a PIK3CA mutation commonly detected in human cancers (the H1047R mutation) could be conditionally knocked into the endogenous Pik3ca locus. Activation of this mutation in the mouse ovary revealed that alone, Pik3caH1047R induced premalignant hyperplasia of the ovarian surface epithelium but no tumors. Concomitantly, we analyzed several human ovarian cancers and found PIK3CA mutations coexistent with KRAS and/or PTEN mutations, raising the possibility that a secondary defect in a co-regulator of PI3K activity may be required for mutant PIK3CA to promote transformation. Consistent with this notion, we found that Pik3caH1047R mutation plus Pten deletion in the mouse ovary led to the development of ovarian serous adenocarcinomas and granulosa cell tumors. Both mutational events were required for early, robust Akt activation. Pharmacological inhibition of PI3K/mTOR in these mice delayed tumor growth and prolonged survival. These results demonstrate that the Pik3caH1047R mutation with loss of Pten is enough to promote ovarian cell transformation and that we have developed a model system for studying possible therapies.

| S-EPMC3266789 | biostudies-literature

Transient rRNA synthesis inhibition with CX-5461 is sufficient to elicit growth arrest and cell death in acute lymphoblastic leukemia cells.

Project description:Enhanced rRNA synthesis is a downstream effect of many of the signaling pathways that are aberrantly activated in cancer, such as the PI3K/mTOR and MAP kinase pathways. Recently, two new rRNA synthesis inhibitors have demonstrated therapeutic effects on cancer cells while sparing normal cells. One of them, CX-5461, is currently in phase 1 clinical trials for hematological malignancies. Here, we investigate the effectiveness of transient treatment with this drug on acute lymphoblastic leukemia cells. Our results show that short exposure to CX-5461 followed by drug washout is sufficient to induce persistent G2 cell-cycle arrest and irreversible commitment to cell death, in spite of rRNA synthesis returning to normal within 24 hours of drug washout. The magnitude of cell death after transient exposure is similar to continuous exposure, but the time to cell death is relatively delayed with transient exposure. In this report, we also investigate rational drug combinations that can potentiate the effect of continuous CX-5461 treatment. We show that the checkpoint abrogator UCN-01 can relieve CX-5461-induced G2 arrest and potentiate the cytotoxic effects of CX-5461. Finally, we show that ERK1/2 is activated upon CX-5461 treatment, and that pharmacological inhibition of MEK1/2 leads to enhanced cell death in combination with CX-5461. In summary, our results provide evidence for the effectiveness of CX-5461 pulse treatment, which may minimize drug related toxicity, and evidence for enhanced effectiveness of CX-5461 in combination with other targeted agents.

| S-EPMC4741494 | biostudies-literature

Neuronal Stimulation Triggers Neuronal Glycolysis and Not Lactate Uptake.

Project description:Proper brain function requires a substantial energy supply, up to 20% of whole-body energy in humans, and brain activation produces large dynamic variations in energy demand. While local increases in cerebral blood flow are well known, the cellular responses to energy demand are controversial. During brain excitation, glycolysis of glucose to lactate temporarily exceeds the rate of mitochondrial fuel oxidation; although the increased energy demand occurs mainly within neurons, some have suggested this glycolysis occurs mainly in astrocytes, which then shuttle lactate to neurons as their primary fuel. Using metabolic biosensors in acute hippocampal slices and brains of awake mice, we find that neuronal metabolic responses to stimulation do not depend on astrocytic stimulation by glutamate release, nor do they require neuronal uptake of lactate; instead they reflect increased direct glucose consumption by neurons. Neuronal glycolysis temporarily outstrips oxidative metabolism, and provides a rapid response to increased energy demand.

| S-EPMC5559896 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data