Four-Dimensional Neuronal Signaling by Nitric Oxide: A Computational Analysis

Nitric oxide (NO) is now recognized as a transmitter of neurons that express the neuronal isoform of the enzyme nitric oxide synthase. NO, however, violates some of the key tenets of chemical transmission, which is classically regarded as occurring at points of close apposition between neurons. It is the ability of NO to diffuse isotropically in aqueous and lipid environments that has suggested a radically different form of signaling in which the transmitter acts four-dimensionally in space and time, affecting volumes of the brain containing many neurons and synapses. Although ¿volume signaling¿ clearly challenges simple connectionist models of neural processing, crucial to its understanding are the spatial and temporal dynamics of the spread of NO within the brain. Existing models of NO diffusion, however, have serious shortcomings because they represent solutions for ¿point-sources,¿ which have no physical dimensions. Methods for overcoming these difficulties are presented here, and results are described that show how NO spreads from realistic neural architectures with both simple symmetrical and irregular shapes. By highlighting the important influence of the geometry of NO sources, our results provide insights into the four-dimensional spread of a diffusing messenger. We show for example that reservoirs of NO that accumulate in volumes of the nervous system where NO is not synthesized contribute significantly to the temporal and spatial dynamics of NO spread

Flexible couplings: diffusing neuromodulators and adaptive robotics

Recent years have seen the discovery of freely diffusing gaseous neurotransmitters, such as nitric oxide (NO), in biological nervous systems. A type of artificial neural network (ANN) inspired by such gaseous signaling, the GasNet, has previously been shown to be more evolvable than traditional ANNs when used as an artificial nervous system in an evolutionary robotics setting, where evolvability means consistent speed to very good solutions¿here, appropriate sensorimotor behavior-generating systems. We present two new versions of the GasNet, which take further inspiration from the properties of neuronal gaseous signaling. The plexus model is inspired by the extraordinary NO-producing cortical plexus structure of neural fibers and the properties of the diffusing NO signal it generates. The receptor model is inspired by the mediating action of neurotransmitter receptors. Both models are shown to significantly further improve evolvability. We describe a series of analyses suggesting that the reasons for the increase in evolvability are related to the flexible loose coupling of distinct signaling mechanisms, one ¿chemical¿ and one ¿electrical.

Neuronal Expression of Neural Nitric Oxide Synthase (nNOS) Protein is Suppressed by an Antisense RNA Transcribed from an NOS Pseudogene

Here, we show that a nitric oxide synthase (NOS) pseudogene is expressed in the CNS of the snail Lymnaea stagnalis. The pseudo-NOS transcript includes a region of significant antisense homology to a previously reported neuronal NOS (nNOS)-encoding mRNA. This suggested that the pseudo-NOS transcript acts as a natural antisense regulator of nNOS protein synthesis. In support of this, we show that both the nNOS-encoding and the pseudo-NOS transcripts are coexpressed in giant identified neurons (the cerebral giant cells) in the cerebral ganglion. Moreover, reverse transcription-PCR experiments on RNA isolated from the CNS establish that stable RNA-RNA duplex molecules do form between the two transcripts in vivo. Using an in vitro translation assay, we further demonstrate that the antisense region of the pseudogene transcript prevents the translation of nNOS protein from the nNOS-encoding mRNA. By analyzing NOS RNA and nNOS protein expression in two different identified neurons, we find that when both the nNOS-encoding and the pseudo-NOS transcripts are present in the same neuron, nNOS enzyme activity is substantially suppressed. Importantly, these results show that a natural antisense mechanism can mediate the translational control of nNOS expression in the Lymnaea CNS. Our findings also suggest that transcribed pseudogenes are not entirely without purpose and are a potential source of a new class of regulatory gene in the nervous system

Anterograde Signalling by Nitric Oxide: Characterisation and In Vitro Reconstitution of an Identified Nitrergic Synapse

Nitric oxide (NO) is recognized as a signaling molecule in the CNS where it is a candidate retrograde neurotransmitter. Here we provide direct evidence that NO mediates slow excitatory anterograde transmission between the NO synthase (NOS)-expressing B2 neuron and an NO-responsive follower neuron named B7nor. Both are motoneurons located in the buccal ganglia of the snail Lymnaea stagnalis where they participate in feeding behavior. Transmission between B2 and B7nor is blocked by inhibiting NOS and is suppressed by extracellular scavenging of NO. Furthermore, focal application of NO to the cell body of the B7nor neuron causes a depolarization that mimics the effect of B2 activity. The slow interaction between the B2 and B7nor neurons can be re-established when the two neurons are cocultured, and it shows the same susceptibility to NOS inhibition and NO scavenging. In cell culture we have also examined spatial aspects of NO signaling. We show that before the formation of an anatomical connection, the presynaptic neuron can cause depolarizing potentials in the follower neuron at distances up to 50 micro(m). The strength of the interaction increases when the distance between the cells is reduced. Our results suggest that NO can function as both a synaptic and a nonsynaptic signaling molecul

Expected job loss in East Germany shortly before German unification

We investigate expectations concerning future job loss in the former German Democratic Republic shortly before the economic, monetary and social union in July 1990. In order to model these expectations, we take detailed account of individual heterogeneity, the availability and interpretation of information, and the economic and social environment of the individual. Our data base is the Socio-Economic Panel (SOEP) East. We find that, with some exceptions, East Germans hold expectations comparable to those held by individuals having experienced a market economy, which is surprising given the lack of such an economy in the previous German Democratic Republic. Since these expectations are only observed ordinally, an adequate estimation method is the ordinal logit model. The corresponding stochastic assumptions are tested extensively using pseudo-Lagrange multiplier tests against omitted variables, nonlinearity, asymmetry of distribution and heteroscedasticity. Furthermore, we apply Hausman tests to check the validity of the classification of the endogenous variable. --

Photoionization of Clustered Halos by the First Stars

We present numerical simulations of the photoevaporation of cosmological halos clustered around a 120 M$_\odot$ primordial star, confining our study to structures capable of hosting Population III star formation. The calculations include self-consistent multifrequency conservative transfer of UV photons together with nine-species primordial chemistry and all relevant radiative processes. The ultimate fates of these halos varies with central density and proximity to the central source but generally fall into one of four categories. Diffuse halos with central densities below 2 - 3 cm$^{-3}$ are completely ionized and evaporated by the central star anywhere in the cluster. More evolved halo cores at densities above 2000 cm$^{-3}$ are impervious to both ionizing and Lyman-Werner flux at most distances from the star and collapse of their cores proceeds without delay. Radiative feedback in halos of intermediate density can be either positive or negative, depending on how the I-front remnant shock both compresses and deforms the core and enriches it with H$_2$. We find that the 120 M$_\odot$ star photodissociates H$_2$ in most halos within the cluster but that catalysis by H- rapidly restores molecular hydrogen within a few hundred Kyr after the death of the star, with little delay in star formation. Our models exhibit significant departures from previous one-dimensional spherically-symmetric simulations, which are prone to serious errors due to unphysical geometric focusing effects.Comment: 5 pages, 5 figures, to appear in "First Stars III", eds. B. O'Shea, A. Heger and T. Abe

The First Population II Stars Formed in Externally Enriched Mini-halos

We present a simulation of the formation of the earliest Population II stars, starting from cosmological initial conditions and ending when metals created in the first supernovae are incorporated into a collapsing gas-cloud. This occurs after a supernova blast-wave collides with a nearby mini-halo, inducing further turbulence that efficiently mixes metals into the dense gas in the center of the halo. The gas that first collapses has been enriched to a metallicity of Z ~ 2e-5 Zsun. Due to the extremely low metallicity, collapse proceeds similarly to metal-free gas until dust cooling becomes efficient at high densities, causing the cloud to fragment into a large number of low mass objects. This external enrichment mechanism provides a plausible origin for the most metal-poor stars observed, such as SMSS J031300.36-670839.3, that appear to have formed out of gas enriched by a single supernova. This mechanism operates on shorter timescales than the time for low-mass mini-halos (M < 5e5 Msun) to recover their gas after experiencing a supernova. As such, metal-enriched stars will likely form first via this channel if the conditions are right for it to occur. We identify a number of other externally enriched halos that may form stars in this manner. These halos have metallicities as high as 0.01 Zsun, suggesting that some members of the first generation of metal-enriched stars may be hiding in plain sight in current stellar surveys.Comment: Accepted for publication in MNRAS. Minor updates and one additional figure. Movies and images available at http://www.roe.ac.uk/~brs/pop2prim

Did Massive Primordial Stars Preenrich the Lyman Alpha Forest?

We examine the dynamical evolution and statistical properties of the supernova ejecta of massive primordial stars in a cosmological framework to determine whether this first population of stars could have enriched the universe to the levels and dispersions seen by the most recent observations of the Lyman-Alpha forest. We evolve a lambda CDM model in a 1 Mpc^3 volume to a redshift of z = 15 and add ``bubbles'' of metal corresponding to the supernova ejecta of the first generation of massive stars in all dark matter halos with masses greater than 5 times 10^5 solar masses. These initial conditions are then evolved to z = 3 and the distribution and levels of metals are compared to observations. In the absence of further star formation the primordial metal is initially contained in halos and filaments. Photoevaporation of metal-enriched gas due to the metagalactic ultraviolet background radiation at the epoch of reionization (z ~ 6) causes a sharp increase of the metal volume filling factor. At z = 3, ~ 2.5% of the simulation volume (approx. 20% of the total gas mass) is filled with gas enriched above a metallicity of 10^-4 Z_solar, and less than 0.6% of the volume is enriched above a metallicity of 10^-3 Z_solar. This suggests that, even with the most optimistic prescription for placement of primordial supernova and the amount of metals produced by each supernova, this population of stars cannot entirely be responsible for the enrichment of the Lyman-$\alpha$ forest to the levels and dispersions seen by current observations unless we have severely underestimated the duration of the Pop III epoch. However, comparison to observations show that Pop III supernovae can be significant contributors to the very low overdensity Lyman-Alpha forest.Comment: 4 pages, 3 figures (color). Accepted to ApJ Letters. Replaced version has some correction

How the First Stars Regulated Local Star Formation I: Radiative Feedback

We present numerical simulations of how a 120 M$_\odot$ primordial star regulates star formation in nearby cosmological halos at $z \sim$ 20 by photoevaporation. Our models include nine-species primordial chemistry and self-consistent multifrequency conservative transfer of UV photons with all relevant radiative processes. Whether or not new stars form in halos clustered around a Population III star ultimately depends on their core densities and proximity to the star. Diffuse halos with central densities below 2 - 3 cm$^{-3}$ are completely ionized and evaporated anywhere in the cluster. Evolved halos with core densities above 2000 cm$^{-3}$ are impervious to both ionizing and Lyman-Werner flux at most distances from the star and collapse as quickly as they would in its absence. Star formation in halos of intermediate density can be either promoted or suppressed depending on how the I-front remnant shock compresses, deforms and enriches the core with H$_2$. We find that the 120 M$_\odot$ star photodissociates H$_2$ in most halos in the cluster but that catalysis by H- restores it a few hundred kyr after the death of the star, with little effect on star formation. Our models exhibit significant departures from previous one-dimensional spherically-symmetric simulations, which are prone to serious errors due to unphysical geometric focusing effects.Comment: 20 pages, 19 figures, accepted by ApJ, title and abstract change

Associative memory stored by functional novel pathway rather than modifications of preexisting neuronal pathways

Associative conditioning involves changes in the processing pathways activated by sensory information to link the conditioned stimulus (CS) to the conditioned behavior. Thus, conditioning can recruit neuronal elements to form new pathways for the processing of the CS and/or can change the strength of existing pathways. Using a behavioral and systems level electrophysiological approach on a tractable invertebrate circuit generating feeding in the mollusk Lymnaea stagnalis, we identified three independent pathways for the processing of the CS amyl acetate used in appetitive conditioning. Two of these pathways, one suppressing and the other stimulating feeding, mediate responses to the CS in naive animals. The effects ofthese two pathways on feeding behavior are unaltered by conditioning. In contrast, the CS response ofa third stimulatory pathway is significantly enhanced after conditioning, becoming an importantcontributor to the overall CS response. This is unusual because, in most of the previous examples in which naive animals already respond to the CS, memory formation results from changes in the strength of pathways that mediate the existing response. Here, we show that, in the molluscan feeding system, both modified and unmodified pathways are activated in parallel by the CS after conditioning, and it is their integration that results in the conditioned respons