A model of working memory for encoding multiple items and ordered sequences exploiting the theta-gamma code

Recent experimental evidence suggests that oscillatory activity plays a pivotal role in the maintenance of information in working memory, both in rodents and humans. In particular, cross-frequency coupling between theta and gamma oscillations has been suggested as a core mechanism for multi-item memory. The aim of this work is to present an original neural network model, based on oscillating neural masses, to investigate mechanisms at the basis of working memory in different conditions. We show that this model, with different synapse values, can be used to address different problems, such as the reconstruction of an item from partial information, the maintenance of multiple items simultaneously in memory, without any sequential order, and the reconstruction of an ordered sequence starting from an initial cue. The model consists of four interconnected layers; synapses are trained using Hebbian and anti-Hebbian mechanisms, in order to synchronize features in the same items, and desynchronize features in different items. Simulations show that the trained network is able to desynchronize up to nine items without a fixed order using the gamma rhythm. Moreover, the network can replicate a sequence of items using a gamma rhythm nested inside a theta rhythm. The reduction in some parameters, mainly concerning the strength of GABAergic synapses, induce memory alterations which mimic neurological deficits. Finally, the network, isolated from the external environment ("imagination phase") and stimulated with high uniform noise, can randomly recover sequences previously learned, and link them together by exploiting the similarity among items

Snake and spider toxins induce a rapid recovery of function of botulinum neurotoxin paralysed neuromuscular junction

Botulinum neurotoxins (BoNTs) and some animal neurotoxins (-Bungarotoxin, -Btx, from elapid snakes and -Latrotoxin, -Ltx, from black widow spiders) are pre-synaptic neurotoxins that paralyse motor axon terminals with similar clinical outcomes in patients. However, their mechanism of action is different, leading to a largely-different duration of neuromuscular junction (NMJ) blockade. BoNTs induce a long-lasting paralysis without nerve terminal degeneration acting via proteolytic cleavage of SNARE proteins, whereas animal neurotoxins cause an acute and complete degeneration of motor axon terminals, followed by a rapid recovery. In this study, the injection of animal neurotoxins in mice muscles previously paralyzed by BoNT/A or /B accelerates the recovery of neurotransmission, as assessed by electrophysiology and morphological analysis. This result provides a proof of principle that, by causing the complete degeneration, reabsorption, and regeneration of a paralysed nerve terminal, one could favour the recovery of function of a biochemically- or genetically-altered motor axon terminal. These observations might be relevant to dying-back neuropathies, where pathological changes first occur at the neuromuscular junction and then progress proximally toward the cell body

The role of the single interchains disulfide bond in tetanus and botulinum neurotoxins and the development of antitetanus and antibotulism drugs

A large number of bacterial toxins consist of active and cell binding protomers linked by an interchain disulfide bridge. The largest family of such disulfide-bridged exotoxins is that of the clostridial neurotoxins that consist of two chains and comprise the tetanus neurotoxins causing tetanus and the botulinum neurotoxins causing botulism. Reduction of the interchain disulfide abolishes toxicity, and we discuss the experiments that revealed the role of this structural element in neuronal intoxication. The redox couple thioredoxin reductase-thioredoxin (TrxR-Trx) was identified as the responsible for reduction of this disulfide occurring on the cytosolic surface of synaptic vesicles. We then discuss the very relevant finding that drugs that inhibit TrxR-Trx also prevent botulism. On this basis, we propose that ebselen and PX-12, two TrxR-Trx specific drugs previously used in clinical trials in humans, satisfy all the requirements for clinical tests aiming at evaluating their capacity to effectively counteract human and animal botulism arising from intestinal toxaemias such as infant botulism

Automated microwave device characterization set-up based on a technology-independent generalized Bias System

In this paper an automated laboratory set-up for the characterization of micro- and millimeter-wave electron devices under DC, small- and large-signal operation is described, which is based on a generalized, technology-independent bias system. The biasing parameters adopted, which are a linear combination between currents and voltages at the device ports, allow for a complete characterization of the desired empirical data (e.g. multi-frequency S-matrix) throughout all the regions in which the quiescent operation of the device can be conventionally divided, without any need for the switch between different biasing strategies. The look-up tables of experimental data obtained, which are carried out homogeneously with respect to the same couple of bias parameters, independently of the quiescent regions investigated, are particularly suitable for the characterization of empirical non-linear dynamic models for the electron device

Evolutionary Implications of Environmental Toxicant Exposure

Homo sapiens have been exposed to various toxins and harmful compounds that change according to various phases of human evolution. Population genetics studies showed that such exposures lead to adaptive genetic changes; while observing present exposures to different toxicants, the first molecular mechanism that confers plasticity is epigenetic remodeling and, in particular, DNA methylation variation, a molecular mechanism proposed for medium-term adaptation. A large amount of scientific literature from clinical and medical studies revealed the high impact of such exposure on human biology; thus, in this review, we examine and infer the impact that different environmental toxicants may have in shaping human evolution. We first describe how environmental toxicants shape natural human variation in terms of genetic and epigenetic diversity, and then we describe how DNA methylation may influence mutation rate and, thus, genetic variability. We describe the impact of these substances on biological fitness in terms of reproduction and survival, and in conclusion, we focus on their effect on brain evolution and physiology

Push-push X band GaInP/GaAs VCO with a fully monolithic microstrip resonator

In this paper the design of a VCO using GaInP/GaAs HBT technology is presented. The VCO is designed to be a part of a PDH point to point radio system. To achieve low phase noise performances GaInP/GaAs HBT technology and push-push topology have been chosen. The MMIC includes predistorters to emphasize the second harmonic, f/sub 0//2 prescalers for PLL locking and buffer amplifiers. A fully monolithic microstrip resonator is coupled with integrated varactors to achieve the specified tuning bandwidth. Phase noise, bandwidth and power measurements will also be presente

The impact of radiosounding observations on numerical weather prediction analyses in the Arctic

The radiosounding network in the Arctic, despite being sparse, is a crucial part of the atmospheric observing system for weather prediction and reanalysis. The spatial coverage of the network was evaluated using a numerical weather prediction model, comparing radiosonde observations from Arctic land stations and expeditions in the central Arctic Ocean with operational analyses and background fields (12h forecasts) from ECMWF for January 2016 – September 2018. The results show that the impact of radiosonde observations on analyses has large geographical variation. In data‐sparse areas, such as the central Arctic Ocean, high‐quality radiosonde observations substantially improve the analyses, while satellite observations are not able to compensate for the large spatial gap in the radiosounding network. In areas where the network is reasonably dense, the quality of background field is more related to how radiosonde observations are utilized in the assimilation and to the quality of those observations

Changes in brain rhythms and connectivity tracking fear acquisition and reversal

Fear conditioning is used to investigate the neural bases of threat and anxiety, and to understand their flexible modifications when the environment changes. This study aims to examine the temporal evolution of brain rhythms using electroencephalographic signals recorded in healthy volunteers during a protocol of Pavlovian fear conditioning and reversal. Power changes and Granger connectivity in theta, alpha, and gamma bands are investigated from neuroelectrical activity reconstructed on the cortex. Results show a significant increase in theta power in the left (contralateral to electrical shock) portion of the midcingulate cortex during fear acquisition, and a significant decrease in alpha power in a broad network over the left posterior-frontal and parietal cortex. These changes occur since the initial trials for theta power, but require more trials (3/4) to develop for alpha, and are also present during reversal, despite being less pronounced. In both bands, relevant changes in connectivity are mainly evident in the last block of reversal, just when power differences attenuate. No significant changes in the gamma band were detected. We conclude that the increased theta rhythm in the cingulate cortex subserves fear acquisition and is transmitted to other cortical regions via increased functional connectivity allowing a fast theta synchronization, whereas the decrease in alpha power can represent a partial activation of motor and somatosensory areas contralateral to the shock side in the presence of a dangerous stimulus. In addition, connectivity changes at the end of reversal may reflect long-term alterations in synapses necessary to reverse the previously acquired contingencies

A CXCR4 receptor agonist strongly stimulates axonal regeneration after damage

Objective: To test whether the signaling axis CXCL12\u3b1-CXCR4 is activated upon crush/cut of the sciatic nerve and to test the activity of NUCC-390, a new CXCR4 agonist, in promoting nerve recovery from damage. Methods: The sciatic nerve was either crushed or cut. Expression and localization of CXCL12\u3b1 and CXCR4 were evaluated by imaging with specific antibodies. Their functional involvement in nerve regeneration was determined by antibody-neutralization of CXCL12\u3b1, and by the CXCR4 specific antagonist AMD3100, using as quantitative read-out the compound muscle action potential (CMAP). NUCC-390 activity on nerve regeneration was determined by imaging and CMAP recordings. Results: CXCR4 is expressed at the injury site within the axonal compartment, whilst its ligand CXCL12\u3b1 is expressed in Schwann cells. The CXCL12\u3b1-CXCR4 axis is involved in the recovery of neurotransmission of the injured nerve. More importantly, the small molecule NUCC-390 is a strong promoter of the functional and anatomical recovery of the nerve, by acting very similarly to CXCL12\u3b1. This pharmacological action is due to the capability of NUCC-390 to foster elongation of motor neuron axons both in vitro and in vivo. Interpretation: Imaging and electrophysiological data provide novel and compelling evidence that the CXCL12\u3b1-CXCR4 axis is involved in sciatic nerve repair after crush/cut. This makes NUCC-390 a strong candidate molecule to stimulate nerve repair by promoting axonal elongation. We propose this molecule to be tested in other models of neuronal damage, to lay the basis for clinical trials on the efficacy of NUCC-390 in peripheral nerve repair in humans

CXCL12/SDF-1 from perisynaptic Schwann cells promotes regeneration of injured motor axonterminals

The neuromuscular junction has retained through evolution the capacity to regenerate after damage, but little is known on the inter-cellular signals involved in its functional recovery from trauma, autoimmune attacks, or neurotoxins. We report here that CXCL12, also abbreviated as stromal-derived factor-1 (SDF-1), is produced specifically by perisynaptic Schwann cells following motor axon terminal degeneration induced by -latrotoxin. CXCL12 acts via binding to the neuronal CXCR4 receptor. A CXCL12-neutralizing antibody or a specific CXCR4 inhibitor strongly delays recovery from motor neuron degeneration invivo. Recombinant CXCL12 invivo accelerates neurotransmission rescue upon damage and very effectively stimulates the axon growth of spinal cord motor neurons invitro. These findings indicate that the CXCL12-CXCR4 axis plays an important role in the regeneration of the neuromuscular junction after motor axon injury. The present results have important implications in the effort to find therapeutics and protocols to improve recovery of function after different forms of motor axon terminal damage