Neutral Sphingomyelinase is an Affective Valence-Dependent Regulator of Learning and Memory

2020 ◽  
Author(s):  
Liubov S Kalinichenko ◽  
Laila Abdel-Hafiz ◽  
An-Li Wang ◽  
Christiane Mühle ◽  
Nadine Rösel ◽  
...  
Keyword(s):  
Learning And Memory ◽  
Behavioral Plasticity ◽  
De Novo ◽  
Positive Association ◽  
Superior Performance ◽  
Affective Valence ◽  
Neutral Sphingomyelinase ◽  
Healthy Humans

Abstract Sphingolipids and enzymes of the sphingolipid rheostat determine synaptic appearance and signaling in the brain, but sphingolipid contribution to normal behavioral plasticity is little understood. Here we asked how the sphingolipid rheostat contributes to learning and memory of various dimensions. We investigated the role of these lipids in the mechanisms of two different types of memory, such as appetitively and aversively motivated memory, which are considered to be mediated by different neural mechanisms. We found an association between superior performance in short- and long-term appetitively motivated learning and regionally enhanced neutral sphingomyelinase (NSM) activity. An opposite interaction was observed in an aversively motivated task. A valence-dissociating role of NSM in learning was confirmed in mice with genetically reduced NSM activity. This role may be mediated by the NSM control of N-methyl-d-aspartate receptor subunit expression. In a translational approach, we confirmed a positive association of serum NSM activity with long-term appetitively motivated memory in nonhuman primates and in healthy humans. Altogether, these data suggest a new sphingolipid mechanism of de-novo learning and memory, which is based on NSM activity.

scholarly journals Neutral ceramidase is a marker for cognitive performance in rats and monkeys

2020 ◽  
Author(s):  
Liubov S. Kalinichenko ◽  
An-Li Wang ◽  
Christiane Mühle ◽  
Laila Abdel-Hafiz ◽  
Erich Gulbins ◽  
...  
Keyword(s):  
Behavioral Plasticity ◽  
Memory Performance ◽  
Superior Performance ◽  
Long Term Memory ◽  
Term Memory ◽  
Object Memory ◽  
Predictive Role ◽  
Short And Long Term

Abstract Background Ceramides are lipid molecules determining cell integrity and intercellular signaling, and thus, involved in the pathogenesis of several psychiatric and neurodegenerative disorders. However, little is known about the role of particular enzymes of the ceramide metabolism in the mechanisms of normal behavioral plasticity. Here, we studied the contribution of neutral ceramidase (NC), one of the main enzymes mediating ceramide degradation, in the mechanisms of learning and memory in rats and non-human primates. Methods Naïve Wistar rats and black tufted-ear marmosets (Callithrix penicillata) were tested in several tests for short- and long-term memory and then divided into groups with various memory performance. The activities of NC and acid ceramidase (AC) were measured in these animals. Additionally, anxiety and depression-like behavior and brain levels of monoamines were assessed in the rats. Results We observed a predictive role of NC activity in the blood serum for superior performance of long-term object memory tasks in both species. A brain area analysis suggested that high NC activity in the ventral mesencephalon (VM) predicts better short-term memory performance in rats. High NC activity in the VM was also associated with worse long-term object memory, which might be mediated by an enhanced depression-like state and a monoaminergic imbalance. Conclusions Altogether, these data suggest a role for NC in short- and long-term memory of various mammalian species. Serum activity of NC may possess a predictive role in the assessing the performance of certain types of memory.

scholarly journals The Role of mTOR Inhibitors in Liver Transplantation: Reviewing the Evidence

2014 ◽  
Vol 2014 ◽  
pp. 1-45 ◽  
Author(s):  
Goran B. Klintmalm ◽  
Björn Nashan
Keyword(s):  
Metabolic Syndrome ◽  
Liver Transplantation ◽  
Renal Function ◽  
De Novo ◽  
Immunosuppressive Agents ◽  
Mammalian Target Of Rapamycin ◽  
Calcineurin Inhibitors ◽  
Mtor Inhibitors

Despite the success of liver transplantation, long-term complications remain, includingde novomalignancies, metabolic syndrome, and the recurrence of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC). The current mainstay of treatment, calcineurin inhibitors (CNIs), can also worsen posttransplant renal dysfunction, neurotoxicity, and diabetes. Clearly there is a need for better immunosuppressive agents that maintain similar rates of efficacy and renal function whilst minimizing adverse effects. The mammalian target of rapamycin (mTOR) inhibitors with a mechanism of action that is different from other immunosuppressive agents has the potential to address some of these issues. In this review we surveyed the literature for reports of the use of mTOR inhibitors in adult liver transplantation with respect to renal function, efficacy, safety, neurological symptoms,de novotumors, and the recurrence of HCC and HCV. The results of our review indicate that mTOR inhibitors are associated with efficacy comparable to CNIs while having benefits on renal function in liver transplantation. We also consider newer dosing schedules that may limit side effects. Finally, we discuss evidence that mTOR inhibitors may have benefits in the oncology setting and in relation to HCV-related allograft fibrosis, metabolic syndrome, and neurotoxicity.

scholarly journals Isoflurane Is More Deleterious to Developing Brain Than Desflurane: The Role of the Akt/GSK3βSignaling Pathway

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Guorong Tao ◽  
Qingsheng Xue ◽  
Yan Luo ◽  
Guohui Li ◽  
Yimeng Xia ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Learning And Memory ◽  
Pediatric Anesthesia ◽  
Developmental Neurotoxicity ◽  
Developing Brain ◽  
Spatial Learning And Memory ◽  
Postnatal Exposure ◽  
Multiple Exposures

Demand is increasing for safer inhalational anesthetics for use in pediatric anesthesia. In this regard, researchers have debated whether isoflurane is more toxic to the developing brain than desflurane. In the present study, we compared the effects of postnatal exposure to isoflurane with those of desflurane on long-term cognitive performance and investigated the role of the Akt/GSK3βsignaling pathway. Postnatal day 6 (P6) mice were exposed to either isoflurane or desflurane, after which the phosphorylation levels of Akt/GSK3βand learning and memory were assessed at P8 or P31. The phosphorylation levels of Akt/GSK3βand learning and memory were examined after intervention with lithium. We found that isoflurane, but not desflurane, impaired spatial learning and memory at P31. Accompanied by behavioral change, only isoflurane decreased p-Akt (ser473) and p-GSK3β(ser9) expressions, which led to GSK3βoveractivation. Lithium prevented GSK3βoveractivation and alleviated isoflurane-induced cognitive deficits. These results suggest that isoflurane is more likely to induce developmental neurotoxicity than desflurane in context of multiple exposures and that the Akt/GSK3βsignaling pathway partly participates in this process. GSK3βinhibition might be an effective way to protect against developmental neurotoxicity.

scholarly journals A Novel Role of IGF1 in Apo2L/TRAIL-Mediated Apoptosis of Ewing Tumor Cells

Sarcoma ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Frans van Valen ◽  
Henning Harrer ◽  
Marc Hotfilder ◽  
Uta Dirksen ◽  
Thomas Pap ◽  
...  
Keyword(s):  
De Novo ◽  
Fumonisin B1 ◽  
Chemotherapeutic Agents ◽  
Ceramide Synthase ◽  
Short Term ◽  
Igf1 Receptor ◽  
Induced Apoptosis ◽  
Survival Effect

Insulin-like growth factor 1 (IGF1) reputedly opposes chemotoxicity in Ewing sarcoma family of tumor (ESFT) cells. However, the effect of IGF1 on apoptosis induced by apoptosis ligand 2 (Apo2L)/tumor necrosis factor (TNF-) related apoptosis-inducing ligand (TRAIL) remains to be established. We find that opposite to the partial survival effect of short-term IGF1 treatment, long-term IGF1 treatment amplified Apo2L/TRAIL-induced apoptosis in Apo2L/TRAIL-sensitive but not resistant ESFT cell lines. Remarkably, the specific IGF1 receptor (IGF1R) antibodyα-IR3 was functionally equivalent to IGF1. Short-term IGF1 incubation of cells stimulated survival kinase AKT and increased X-linked inhibitor of apoptosis (XIAP) protein which was associated with Apo2L/TRAIL resistance. In contrast, long-term IGF1 incubation resulted in repression of XIAP protein through ceramide (Cer) formation derived from de novo synthesis which was associated with Apo2L/TRAIL sensitization. Addition of ceramide synthase (CerS) inhibitor fumonisin B1 during long-term IGF1 treatment reduced XIAP repression and Apo2L/TRAIL-induced apoptosis. Noteworthy, the resistance to conventional chemotherapeutic agents was maintained in cells following chronic IGF1 treatment. Overall, the results suggest that chronic IGF1 treatment renders ESFT cells susceptible to Apo2L/TRAIL-induced apoptosis and may have important implications for the biology as well as the clinical management of refractory ESFT.

scholarly journals Inherited human IRAK-1 deficiency selectively impairs TLR signaling in fibroblasts

2017 ◽  
Vol 114 (4) ◽  
pp. E514-E523 ◽  
Author(s):  
Erika Della Mina ◽  
Alessandro Borghesi ◽  
Hao Zhou ◽  
Salim Bougarn ◽  
Sabri Boughorbel ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
De Novo ◽  
Interleukin 1 ◽  
Toll Like Receptor ◽  
Peripheral Blood Mononuclear ◽  
Bacterial Diseases ◽  
Clinical Consequences ◽  
Redundant Role

Most members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) families transduce signals via a canonical pathway involving the MyD88 adapter and the interleukin-1 receptor-associated kinase (IRAK) complex. This complex contains four molecules, including at least two (IRAK-1 and IRAK-4) active kinases. In mice and humans, deficiencies of IRAK-4 or MyD88 abolish most TLR (except for TLR3 and some TLR4) and IL-1R signaling in both leukocytes and fibroblasts. TLR and IL-1R responses are weak but not abolished in mice lacking IRAK-1, whereas the role of IRAK-1 in humans remains unclear. We describe here a boy with X-linked MECP2 deficiency-related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1. Like many boys with MECP2 null mutations, this child died very early, at the age of 7 mo. Unlike most IRAK-4– or MyD88-deficient patients, he did not suffer from invasive bacterial diseases during his short life. The IRAK-1 protein was completely absent from the patient’s fibroblasts, which responded very poorly to all TLR2/6 (PAM2CSK4, LTA, FSL-1), TLR1/2 (PAM3CSK4), and TLR4 (LPS, MPLA) agonists tested but had almost unimpaired responses to IL-1β. By contrast, the patient’s peripheral blood mononuclear cells responded normally to all TLR1/2, TLR2/6, TLR4, TLR7, and TLR8 (R848) agonists tested, and to IL-1β. The death of this child precluded long-term evaluations of the clinical consequences of inherited IRAK-1 deficiency. However, these findings suggest that human IRAK-1 is essential downstream from TLRs but not IL-1Rs in fibroblasts, whereas it plays a redundant role downstream from both TLRs and IL-1Rs in leukocytes.

Adult Neurogenesis in the Songbird: Region-Specific Contributions of New Neurons to Behavioral Plasticity and Stability

2016 ◽  
Vol 87 (3) ◽  
pp. 191-204 ◽  
Author(s):  
Carolyn L. Pytte
Keyword(s):  
Behavioral Plasticity ◽  
Brain Regions ◽  
Long Term Storage ◽  
Behavioral Stability ◽  
New Information ◽  
Neuron Function ◽  
Motor Production ◽  
Term Storage

Our understanding of the role of new neurons in learning and encoding new information has been largely based on studies of new neurons in the mammalian dentate gyrus and olfactory bulb - brain regions that may be specialized for learning. Thus the role of new neurons in regions that serve other functions has yet to be fully explored. The song system provides a model for studying new neuron function in brain regions that contribute differently to song learning, song auditory discrimination, and song motor production. These regions subserve learning as well as long-term storage of previously learned information. This review examines the differences between learning-based and activity-based retention of new neurons and explores the potential contributions of new neurons to behavioral stability in the song motor production pathway.

scholarly journals Candida albicans and Bacterial Microbiota Interactions in the Cecum during Recolonization following Broad-Spectrum Antibiotic Therapy

2012 ◽  
Vol 80 (10) ◽  
pp. 3371-3380 ◽  
Author(s):  
Katie L. Mason ◽  
John R. Erb Downward ◽  
Kelly D. Mason ◽  
Nicole R. Falkowski ◽  
Kathryn A. Eaton ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Bacterial Diversity ◽  
Vital Role ◽  
Gi Tract ◽  
Content Type ◽  
Healthy Humans ◽  
Life Threatening Illness ◽  
Bacterial Microbiota

ABSTRACTCandida albicansis a normal member of the gastrointestinal (GI) tract microbiota of healthy humans, but during host immunosuppression or alterations in the bacterial microbiota,C. albicanscan disseminate and cause life-threatening illness. The bacterial microbiome of the GI tract, including lactic acid bacteria (LAB), plays a vital role in preventing fungal invasion. However, little is known about the role ofC. albicansin shaping the bacterial microbiota during antibiotic recovery. We investigated the fungal burdens in the GI tracts of germfree mice and mice with a disturbed microbiome to demonstrate the role of the microbiota in preventingC. albicanscolonization. Histological analysis demonstrated that colonization withC. albicansduring antibiotic treatment does not trigger overt inflammation in the murine cecum. Bacterial diversity is reduced long term following cefoperazone treatment, but the presence ofC. albicansduring antibiotic recovery promoted the recovery of bacterial diversity. Cefoperazone diminishesBacteroidetespopulations long term in the ceca of mice, but the presence ofC. albicansduring cefoperazone recovery promotedBacteroidetespopulation recovery. However, the presence ofC. albicansresulted in a long-term reduction inLactobacillusspp. and promotedEnterococcus faecalispopulations. Previous studies have focused on the ability of bacteria to alterC. albicans; this study addresses the ability ofC. albicansto alter the bacterial microbiota during nonpathogenic colonization.

scholarly journals Cholesterol and Copper Affect Learning and Memory in the Rabbit

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Bernard G. Schreurs
Keyword(s):  
Learning And Memory ◽  
Rabbit Model ◽  
Dietary Cholesterol ◽  
Long Term Memory ◽  
Cholesterol Diet ◽  
Term Memory ◽  
Model Of Alzheimer’S Disease ◽  
Amyloid Accumulation

A rabbit model of Alzheimer’s disease based on feeding a cholesterol diet for eight weeks shows sixteen hallmarks of the disease including beta amyloid accumulation and learning and memory changes. Although we have shown that feeding 2% cholesterol and adding copper to the drinking water can retard learning, other studies have shown that feeding dietary cholesterol before learning can improve acquisition and feeding cholesterol after learning can degrade long-term memory. We explore the development of this model, the issues surrounding the role of copper, and the particular contributions of the late D. Larry Sparks.

scholarly journals Ceramide sensitizes astrocytes to oxidative stress: protective role of cannabinoids

2004 ◽  
Vol 380 (2) ◽  
pp. 435-440 ◽  
Author(s):  
Arkaitz CARRACEDO ◽  
Math J. H. GEELEN ◽  
María DIEZ ◽  
Kentaro HANADA ◽  
Manuel GUZMÁN ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
De Novo ◽  
Glioma Cells ◽  
Protective Role ◽  
Dependent Manner ◽  
Ceramide Synthesis ◽  
Ceramide Accumulation ◽  
Stimulation Of

Cannabinoids induce apoptosis on glioma cells via stimulation of ceramide synthesis de novo, whereas they do not affect viability of primary astrocytes. In the present study, we show that incubation with Δ9-tetrahydrocannabinol did not induce accumulation of ceramide on astrocytes, although incubation of these cells in a serum-free medium (with or without cannabinoids) led to stimulation of ceramide synthesis de novo and sensitization to oxidative stress. Thus treatment with H2O2 induced apoptosis of 5-day-serum-deprived astrocytes and this effect was abrogated by pharmacological blockade of ceramide synthesis de novo. The sensitizing effect of ceramide accumulation may depend on p38 mitogen-activated protein kinase activation rather than on other ceramide targets. Finally, a protective role of cannabinoids on astrocytes is shown as a long-term incubation with cannabinoids prevented H2O2-induced loss of viability in a CB1 receptor-dependent manner. In summary, our results show that whereas challenge of glioma cells with cannabinoids induces accumulation of de novo-synthesized ceramide and apoptosis, long-term treatment of astrocytes with these compounds does not stimulate this pathway and also abrogates the sensitizing effects of ceramide accumulation.

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