scholarly journals Environmental Enrichment Normalizes Hippocampal Timing Coding in a Malformed Hippocampus

2017 ◽  
Author(s):  
Amanda E. Hernan ◽  
J. Matthew Mahoney ◽  
Willie Curry ◽  
Greg Richard ◽  
Marcella M. Lucas ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Spatial Cognition ◽  
Environmental Enrichment ◽  
Pyramidal Neurons ◽  
Spatial Coherence ◽  
Spike Timing ◽  
Cognitive Outcome ◽  
List Type ◽  
Linear Modeling

ABSTRACTNeurodevelopmental insults such as malformations of cortical development (MCD) are a common cause of psychiatric disorders, learning impairments and epilepsy. Animals with MCDs have impairments in spatial cognition that, remarkably, are improved by post-weaning environmental enrichment (EE). To establish the network-level mechanisms responsible for these impacts, hippocampal in vivo single unit recordings were performed in freely moving animals in an open arena. We took a generalized linear modeling approach to extract fine spike timing (FST) characteristics and related these to place cell fidelity used as a surrogate of spatial cognition. We find that MCDs disrupt FST and place-modulated rate coding in hippocampal CA1 and that EE restores both to normal. Moreover, FST parameters predict spatial coherence of neurons, suggesting that mechanisms determining FST are critical for cognition. This suggests that FST parameters could represent a therapeutic target to improve cognition even in the context of a structurally abnormal brain.HIGHLIGHTSEnvironmental enrichment (EE) in rats with cortical malformations improves cognition.EE resolves impaired rate and timing coding of hippocampal pyramidal neurons.Taken together, circuit-level dynamics directly affect quality of the cognitive map.RESEARCH IN CONTEXTInsults during neurodevelopment, particularly those that result in physical malformations in the brain, lead to cognitive impairment, psychiatric disorders and epilepsy. Environmental enrichment (EE) improves cognitive outcome in patients and animal models with brain malformations. Understanding how EE can improve cognition at the level of neural networks can lead to new treatment targets. Remarkably, using an approach that mathematically models neuron firing we show that firing is mistimed in animals with malformations and that EE improves this abnormality. Importantly, timing abnormalities predict abnormalities in cognition at the single neuron level, suggesting that restoring timing could improve learning and memory deficits.

scholarly journals Microglia inhibition rescues developmental hypofrontality in a mouse model of mental illness

2018 ◽  
Author(s):  
Mattia Chini ◽  
Christoph Lindemann ◽  
Jastyn A. Pöpplau ◽  
Xiaxia Xu ◽  
Joachim Ahlbeck ◽  
...  
Keyword(s):  
Mental Illness ◽  
Cognitive Deficits ◽  
Pyramidal Neurons ◽  
List Type ◽  
Spine Density ◽  
Abnormal Rate ◽  
Hippocampal Networks ◽  
Local Circuits ◽  
Circuit Function

SUMMARYCognitive deficits, core features of mental illness, largely result from dysfunction of prefrontal-hippocampal networks. This dysfunction emerges already during early development, before a detectable behavioral readout, yet the cellular elements controlling the abnormal maturation are still unknown. Combining in vivo electrophysiology and optogenetics with neuroanatomy and pharmacology in neonatal mice mimicking the dual genetic - environmental etiology of psychiatric disorders, we identified pyramidal neurons in layer II/III of the prefrontal cortex as key elements causing disorganized oscillatory entrainment of local circuits in beta-gamma frequencies. Their abnormal firing rate and timing result from sparser dendritic arborization and lower spine density. Pharmacological modulation of aberrantly hyper-mature microglia rescues morphological, synaptic and functional neuronal deficits and restores the early circuit function. Elucidation of the cellular substrate of developmental miswiring related to later cognitive deficits opens new perspectives for identification of neurobiological targets, amenable to therapies.HighlightsMice mimicking the etiology of mental illness have dysregulated prefrontal networkStructural and synaptic deficits cause abnormal rate and timing of pyramidal firingWeaker activation of prefrontal circuits results from deficits of pyramidal neuronsRescue of microglial function restores developing prefrontal circuits

scholarly journals Environmental enrichment shapes striatal spike-timing-dependent plasticity in vivo

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Teresa Morera-Herreras ◽  
Yves Gioanni ◽  
Sylvie Perez ◽  
Gaetan Vignoud ◽  
Laurent Venance
Keyword(s):  
Failure Rate ◽  
Environmental Enrichment ◽  
Hebbian Learning ◽  
Learning Rule ◽  
Spike Timing ◽  
Long Term Effects ◽  
Spike Timing Dependent Plasticity ◽  
Temporal Window ◽  
Dependent Plasticity

AbstractBehavioural experience, such as environmental enrichment (EE), induces long-term effects on learning and memory. Learning can be assessed with the Hebbian paradigm, such as spike-timing-dependent plasticity (STDP), which relies on the timing of neuronal activity on either side of the synapse. Although EE is known to control neuronal excitability and consequently spike timing, whether EE shapes STDP remains unknown. Here, using in vivo long-duration intracellular recordings at the corticostriatal synapses we show that EE promotes asymmetric anti-Hebbian STDP, i.e. spike-timing-dependent-potentiation (tLTP) for post-pre pairings and spike-timing-dependent-depression (tLTD) for pre-post pairings, whereas animals grown in standard housing show mainly tLTD and a high failure rate of plasticity. Indeed, in adult rats grown in standard conditions, we observed unidirectional plasticity (mainly symmetric anti-Hebbian tLTD) within a large temporal window (~200 ms). However, rats grown for two months in EE displayed a bidirectional STDP (tLTP and tLTD depending on spike timing) in a more restricted temporal window (~100 ms) with low failure rate of plasticity. We also found that the effects of EE on STDP characteristics are influenced by the anaesthesia status: the deeper the anaesthesia, the higher the absence of plasticity. These findings establish a central role for EE and the anaesthetic regime in shaping in vivo, a synaptic Hebbian learning rule such as STDP.

LACK OF EFFECT OF CORTICOSTEROIDS ON THE IN VIVO DISAPPEARANCE OF SULFHYDRYL-INHIBITED AND ANTIBODY-COATED ERYTHROCYTES

1964 ◽  
Vol 47 (3_Suppl) ◽  
pp. S28-S36
Author(s):  
Kailash N. Agarwal
Keyword(s):  
Red Cells ◽  
List Type ◽  
Red Cell

ABSTRACT Red cells were incubated in vitro with sulfhydryl inhibitors and Rhantibody with and without prior incubation with prednisolone-hemisuccinate. These erythrocytes were labelled with Cr51 and P32 and their disappearance in vivo after autotransfusion was measured. Prior incubation with prednisolone-hemisuccinate had no effect on the rate of red cell disappearance. The disappearance of the cells was shown to take place without appreciable intravascular destruction.

STUDIES IN CONGENITAL GENERALIZED LIPODYSTROPHY

1973 ◽  
Vol 72 (3) ◽  
pp. 495-505 ◽  
Author(s):  
Oddmund Søvik ◽  
Svein Oseid
Keyword(s):  
Biological Activity ◽  
Insulin Response ◽  
Epididymal Adipose Tissue ◽  
Large Individual ◽  
Immunoreactive Insulin ◽  
List Type ◽  
Glucose Load ◽  
Congenital Generalized Lipodystrophy ◽  
The One

ABSTRACT The biological activity of plasma insulin from 4 cases of congenital generalized lipodystrophy has been studied, using rat diaphragm and epididymal adipose tissue in vivo. The results are compared with previous data on plasma immunoreactive insulin obtained in these patients. 2 of the 4 cases exhibited unusually high biological insulin activities during the fasting state as well as after an intravenous (iv) glucose load. In the fat pad assay activities as high as 10 000 μU insulin per ml were observed. During childhood the biological insulin activities were generally high, although there were large individual variations. However, in the one case studied after the age of puberty, the insulin response to a glucose load was negligible. Taken together, the biological and immunological activities observed strongly suggest the presence of pancreatic insulin in these patients. It appears that the circulating insulin has a fully biological activity. The decreasing insulin activities after cessation of growth are in agreement with the appearance of frank diabetes at this time.

scholarly journals Conditioned medium-preconditioned EPCs enhanced the ability in oligovascular repair in cerebral ischemia neonatal rats

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ning Zhou ◽  
Lei Wang ◽  
Ping Fu ◽  
Zihao Cui ◽  
Yuhang Ge ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Western Blot ◽  
Conditioned Medium ◽  
Cognitive Outcome ◽  
Adult Brain ◽  
Neonatal Rat ◽  
Vascular Density ◽  
Cxcr4 Axis

Abstract Background Oligovascular niche mediates interactions between cerebral endothelial cells and oligodendrocyte precursor cells (OPCs). Disruption of OPC-endothelium trophic coupling may aggravate the progress of cerebral white matter injury (WMI) because endothelial cells could not provide sufficient support under diseased conditions. Endothelial progenitor cells (EPCs) have been reported to ameliorate WMI in the adult brain by boosting oligovascular remodeling. It is necessary to clarify the role of the conditioned medium from hypoxic endothelial cells preconditioned EPCs (EC-pEPCs) in WMI since EPCs usually were recruited and play important roles under blood-brain barrier disruption. Here, we investigated the effects of EC-pEPCs on oligovascular remodeling in a neonatal rat model of WMI. Methods In vitro, OPC apoptosis induced by the conditioned medium from oxygen-glucose deprivation-injured brain microvascular endothelial cells (OGD-EC-CM) was analyzed by TUNEL and FACS. The effects of EPCs on EC damage and the expression of cytomokine C-X-C motif ligand 12 (CXCL12) were examined by western blot and FACS. The effect of the CM from EC-pEPCs against OPC apoptosis was also verified by western blot and silencing RNA. In vivo, P3 rat pups were subjected to right common carotid artery ligation and hypoxia and treated with EPCs or EC-pEPCs at P7, and then angiogenesis and myelination together with cognitive outcome were evaluated at the 6th week. Results In vitro, EPCs enhanced endothelial function and decreased OPC apoptosis. Meanwhile, it was confirmed that OGD-EC-CM induced an increase of CXCL12 in EPCs, and CXCL12-CXCR4 axis is a key signaling since CXCR4 knockdown alleviated the anti-apoptosis effect of EPCs on OPCs. In vivo, the number of EPCs and CXCL12 protein level markedly increased in the WMI rats. Compared to the EPCs, EC-pEPCs significantly decreased OPC apoptosis, increased vascular density and myelination in the corpus callosum, and improved learning and memory deficits in the neonatal rat WMI model. Conclusions EC-pEPCs more effectively promote oligovascular remodeling and myelination via CXCL12-CXCR4 axis in the neonatal rat WMI model.

734 A novel NQO1 specific anti-tumor agent, SBSC-S3001, selectively regresses the growth of tumors with high NQO1 expression

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A778-A778
Author(s):  
Minhyuk Yun ◽  
Goo-Young Kim ◽  
Sang Woo Jo ◽  
Changhoon In ◽  
Gyu-Young Moon ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Cancer Cells ◽  
Poor Prognosis ◽  
High Expression ◽  
List Type ◽  
Dependent Manner ◽  
Breast Cancers ◽  
Quinone Oxidoreductase ◽  
Key Enzymes

BackgroundNAD(P)H-quinone oxidoreductase 1 (NQO1) is a cytosolic two-electron oxidoreductase overexpressed in many types of cancers, including breast cancer, pancreatic cancer, colorectal cancer, cholangiocarcinoma, uterine cervical cancer, melanoma, and lung cancer.1Up-regulation of NQO1 protects cells from oxidative stress and various cytotoxic quinones and is associated with late clinical stage, poor prognosis and lymph node metastasis.2 3 NQO1 increases stability of HIF-1α protein, which has been implicated in survival, proliferation, and malignance of cancer.1 Therefore, accumulating evidences suggest NQO1 as a promising therapeutic target for cancer. Accordingly, we have characterized the effect of a novel synthetic NQO1 substrate SBSC-S3001, and demonstrated its selective cytotoxic effects in cancer cells with high expression of NQO1.MethodsIn vitro cytotoxicity was determined by sulforhodamine B (SRB) assay in cancer cells with high NQO1 expression and CRISPR-mediated NQO1 knockout cells. The effect of SBSC-S3001 on the energy metabolism pathway was evaluated by western blot analysis of metabolism associated proteins from NQO1-overexpressed cancer cells treated with the compound for 24 hours. In vivo anti-tumor activity was evaluated in MC38 syngeneic and DLD-1 orthotopic mice models.ResultsSBSC-S3001 exhibited selective cytotoxicity in cancer cells with high expression of NQO1 in a dose-dependent manner. The cytotoxicity was observed in both normoxia and hypoxia conditions, correlating with the energy metabolism, mitochondrial biogenesis, and cancer proliferative pathways. Also, stronger cytotoxicity was observed in NQO1-overexpressed cancer cells treated with SBSC-S3001 compared to beta-lapachone and analogue treatment.4 When evaluated in vivo, SBSC-S3001 effectively inhibited the growth of syngeneic and orthotopic tumors when administered as a monotherapy. SBSC-S3001 treatment associated with reduction in key enzymes of the glycolytic pathway (LDHa and GAPDH) and HIF-1α and increase in levels of mitochondrial oxidative phosphorylation (OXPHOS) complex.ConclusionsTreatment of SBSC-S3001, a novel, NQO1-specific substrate reduces HIF-1α and key enzymes associated with glycolysis and suppresses the growth of tumors overexpressing NQO1. Further characterization of SBSC-S3001 as a novel metabolic anti-cancer agent for cancers with NQO1 overexpression is warranted.Ethics ApprovalThe study was approved by Samyang Biopharmaceuticals Institution’s Ethics Board, approval number SYAU2031.ReferencesOh ET, Kim JW, Kim JMet. al., NQO1 inhibits proteasome-mediated degradation of HIF-1α. Nat Commun 2016; 14:13593.Ma, Y. et al. NQO1 overexpression is associated with poor prognosis in squamous cell carcinoma of the uterine cervix. BMC Cancer 2014;14: 414Yang, Y. et al. Clinical implications of high NQO1 expression in breast cancers. J. Exp. Clin. Cancer Res 2014;33:144.Yang Y, Zhou X, Xu M, et al., β-lapachone suppresses tumour progression by inhibiting epithelial-to-mesenchymal transition in NQO1-positive breast cancers. Sci Rep 2017;7:2681.

scholarly journals Dynamic modulation of spike timing-dependent calcium influx during corticostriatal upstates

2013 ◽  
Vol 110 (7) ◽  
pp. 1631-1645 ◽  
Author(s):  
R. C. Evans ◽  
Y. M. Maniar ◽  
K. T. Blackwell
Keyword(s):  
Synaptic Plasticity ◽  
Slow Wave Sleep ◽  
Calcium Influx ◽  
Spike Timing ◽  
Medium Spiny Neuron ◽  
Calcium Transients ◽  
Biophysical Model ◽  
Published Data ◽  
High Calcium

The striatum of the basal ganglia demonstrates distinctive upstate and downstate membrane potential oscillations during slow-wave sleep and under anesthetic. The upstates generate calcium transients in the dendrites, and the amplitude of these calcium transients depends strongly on the timing of the action potential (AP) within the upstate. Calcium is essential for synaptic plasticity in the striatum, and these large calcium transients during the upstates may control which synapses undergo plastic changes. To investigate the mechanisms that underlie the relationship between calcium and AP timing, we have developed a realistic biophysical model of a medium spiny neuron (MSN). We have implemented sophisticated calcium dynamics including calcium diffusion, buffering, and pump extrusion, which accurately replicate published data. Using this model, we found that either the slow inactivation of dendritic sodium channels (NaSI) or the calcium inactivation of voltage-gated calcium channels (CDI) can cause high calcium corresponding to early APs and lower calcium corresponding to later APs. We found that only CDI can account for the experimental observation that sensitivity to AP timing is dependent on NMDA receptors. Additional simulations demonstrated a mechanism by which MSNs can dynamically modulate their sensitivity to AP timing and show that sensitivity to specifically timed pre- and postsynaptic pairings (as in spike timing-dependent plasticity protocols) is altered by the timing of the pairing within the upstate. These findings have implications for synaptic plasticity in vivo during sleep when the upstate-downstate pattern is prominent in the striatum.

scholarly journals Neuronal pannexin-1 channels are not molecular routes of water influx during spreading depolarization-induced dendritic beading

2016 ◽  
Vol 37 (5) ◽  
pp. 1626-1633 ◽  
Author(s):  
Jeremy Sword ◽  
Deborah Croom ◽  
Phil L Wang ◽  
Roger J Thompson ◽  
Sergei A Kirov
Keyword(s):  
Pyramidal Neurons ◽  
Transport Mechanisms ◽  
Coupled Transport ◽  
Pannexin 1 ◽  
Two Photon ◽  
Spreading Depolarization ◽  
Water Influx ◽  
Membrane Bound ◽  
Genetic Deletion

Spreading depolarization-induced focal dendritic swelling (beading) is an early hallmark of neuronal cytotoxic edema. Pyramidal neurons lack membrane-bound aquaporins posing a question of how water enters neurons during spreading depolarization. Recently, we have identified chloride-coupled transport mechanisms that can, at least in part, participate in dendritic beading. Yet transporter-mediated ion and water fluxes could be paralleled by water entry through additional pathways such as large-pore pannexin-1 channels opened by spreading depolarization. Using real-time in vivo two-photon imaging in mice with pharmacological inhibition or conditional genetic deletion of pannexin-1, we showed that pannexin-1 channels are not required for spreading depolarization-induced focal dendritic swelling.

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