Serotonin synthesis, release and reuptake in terminals: a mathematical model

<p>Abstract</p> <p>Background</p> <p>Serotonin is a neurotransmitter that has been linked to a wide variety of behaviors including feeding and body-weight regulation, social hierarchies, aggression and suicidality, obsessive compulsive disorder, alcoholism, anxiety, and affective disorders. Full understanding of serotonergic systems in the central nervous system involves genomics, neurochemistry, electrophysiology, and behavior. Though associations have been found between functions at these different levels, in most cases the causal mechanisms are unknown. The scientific issues are daunting but important for human health because of the use of selective serotonin reuptake inhibitors and other pharmacological agents to treat disorders in the serotonergic signaling system.</p> <p>Methods</p> <p>We construct a mathematical model of serotonin synthesis, release, and reuptake in a single serotonergic neuron terminal. The model includes the effects of autoreceptors, the transport of tryptophan into the terminal, and the metabolism of serotonin, as well as the dependence of release on the firing rate. The model is based on real physiology determined experimentally and is compared to experimental data.</p> <p>Results</p> <p>We compare the variations in serotonin and dopamine synthesis due to meals and find that dopamine synthesis is insensitive to the availability of tyrosine but serotonin synthesis is sensitive to the availability of tryptophan. We conduct <it>in silico </it>experiments on the clearance of extracellular serotonin, normally and in the presence of fluoxetine, and compare to experimental data. We study the effects of various polymorphisms in the genes for the serotonin transporter and for tryptophan hydroxylase on synthesis, release, and reuptake. We find that, because of the homeostatic feedback mechanisms of the autoreceptors, the polymorphisms have smaller effects than one expects. We compute the expected steady concentrations of serotonin transporter knockout mice and compare to experimental data. Finally, we study how the properties of the the serotonin transporter and the autoreceptors give rise to the time courses of extracellular serotonin in various projection regions after a dose of fluoxetine.</p> <p>Conclusions</p> <p>Serotonergic systems must respond robustly to important biological signals, while at the same time maintaining homeostasis in the face of normal biological fluctuations in inputs, expression levels, and firing rates. This is accomplished through the cooperative effect of many different homeostatic mechanisms including special properties of the serotonin transporters and the serotonin autoreceptors. Many difficult questions remain in order to fully understand how serotonin biochemistry affects serotonin electrophysiology and vice versa, and how both are changed in the presence of selective serotonin reuptake inhibitors. Mathematical models are useful tools for investigating some of these questions.</p

Design, upgrade and characterization of the silicon photomultiplier front-end for the AMIGA detector at the Pierre Auger Observatory

AMIGA (Auger Muons and Infill for the Ground Array) is an upgrade of the Pierre Auger Observatory to complement the study of ultra-high-energy cosmic rays (UHECR) by measuring the muon content of extensive air showers (EAS). It consists of an array of 61 water Cherenkov detectors on a denser spacing in combination with underground scintillation detectors used for muon density measurement. Each detector is composed of three scintillation modules, with 10 m$^2$ detection area per module, buried at 2.3 m depth, resulting in a total detection area of 30 m$^2$. Silicon photomultiplier sensors (SiPM) measure the amount of scintillation light generated by charged particles traversing the modules. In this paper, the design of the front-end electronics to process the signals of those SiPMs and test results from the laboratory and from the Pierre Auger Observatory are described. Compared to our previous prototype, the new electronics shows a higher performance, higher efficiency and lower power consumption, and it has a new acquisition system with increased dynamic range that allows measurements closer to the shower core. The new acquisition system is based on the measurement of the total charge signal that the muonic component of the cosmic ray shower generates in the detector.Comment: 40 pages, 33 figure

Extraction of the Muon Signals Recorded with the Surface Detector of the Pierre Auger Observatory Using Recurrent Neural Networks

The Pierre Auger Observatory, at present the largest cosmic-ray observatory ever built, is instrumented with a ground array of 1600 water-Cherenkov detectors, known as the Surface Detector (SD). The SD samples the secondary particle content (mostly photons, electrons, positrons and muons) of extensive air showers initiated by cosmic rays with energies ranging from $10^{17}~$eV up to more than $10^{20}~$eV. Measuring the independent contribution of the muon component to the total registered signal is crucial to enhance the capability of the Observatory to estimate the mass of the cosmic rays on an event-by-event basis. However, with the current design of the SD, it is difficult to straightforwardly separate the contributions of muons to the SD time traces from those of photons, electrons and positrons. In this paper, we present a method aimed at extracting the muon component of the time traces registered with each individual detector of the SD using Recurrent Neural Networks. We derive the performances of the method by training the neural network on simulations, in which the muon and the electromagnetic components of the traces are known. We conclude this work showing the performance of this method on experimental data of the Pierre Auger Observatory. We find that our predictions agree with the parameterizations obtained by the AGASA collaboration to describe the lateral distributions of the electromagnetic and muonic components of extensive air showers.Comment: 23 pages, 15 figures. Version accepted for publication in JINS

Design and implementation of the AMIGA embedded system for data acquisition

The Auger Muon Infill Ground Array (AMIGA) is part of the AugerPrime upgrade of the Pierre Auger Observatory. It consists of particle counters buried 2.3 m underground next to the water-Cherenkov stations that form the 23.5 km$^2$ large infilled array. The reduced distance between detectors in this denser area allows the lowering of the energy threshold for primary cosmic ray reconstruction down to about 10$^{17}$ eV. At the depth of 2.3 m the electromagnetic component of cosmic ray showers is almost entirely absorbed so that the buried scintillators provide an independent and direct measurement of the air showers muon content. This work describes the design and implementation of the AMIGA embedded system, which provides centralized control, data acquisition and environment monitoring to its detectors. The presented system was firstly tested in the engineering array phase ended in 2017, and lately selected as the final design to be installed in all new detectors of the production phase. The system was proven to be robust and reliable and has worked in a stable manner since its first deployment.Comment: Accepted for publication at JINST. Published version, 34 pages, 15 figures, 4 table

Constraining Lorentz Invariance Violation using the muon content of extensive air showers measured at the Pierre Auger Observatory

Lorentz Invariance (LI) implies that the space-time structure is the same for all observers. On the other hand, various quantum gravity theories suggest that it may be violated when approaching the Planck scale. At extreme energies, like those available in the collision of Ultra-High Energy Cosmic Rays (UHECRs) with atmosphere nuclei, one should also expect a change in the interactions due to Lorentz Invariance Violation (LIV). In this work, the effects of LIV on the development of Extensive Air Showers (EAS) have been considered. After having introduced LIV as a perturbation term in the single-particle dispersion relation, a library of simulated showers with different energies, primary particles and LIV strengths has been produced. Possible LIV has been studied using the muon content of air showers measured at the Pierre Auger Observatory. Limits on LIV parameters have been derived from a comparison between the Monte Carlo expectations and muon fluctuation measurements from the Pierre Auger Observatory

A search for ultra-high-energy photons at the Pierre Auger Observatory exploiting air-shower Universality

The Pierre Auger Observatory is the most sensitive detector to primary photons with energies above ∼ 0.2 EeV. It measures extensive air showers using a hybrid technique that combines a fluorescence detector (FD) with a ground array of particle detectors (SD). The signatures of a photon-induced air shower are a larger atmospheric depth at the shower maximum (Xmax) and a steeper lateral distribution function, along with a lower number of muons with respect to the bulk of hadron-induced background. Using observables measured by the FD and SD, three photon searches in different energy bands are performed. In particular, between threshold energies of 1–10 EeV, a new analysis technique has been developed by combining the FD-based measurement of Xmax with the SD signal through a parameter related to its muon content, derived from the universality of the air showers. This technique has led to a better photon/hadron separation and, consequently, to a higher search sensitivity, resulting in a tighter upper limit than before. The outcome of this new analysis is presented here, along with previous results in the energy ranges below 1 EeV and above 10 EeV. From the data collected by the Pierre Auger Observatory in about 15 years of operation, the most stringent constraints on the fraction of photons in the cosmic flux are set over almost three decades in energy

Measurement of the fluctuations in the number of muons in extensive air showers with the Pierre Auger Observatory

We present the first measurement of the fluctuations in the number of muons in extensive air showers produced by ultra-high energy cosmic rays. We find that the measured fluctuations are in good agreement with predictions from air shower simulations. This observation provides new insights into the origin of the previously reported deficit of muons in air shower simulations and constrains models of hadronic interactions at ultra-high energies. Our measurement is compatible with the muon deficit originating from small deviations in the predictions from hadronic interaction models of particle production that accumulate as the showers develop.Comment: Accepted for publication in PR

Status and performance of the underground muon detector of the Pierre Auger Observatory

The Auger Muons and Infill for the Ground Array (AMIGA) is an enhancement of the Pierre Auger Observatory, whose purpose is to lower the energy threshold of the observatory down to 1016.5 eV, and to measure the muonic content of air showers directly. These measurements will significantly contribute to the determination of primary particle masses in the range between the second knee and the ankle, to the study of hadronic interaction models with air showers, and, in turn, to the understanding of the muon puzzle. The underground muon detector of AMIGA is concomitant to two triangular grids of water-Cherenkov stations with spacings of 433 and 750 m; each grid position is equipped with a 30 m2 plastic scintillator buried at 2.3 m depth. After the engineering array completion in early 2018 and general improvements to the design, the production phase commenced. In this work, we report on the status of the underground muon detector, the progress of its deployment, and the performance achieved after two years of operation. The detector construction is foreseen to finish by mid-2022

A Catalog of the Highest-energy Cosmic Rays Recorded during Phase I of Operation of the Pierre Auger Observatory

A catalog containing details of the highest-energy cosmic rays recorded through the detection of extensive air-showers at the Pierre Auger Observatory is presented with the aim of opening the data to detailed examination. Descriptions of the 100 showers created by the highest-energy particles recorded between 1 January 2004 and 31 December 2020 are given for cosmic rays that have energies in the range 78 EeV to 166 EeV. Details are also given of a further nine very-energetic events that have been used in the calibration procedure adopted to determine the energy of each primary. A sky plot of the arrival directions of the most energetic particles is shown. No interpretations of the data are offered