Phosphorylation of PSD-95 at serine 73 in dCA1 is required for extinction of contextual fear.

The updating of contextual memories is essential for survival in a changing environment. Accumulating data indicate that the dorsal CA1 area (dCA1) contributes to this process. However, the cellular and molecular mechanisms of contextual fear memory updating remain poorly understood. Postsynaptic density protein 95 (PSD-95) regulates the structure and function of glutamatergic synapses. Here, using dCA1-targeted genetic manipulations in vivo, combined with ex vivo 3D electron microscopy and electrophysiology, we identify a novel, synaptic mechanism that is induced during attenuation of contextual fear memories and involves phosphorylation of PSD-95 at Serine 73 in dCA1. Our data provide the proof that PSD-95-dependent synaptic plasticity in dCA1 is required for updating of contextual fear memory.

Coexistence of Short- and Long-Range Ferromagnetic Proximity Effects in a Fe/(Cd,Mg)Te/CdTe Quantum Well Hybrid Structure.

In a Fe/(Cd,Mg)Te/CdTe quantum well hybrid structure, short-range and long-range ferromagnetic proximity effects are found to coexist. The former is observed for conduction band electrons, while the latter is observed for holes bound to shallow acceptors in the CdTe quantum well. These effects arise from the interaction of charge carriers confined in the quantum well with different ferromagnets, where electrons interact with the Fe film and holes with an interfacial ferromagnet at the Fe/(Cd,Mg)Te interface. The two proximity effects originate from fundamentally different physical mechanisms. The short-range proximity effect for electrons is determined by the overlap of their wave functions with d-electrons of the Fe film. On the contrary, the long-range effect for holes bound to acceptors is not associated with overlapping wave functions and can be mediated by elliptically polarized phonons. The coexistence of the two ferromagnetic proximity effects reveals the presence of a nontrivial spin texture within the same heterostructure.

Near-infrared emission from spatially indirect excitons in type II ZnTe/CdSe/(Zn,Mg)Te core/double-shell nanowires.

ZnTe/CdSe/(Zn, Mg)Te core/double-shell nanowires are grown by molecular beam epitaxy by employing the vapor-liquid-solid growth mechanism assisted with gold catalysts. A photoluminescence study of these structures reveals the presence of an optical emission in the near infrared. We assign this emission to the spatially indirect exciton recombination at the ZnTe/CdSe type II interface. This conclusion is confirmed by the observation of a significant blue-shift of the emission energy with an increasing excitation fluence induced by the electron-hole separation at the interface. Cathodoluminescence measurements reveal that the optical emission in the near infrared originates from nanowires and not from two-dimensional residual deposits between them. Moreover, it is demonstrated that the emission energy in the near infrared depends on the average CdSe shell thickness and the average Mg concentration within the (Zn, Mg)Te shell. The main mechanism responsible for these changes is associated with the strain induced by the (Zn, Mg)Te shell in the entire core/shell nanowire heterostructure.

Stress-induced Changes in the S-palmitoylation and S-nitrosylation of Synaptic Proteins.

The precise regulation of synaptic integrity is critical for neuronal network connectivity and proper brain function. Essential aspects of the activity and localization of synaptic proteins are regulated by posttranslational modifications. S-palmitoylation is a reversible covalent modification of the cysteine with palmitate. It modulates affinity of the protein for cell membranes and membranous compartments. Intracellular palmitoylation dynamics are regulated by crosstalk with other posttranslational modifications, such as S-nitrosylation. S-nitrosylation is a covalent modification of cysteine thiol by nitric oxide and can modulate protein functions. Therefore, simultaneous identification of endogenous site-specific proteomes of both cysteine modifications under certain biological conditions offers new insights into the regulation of functional pathways. Still unclear, however, are the ways in which this crosstalk is affected in brain pathology, such as stress-related disorders. Using a newly developed mass spectrometry-based approach Palmitoylation And Nitrosylation Interplay Monitoring (PANIMoni), we analyzed the endogenous S-palmitoylation and S-nitrosylation of postsynaptic density proteins at the level of specific single cysteine in a mouse model of chronic stress. Among a total of 813 S-PALM and 620 S-NO cysteine sites that were characterized on 465 and 360 proteins, respectively, we sought to identify those that were differentially affected by stress. Our data show involvement of S-palmitoylation and S-nitrosylation crosstalk in the regulation of 122 proteins including receptors, scaffolding proteins, regulatory proteins and cytoskeletal components. Our results suggest that atypical crosstalk between the S-palmitoylation and S-nitrosylation interplay of proteins involved in synaptic transmission, protein localization and regulation of synaptic plasticity might be one of the main events associated with chronic stress disorder, leading to destabilization in synaptic networks.

RFCM-PALM: In-Silico Prediction of S-Palmitoylation Sites in the Synaptic Proteins for Male/Female Mouse Data.

S-palmitoylation is a reversible covalent post-translational modification of cysteine thiol side chain by palmitic acid. S-palmitoylation plays a critical role in a variety of biological processes and is engaged in several human diseases. Therefore, identifying specific sites of this modification is crucial for understanding their functional consequences in physiology and pathology. We present a random forest (RF) classifier-based consensus strategy (RFCM-PALM) for predicting the palmitoylated cysteine sites on synaptic proteins from male/female mouse data. To design the prediction model, we have introduced a heuristic strategy for selection of the optimum set of physicochemical features from the AAIndex dataset using (a) K-Best (KB) features, (b) genetic algorithm (GA), and (c) a union (UN) of KB and GA based features. Furthermore, decisions from best-trained models of the KB, GA, and UN-based classifiers are combined by designing a three-star quality consensus strategy to further refine and enhance the scores of the individual models. The experiment is carried out on three categorized synaptic protein datasets of a male mouse, female mouse, and combined (male + female), whereas in each group, weighted data is used as training, and knock-out is used as the hold-out set for performance evaluation and comparison. RFCM-PALM shows ~80% area under curve (AUC) score in all three categories of datasets and achieve 10% average accuracy (male-15%, female-15%, and combined-7%) improvements on the hold-out set compared to the state-of-the-art approaches. To summarize, our method with efficient feature selection and novel consensus strategy shows significant performance gains in the prediction of S-palmitoylation sites in mouse datasets.

Polarization and magneto-optical properties of excitonic emission from wurtzite CdTe/(Cd,Mg)Te core/shell nanowires.

Wurtzite CdTe and (Cd,Mn)Te nanowires embedded in (Cd,Mg)Te shells are grown by employing vapour-liquid-solid growth mechanism in a system for molecular beam epitaxy. A combined study involving cathodoluminescence, transmission electron microscopy and micro-photoluminescence is used to correlate optical and structural properties in these structures. Typical features of excitonic emission from individual wurtzite nanowires are highlighted including the emission energy of 1.65 eV, polarization properties and the appearance B-exciton related emission at high excitation densities. Angle dependent magneto-optical study performed on individual (Cd,Mn)Te nanowires reveals heavy-hole-like character of A-excitons typical for wurtzite structure and allows to determine the crystal field splitting, ΔCR. The impact of the strain originating from the lattice mismatched shell is discussed and supported by theoretical calculations.

Synaptic Potentiation at Basal and Apical Dendrites of Hippocampal Pyramidal Neurons Involves Activation of a Distinct Set of Extracellular and Intracellular Molecular Cues.

In the central nervous system, several forms of experience-dependent plasticity, learning and memory require the activity-dependent control of synaptic efficacy. Despite substantial progress in describing synaptic plasticity, mechanisms related to heterogeneity of synaptic functions at local circuits remain elusive. Here we studied the functional and molecular aspects of hippocampal circuit plasticity by analyzing excitatory synapses at basal and apical dendrites of mouse hippocampal pyramidal cells (CA1 region) in acute brain slices. In the past decade, activity of metalloproteinases (MMPs) has been implicated as a widespread and critical factor in plasticity mechanisms at various projections in the CNS. However, in the present study we discovered that in striking contrast to apical dendrites, synapses located within basal dendrites undergo MMP-independent synaptic potentiation. We demonstrate that synapse-specific molecular pathway allowing MMPs to rapidly upregulate function of NMDARs in stratum radiatum involved protease activated receptor 1 and intracellular kinases and GTPases activity. In contrast, MMP-independent scaling of synaptic strength in stratum oriens involved dopamine D1/D5 receptors and Src kinases. Results of this study reveal that 2 neighboring synaptic systems differ significantly in extracellular and intracellular cascades that control synaptic gain and provide long-searched transduction pathways relevant for MMP-dependent synaptic plasticity.

Overexpression of STIM1 in neurons in mouse brain improves contextual learning and impairs long-term depression.

STIM1 is an endoplasmic reticulum calcium sensor that is involved in several processes in neurons, including store-operated calcium entry. STIM1 also inhibits voltage-gated calcium channels, such as Cav1.2 and Cav3.1, and is thus considered a multifunctional protein. The aim of this work was to investigate the ways in which transgenic neuronal overexpression of STIM1 in FVB/NJ mice affects animal behavior and the electrophysiological properties of neurons in acute hippocampal slices. We overexpressed STIM1 from the Thy1.2 promoter and verified neuronal expression by quantitative reverse-transcription polymerase chain reaction, Western blot, and immunohistochemistry. Mature primary hippocampal cultures expressed STIM1 but exhibited no changes in calcium homeostasis. Basal synaptic transmission efficiency and short-term plasticity were comparable in slices that were isolated from transgenic mice, similarly as the magnitude of long-term potentiation. However, long-term depression that was induced by the glutamate receptor 1/5 agonist (S)-3,5-dihydroxyphenylglycine was impaired in STIM1 slices. Interestingly, transgenic mice exhibited a decrease in anxiety-like behavior and improvements in contextual learning. In summary, our data indicate that STIM1 overexpression in neurons in the brain perturbs metabotropic glutamate receptor signaling, leading to impairments in long-term depression and alterations in animal behavior. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech.

Aging-associated changes in hippocampal glycogen metabolism in mice. Evidence for and against astrocyte-to-neuron lactate shuttle.

Lactate derived from astrocytic glycogen has been shown to support memory formation in hippocampi of young animals, inhibiting it in old animals. Here we show, using quantitative mass spectrometry-based proteomics, immunofluorescence, and qPCR that aging is associated with an increase of glycogen metabolism enzymes concentration and shift in their localization from astrocytes to neurons. These changes are accompanied with reorganization of hippocampal energy metabolism which is manifested by elevated capacity of aging neurons to oxidize glucose in glycolysis and mitochondria, and decreased ability for fatty acids utilization. Our observations suggest that astrocyte-to-neuron lactate shuttle may operate in young hippocampi, however, during aging neurons become independent on astrocytic lactate and the metabolic crosstalk between the brain's cells is disrupted.

Magnetic field induced mixing of light hole excitonic states in (Cd, Mn)Te/(Cd, Mg)Te core/shell nanowires.

A detailed magneto-photoluminescence study of individual (Cd, Mn)Te/(Cd, Mg)Te core/shell nanowires grown by molecular beam epitaxy is performed. First of all, an enhancement of the Zeeman splitting due to sp-d exchange interaction between band carriers and Mn-spins is evidenced in these nanostructures. Then, it is found that the value of this splitting depends strongly on the magnetic field direction with respect to the nanowire axis. The largest splitting is observed when the magnetic field is applied perpendicular and the smallest when it is applied parallel to the nanowire axis. This effect is explained in terms of magnetic field induced valence band mixing and evidences the light hole character of the excitonic emission. The values of the light and heavy hole splitting are determined for several individual nanowires based on the comparison of experimental results to theoretical calculations.

Mesoscopic Transport in Electrostatically Defined Spin-Full Channels in Quantum Hall Ferromagnets.

In this work, we use electrostatic control of quantum Hall ferromagnetic transitions in CdMnTe quantum wells to study electron transport through individual domain walls (DWs) induced at a specific location. These DWs are formed due to the hybridization of two counterpropagating edge states with opposite spin polarization. Conduction through DWs is found to be symmetric under magnetic field direction reversal, consistent with the helical nature of these DWs. We observe that long domain walls are in the insulating regime with a localization length of 4-6 µm. In shorter DWs, the resistance saturates to a nonzero value at low temperatures. Mesoscopic resistance fluctuations in a magnetic field are investigated. The theoretical model of transport through impurity states within the gap induced by spin-orbit interactions agrees well with the experimental data. Helical DWs have the required symmetry for the formation of synthetic p-wave superconductors. The achieved electrostatic control of a single helical domain wall is a milestone on the path to their reconfigurable network and ultimately to a demonstration of the braiding of non-Abelian excitations.

Spin splitting anisotropy in single diluted magnetic nanowire heterostructures.

We study the impact of the nanowire shape anisotropy on the spin splitting of excitonic photoluminescence. The experiments are performed on individual ZnMnTe/ZnMgTe core/shell nanowires as well as on ZnTe/ZnMgTe core/shell nanowires containing optically active magnetic CdMnTe insertions. When the magnetic field is oriented parallel to the nanowire axis, the spin splitting is several times larger than for the perpendicular field. We interpret this pronounced anisotropy as an effect of mixing of valence band states arising from the strain present in the core/shell geometry. This interpretation is further supported by theoretical calculations which allow to reproduce experimental results.

Diverse impact of neuronal activity at θ frequency on hippocampal long-term plasticity.

Brain oscillatory activity is considered an essential aspect of brain function, and its frequency can vary from <1 Hz to >200 Hz, depending on the brain states and projection. Episodes of rhythmic activity accompany hippocampus-dependent learning and memory in vivo. Therefore, long-term synaptic potentiation (LTP) and long-term depression, which are considered viable substrates of learning and memory, are often experimentally studied in paradigms of patterned high-frequency (>50 Hz) and low-frequency (<5 Hz) stimulation. However, the impact of intermediate frequencies on neuronal plasticity remains less well understood. In particular, hippocampal neurons are specifically tuned for activity at θ frequency (4-8 Hz); this band contributes significantly to electroencephalographic signals, and it is likely to be involved in shaping synaptic strength in hippocampal circuits. Here, we review in vitro and in vivo studies showing that variation of θ-activity duration may affect long-term modification of synaptic strength and neuronal excitability in the hippocampus. Such θ-pulse-induced neuronal plasticity 1) is long-lasting, 2) may be built on previously stabilized potentiation in the synapse, 3) may produce opposite changes in synaptic strength, and 4) requires complex molecular machinery. Apparently innocuous episodes of low-frequency synaptic activity may have a profound impact on network signaling, thereby contributing to information processing in the hippocampus and beyond. In addition, θ-pulse-induced LTP might be an advantageous protocol in studies of specific molecular mechanisms of synaptic plasticity.

Matrix metalloprotease activity shapes the magnitude of EPSPs and spike plasticity within the hippocampal CA3 network.

Matrix metalloproteases (MMP) play a pivotal role in long-term synaptic plasticity, learning, and memory. The roles of different MMP subtypes are emerging, but the proteolytic activity of certain MMPs was shown to support these processes through the structural and functional modification of hippocampal Schaeffer collateral and mossy fiber (MF) synapses. However, certain patterns of synaptic activity are additionally associated with non-synaptic changes, such as the scaling of neuronal excitability. However, the extent to which MMPs affect this process remains unknown. We determined whether MMP activity interferes with excitatory post-synaptic potential EPSP-to-spike (E-S) coupling under conditions of varying synaptic activity. We evoked short- and long-term synaptic plasticity at associational/commissural (A/C) synapses of CA3 pyramidal neurons and simultaneously recorded population spikes (PSs) and EPSPs in acute rat (P30-60) brain slices in the presence of various MMP inhibitors. We found that MMP inhibition significantly reduced E-S coupling and shortened the PS latency associated with 4× 100 Hz stimulation or paired burst activity of MF-CA3 and A/C synapses. Moreover, MMP inhibition interfered with the scaling of amplitude of measured signals during high-frequency trains, thus affecting the induction of long-term potentiation (LTP). The inhibition of L-type voltage-gated calcium channels with 20 µM nifedipine or GABA-A receptors with 1-30 µM picrotoxin did not occlude the effects of MMP inhibitors. However, MMP inhibition significantly reduced the LTP of NMDA receptor-mediated EPSPs. Finally, the analysis of LTP saturation with multiple single (1× 100 Hz) or packed (4× 100 Hz) trains indicated that MMPs support E-S coupling evoked by selected synaptic activity patterns and set the ceiling for tetanically evoked E-S LTP. In conclusion, the activity of MMPs, particularly MMP-3, regulated the magnitude of EPSPs and spike plasticity in the CA3 network and may affect information processing. Our data provide a novel link between MMP activity and neural excitability. Therefore, by limiting the number of firing neurons, MMP may functionally act beyond the synapse.

2-Bromopalmitate treatment attenuates senescence phenotype in human adult cells - possible role of palmitoylation.

Cells may undergo senescence in response to DNA damage, which is associated with cell cycle arrest, altered gene expression and altered cell morphology. Protein palmitoylation is one of the mechanisms by which the DNA damage response is regulated. Therefore, we hypothesized that protein palmitoylation played a role in regulation of the senescent phenotype. Here, we showed that treatment of senescent human vascular smooth muscle cells (VSMCs) with 2-bromopalmitate (2-BP), an inhibitor of protein acyltransferases, is associated with changes in different aspects of the senescent phenotype, including the resumption of cell proliferation, a decrease in DNA damage markers and the downregulation of senescence-associated ß-galactosidase activity. The effects were dose dependent and associated with significantly decreased total protein palmitoylation level. We also showed that the senescence-modifying properties of 2-BP were at least partially mediated by the downregulation of elements of DNA damage-related molecular pathways, such as phosphorylated p53. Our data suggest that cell senescence may be regulated by palmitoylation, which provides a new perspective on the role of this posttranslational modification in age-related diseases.

Long term potentiation affects intracellular metalloproteinases activity in the mossy fiber-CA3 pathway.

Matrix Metalloproteinases (MMPs) are a family of endopeptidases known to process extracellular proteins. In the last decade, studies carried out mainly on the Schaffer collateral-CA1 hippocampal projection have provided solid evidence that MMPs regulate synaptic plasticity and learning. Recently, our group has shown that MMP blockade disrupts LTP maintenance also in the mossy fiber-CA3 (mf-CA3) projection (Wojtowicz and Mozrzymas, 2010), where LTP mechanisms are profoundly different (NMDAR-independent and presynaptic expression site). However, how plasticity of this pathway correlates with activity and expression of MMPs remains unknown. Interestingly, several potential MMP substrates (especially of gelatinases) are localized intracellularly but little is known about MMP activity in this compartment. In the present study we have asked whether LTP is associated with the expression and activity of gelatinases in apparent intra- and extracellular compartments along mf-CA3 projection. In situ zymography showed that LTP induction was associated with increased gelatinases activity in the cytoplasm of the hilar and CA3 neurons. Using gelatin zymography, immunohistochemistry and immunofluorescent staining we found that this effect was due to de novo synthesis and activation of MMP-9 which, 2-3h after LTP induction was particularly evident in the cytoplasm. In contrast, MMP-2 was localized preferentially in the nuclei and was not affected by LTP induction. In conclusion, we demonstrate that LTP induction in the mf-CA3 pathway correlates with increased expression and activity of MMP-9 and provide the first evidence that this increase is particularly evident in the neuronal cytoplasm and nucleus.

Giant spin splitting in optically active ZnMnTe/ZnMgTe core/shell nanowires.

An enhancement of the Zeeman splitting as a result of the incorporation of paramagnetic Mn ions in ZnMnTe/ZnMgTe core/shell nanowires is reported. The studied structures are grown by gold-catalyst assisted molecular beam epitaxy. The near band edge emission of these structures, conspicuously absent in the case of uncoated ZnMnTe nanowires, is activated by the presence of ZnMgTe coating. Giant Zeeman splitting of this emission is studied in ensembles of nanowires with various average Mn concentrations of the order of a few percent, as well as in individual nanowires. Thus, we show convincingly that a strong spin sp-d coupling is indeed present in these structures.

Challenges for ATM management in times of market variability caused by the COVID-19 pandemic crisi.

One of the most important issues related to the management of an Automatic Teller Machine (ATM) network is the correct forecasting of the demand for cash. Typically, this demand, expressed as the value or number of ATM withdrawals, has some regularities that can be used to evaluate future values for these variables. However, forecasting becomes a challenge when a crisis occurs that could affect the behavior of ATM users. In this context, it is important to identify how the development of the crisis and the various information concerning it may affect people's attitudes to cash. This study aims to examine the impact of the COVID-19 pandemic on the behavior of ATM customers. On the basis of daily data from 81 ATMs, we analyze the changes in the value and number of withdrawals just before and during the COVID-19 pandemic in Poland. An event study analysis allows us to determine precisely the moments in which changes in user behavior took place. This means that it is also possible to examine the reaction of ATM users to the announcement and implementation of the pandemic restrictions, and to determine the factors that had an impact on the change in people's attitude to cash. Such a study is also important from a sociological point of view, as it enables one to understand people's reactions to the emerging crisis. Hence, its results may be useful not only for managers of ATM networks, but also for various authorities and policy makers.

The Content of Phenolic Compounds in Stevia rebaudiana (Bertoni) Plants Derived from Melatonin and NaCl Treated Seeds.

Stevia is a plant with many beneficial properties. It contains not only steviol glycosides, which are used as non-caloric natural sweeteners, but also a number of metabolites with antioxidant properties. This study examined the content of both phenolic acids and flavonoids in stevia leaves as an effect of treating seeds with melatonin and conducting germination in NaCl conditions. The results of our research indicated higher amounts of phenolic acids compared to flavonoids in stevia leaves. Among these acids, isochlorogenic, rosmarinic, and chlorogenic acids were accumulated in the largest amounts, regardless of the germination conditions. For 5 and 100 µM of melatonin treatments, the content of both phenolic acids and flavonoids increased. However, in salinity conditions (50 mM NaCl), 500 µM of melatonin had the most favorable effect on the synthesis of phenolic acids. The phenolic acids in that case reached a level three-times higher than that in the samples with the same melatonin concentration but without NaCl. We also found that the content of phenolic compounds varied depending on the age of the leaves. To the best of our knowledge, this is the first study to describe the effect of melatonin and NaCl on the synthesis on phenolic acids and flavonoids in stevia.

S-Palmitoylation of Synaptic Proteins in Neuronal Plasticity in Normal and Pathological Brains.

Protein lipidation is a common post-translational modification of proteins that plays an important role in human physiology and pathology. One form of protein lipidation, S-palmitoylation, involves the addition of a 16-carbon fatty acid (palmitate) onto proteins. This reversible modification may affect the regulation of protein trafficking and stability in membranes. From multiple recent experimental studies, a picture emerges whereby protein S-palmitoylation is a ubiquitous yet discrete molecular switch enabling the expansion of protein functions and subcellular localization in minutes to hours. Neural tissue is particularly rich in proteins that are regulated by S-palmitoylation. A surge of novel methods of detection of protein lipidation at high resolution allowed us to get better insights into the roles of protein palmitoylation in brain physiology and pathophysiology. In this review, we specifically discuss experimental work devoted to understanding the impact of protein palmitoylation on functional changes in the excitatory and inhibitory synapses associated with neuronal activity and neuronal plasticity. The accumulated evidence also implies a crucial role of S-palmitoylation in learning and memory, and brain disorders associated with impaired cognitive functions.