Biomedical subjects

Mark E Nelson

Publications and source records attributed to Mark E Nelson.

8 recordsLinked to original sources

PubMed2006

Short-term synaptic plasticity can enhance weak signal detectability in nonrenewal spike trains.

We study the encoding of weak signals in spike trains with interspike interval (ISI) correlations and the signals' subsequent detection in sensory neurons. Motivated by the observation of negative ISI correlations in auditory and electrosensory afferents, we assess the theoretical performance limits of an individual detector neuron receiving a weak signal distributed across multiple afferent inputs. We assess the functional role of ISI correlations in the detection process using statistical detection theory and derive two sequential likelihood ratio detector models: one for afferents with renewal statistics; the other for afferents with negatively correlated ISIs. We suggest a mechanism that might enable sensory neurons to implicitly compute conditional probabilities of presynaptic spikes by means of short-term synaptic plasticity. We demonstrate how this mechanism can enhance a postsynaptic neuron's sensitivity to weak signals by exploiting the correlation structure of the input spike trains. Our model not only captures fundamental aspects of early electrosensory signal processing in weakly electric fish, but may also bear relevance to the mammalian auditory system and other sensory modalities.

Action Potentials↗

PubMed2004

Modeling signal and background components of electrosensory scenes.

Weakly electric fish are able to detect and localize prey based on microvolt-level perturbations in the fish's self-generated electric field. In natural environments, weak prey-related signals are embedded in much stronger electrosensory background noise. To better characterize the signal and background components associated with natural electrolocation tasks, we recorded transdermal voltage modulations in restrained Apteronotus albifrons in response to moving spheres, tail bends, and large nonconducting boundaries. Spherical objects give rise to ipsilateral images with center-surround structure and contralateral images that are weak and diffuse. Tail bends and laterally placed nonconducting boundaries induce relatively strong ipsilateral and contralateral modulations of opposite polarity. We present a computational model of electric field generation and electrosensory image formation that is able to reproduce the key features of these empirically measured signal and background components in a unified framework. The model comprises an array of point sources and sinks distributed along the midline of the fish, which can conform to arbitrary body bends. The model is computationally fast and can be used to estimate the spatiotemporal pattern of activation across the entire electroreceptor array of the fish during natural behaviors.

Animals↗

PubMed2003

Human alpha4beta2 acetylcholine receptors formed from linked subunits.

We prepared concatamers of alpha4 and beta2 subunits for human nicotinic acetylcholine receptors (AChRs), in which the C terminus of alpha4 was linked to the N terminus of beta2, or vice versa, via a tripeptide sequence repeated 6 or 12 times, and expressed them in Xenopus oocytes. Linkage did not substantially alter channel amplitude or channel open-duration. Linkage at the C terminus of alpha4 prevented AChR potentiation by 17-beta-estradiol by disruption of its binding site. Assembly of AChRs from concatamers was less efficient, but function was much more efficient than that of unlinked subunits. With both linked and free subunits, greater ACh-induced currents per surface AChR were observed with the (alpha4)3(beta2)2 stoichiometry than with the (alpha4)2(beta2)3 stoichiometry. The (alpha4)3(beta2)2 stoichiometry exhibited much lower ACh sensitivity. When concatamers were expressed alone, dipentameric AChRs were formed in which the (alpha4)2(beta2)3 pentamer was linked to the (alpha4)3(beta2)2 pentamer. Dipentamers were selectively expressed on the cell surface, whereas most monopentamers with dangling subunits were retained intracellularly. Coexpression of concatamers with monomeric beta2, beta4, or alpha4 subunits resulted in monopentamers, the stoichiometry of which was determined by the free subunit added. Linkage between the C terminus of beta2 and the N terminus of alpha4 favored formation of ACh-binding sites within the concatamer, whereas linkage between the C terminus of alpha4 and the N terminus of beta2 favored formation of ACh-binding sites between concatamers. These protein-engineering studies provide insight into the structure and function of alpha4beta2 AChRs, emphasizing the functional differences between alpha4beta2 AChRs of different stoichiometries.

Acetylcholine↗

PubMed2003

Alternate stoichiometries of alpha4beta2 nicotinic acetylcholine receptors.

Two functional types of nicotinic acetylcholine receptors (nAChRs) are expressed when human embryonic kidney cells are permanently transfected with equal amounts of human alpha4 and beta2 subunit cDNAs. Most (82%) of these nAChRs exhibit an EC(50) of 74 +/- 6 microM for ACh, a much lower sensitivity than the remaining fraction (EC(50) of 0.7 +/- 0.4 microM) or than expected from expression of equal amounts of alpha4 and beta2 mRNAs in Xenopus laevis oocytes. We have found three conditions that can increase the number of nAChRs with high sensitivity to activation. These are: 1) transient transfection with additional beta2 subunits, 2) overnight incubation in nicotine, or 3) overnight culture at 29 degrees C. Using metabolic labeling with [(35)S]methionine to measure subunit stoichiometry, we found that the majority of nAChRs had a stoichiometry of (alpha4)(3)(beta2)(2). Overnight treatment with nicotine increased the number of nAChRs and increased the proportion of the (alpha4)(2)(beta2)(3) stoichiometry. Alternate alpha4beta2 nAChR stoichiometries with distinct functional properties raise the possibility for an interesting mode of synaptic regulation for nicotinic signaling in the mammalian brain.

Cells, Cultured↗

PubMed2002

First and second transmembrane segments of alpha3, alpha4, beta2, and beta4 nicotinic acetylcholine receptor subunits influence the efficacy and potency of nicotine.

The first three transmembrane segments (M1-M3) of human nicotinic acetylcholine receptors (nAChRs) have been implicated in determining the efficacy of nicotine by studies of alpha3/alpha4 subunit chimeras. Nicotine has full efficacy on the alpha4beta2 nAChR and partial efficacy on the alpha3beta2 nAChR. Now, we have exchanged individually three amino acids between the alpha4 and the alpha3 subunits at positions 226(M1), 258(M2), and 262(M2). Also, similar exchanges were made in the beta2 and beta4 subunits at positions 224(M1), 226(M1), and 254(M2) (using alpha subunit numbering). Expression of these mutated nAChRs in Xenopus laevis oocytes showed that the mutated M1 amino acids were important in influencing the potency of ACh and nicotine. It is hypothesized that these M1 amino acids affect the stability between the resting and activated states of the nAChR. M2 amino acids altered the efficacy of nicotine, usually without altering its potency. When the residue located at position 258 in the M2 region of the alpha subunit was valine (as in the alpha3 subunit), the resulting nAChR exhibited partial efficacy for nicotine that was voltage-dependent. Therefore, we believe that these M2 amino acids contribute to the formation of a binding site for nicotine in the alpha3beta2 nAChR channel, which results in a low-affinity channel block, causing the lower efficacy of nicotine on this nAChR.

Alkaloids↗

PubMed2002

Modeling electrosensory and mechanosensory images during the predatory behavior of weakly electric fish.

Black ghost knifefish (Apteronotus albifrons) are nocturnal, weakly electric fish that feed on insect larvae and small crustaceans in the freshwater rivers of South America. In the absence of visual cues, prey detection and localization in this species is likely to rely on weak electrosensory and mechanosensory cues generated by the prey. In this paper, a modeling approach is used to estimate contributions to prey capture behavior from three octavolateralis modalities: the high- (tuberous) and low- (ampullary) frequency components of the electric sense and the high-frequency (canal neuromast) component of the lateral line mechanosensory system. For each of these modalities, the physical stimulus generated by the prey is approximated using a simple dipole model. Model parameters are constrained using previously published data as well as new empirical data on the electrical impedance characteristics of Daphnia magna. Models of electrosensory and mechanosensory stimuli are combined with actual prey strike trajectories from infrared video recordings to reconstruct spatial images of the prey along the sensory surface of the fish during the behavior. Modeling results suggest that all three modalities might contribute and that the relative contributions may change as a function of environmental conditions (e.g., water conductivity) and as a function of time over the course of the prey capture event.

Animals↗

PubMed2002

A simple model of long-term spike train regularization.

A simple model of spike generation is described that gives rise to negative correlations in the interspike interval (ISI) sequence and leads to long-term spike train regularization. This regularization can be seen by examining the variance of the kth-order interval distribution for large k (the times between spike i and spike i + k). The variance is much smaller than would be expected if successive ISIs were uncorrelated. Such regularizing effects have been observed in the spike trains of electrosensory afferent nerve fibers and can lead to dramatic improvement in the detectability of weak signals encoded in the spike train data (Ratnam & Nelson, 2000). Here, we present a simple neural model in which negative ISI correlations and long-term spike train regularization arise from refractory effects associated with a dynamic spike threshold. Our model is derived from a more detailed model of electrosensory afferent dynamics developed recently by other investigators (Chacron, Longtin, St.-Hilaire, & Maler, 2000;Chacron, Longtin, & Maler, 2001). The core of this model is a dynamic spike threshold that is transiently elevated following a spike and subsequently decays until the next spike is generated. Here, we present a simplified version-the linear adaptive threshold model-that contains a single state variable and three free parameters that control the mean and coefficient of variation of the spontaneous ISI distribution and the frequency characteristics of the driven response. We show that refractory effects associated with the dynamic threshold lead to regularization of the spike train on long timescales. Furthermore, we show that this regularization enhances the detectability of weak signals encoded by the linear adaptive threshold model. Although inspired by properties of electrosensory afferent nerve fibers, such regularizing effects may play an important role in other neural systems where weak signals must be reliably detected in noisy spike trains. When modeling a neuronal system that exhibits this type of ISI correlation structure, the linear adaptive threshold model may provide a more appropriate starting point than conventional renewal process models that lack long-term regularizing effects.

Action Potentials↗

PubMedDate not supplied

Multiscale spike train variability in primary electrosensory afferents.

Spike train variability is of fundamental importance for understanding how information is encoded and processed in the nervous system. Most studies in this area have focused on short-term variability, as characterized by the coefficient of variation of the interspike interval distribution. Here we discuss the importance of extending the analysis of spike train variability to longer time scales that span multiple interspike intervals. Recent experimental and modeling studies of probability coding (P-type) electrosensory afferent nerve fibers in weakly electric fish have provided new insights into the functional importance of multiscale spike train variability. P-type afferent spike trains are moderately irregular on short time scales of a few milliseconds, but show significantly enhanced regularity on time scales of a few hundred milliseconds. This increased regularity is beyond what would be expected for a renewal process model in which successive intervals are uncorrelated. Modeling studies suggest that the correlation structure that underlies spike train regularization arises from relative refractory effects associated with a dynamic spike threshold. Spike train regularization in P-type afferents has been shown to significantly enhance signal detectability and information transmission on time scales that are functionally relevant for electrolocation behavior.

Action Potentials↗