Statistical Analysis of Membrane Potential Fluctuations: Relation with Presynaptic Spike Train

In a study of integration at the single neuron level, the relationships between the postsynaptic membrane potential and the presynaptic spike train were analyzed. Fluctuations in membrane potential of neurons in the visceral ganglion of Aplysia were measured and described by histograms. The histogram estimates the probability density function of the membrane potential. Comparisons were made among histograms when there was no synaptic input, and when there was a single input in which variations were made in the PSP (postsynaptic potential) sign, i.e. excitatory or inhibitory, and arrival statistics, e.g. slow or fast, regular, Poisson-like, or patterned. This was examined in cells where the membrane potential was constant and in cells in which there was spontaneous pacemaker activity. The form of the histogram depended on whether the neuron was spontaneously quiescent or a pacemaker, or whether it received presynaptic input and, if it did, on the sign and temporal characteristics of such input. From such histograms the mean firing rate of output spike trains can be predicted; additional information of a temporal nature is required, however, to predict features of the interval structure of the output train. Suggestions are made concerning the way the nervous system might utilize the information summarized in the membrane potential histogram.     

A Unified Approach to Linking Experimental,Statistical and Computational Analysis of Spike Train Data

A fundamental issue in neuroscience is how to identify the multiple biophysical mechanisms through which neurons generate observed patterns of spiking activity. In previous work, we proposed a method for linking observed patterns of spiking activity to specific biophysical mechanisms based on a state space modeling framework and a sequential Monte Carlo, or particle filter, estimation algorithm. We have shown, in simulation, that this approach is able to identify a space of simple biophysical models that were consistent with observed spiking data (and included the model that generated the data), but have yet to demonstrate the application of the method to identify realistic currents from real spike train data. Here, we apply the particle filter to spiking data recorded from rat layer V cortical neurons, and correctly identify the dynamics of an slow, intrinsic current. The underlying intrinsic current is successfully identified in four distinct neurons, even though the cells exhibit two distinct classes of spiking activity: regular spiking and bursting. This approach – linking statistical, computational, and experimental neuroscience – provides an effective technique to constrain detailed biophysical models to specific mechanisms consistent with observed spike train data.     

Quantifying the Uncertainty of Spontaneous Ca Oscillations in Astrocytes: Particulars of Alzheimer's Disease

The quantification of spontaneous calcium (Ca²⁺) oscillations (SCOs) in astrocytes presents a challenge because of the large irregularities in the amplitudes, durations, and initiation times of the underlying events. In this article, we use a stochastic context to account for such SCO variability, which is based on previous models for cellular Ca²⁺ signaling. First, we found that passive Ca²⁺ influx from the extracellular space determine the basal concentration of this ion in the cytosol. Second, we demonstrated the feasibility of estimating both the inositol 1,4,5-trisphosphate (IP₃) production levels and the average number of IP₃ receptor channels in the somatic clusters from epifluorescent Ca²⁺ imaging through the combination of a filtering strategy and a maximum-likelihood criterion. We estimated these two biophysical parameters using data from wild-type adult mice and age-matched transgenic mice overexpressing the 695-amino-acid isoform of human Alzheimer β-amyloid precursor protein. We found that, together with an increase in the passive Ca²⁺ influx, a significant reduction in the sensitivity of G protein-coupled receptors might lie beneath the abnormalities in the astrocytic Ca²⁺ signaling, as was observed in rodent models of Alzheimer's disease. This study provides new, to our knowledge, indices for a quantitative analysis of SCOs in normal and pathological astrocytes.     

Oscillations,clocks and segmentation

Notch signalling molecules, such as the basic helix-loop-helix factors Hes1 and Hes7, periodically change their expression in the presomitic mesoderm, and each cycle of gene expression is associated with somite formation (every two hours in mouse). This cyclic expression is the manifestation of an intrinsic mechanism, called the segmentation clock, which is essential for coordinated somite segmentation. Interestingly, the oscillatory expression of Hes1 is observed in many cell types after serum stimulation, suggesting that this ultradian clock is not unique to presomitic mesoderm cells but widely distributed. This oscillation depends on the negative feedback loop, and once its promoter is constitutively activated, Hes1 seems to start oscillatory gene expression autonomously. Thus, Hes1 acts as a device that transduces a direct current of input into an alternating current, which ticks the hours in many biological systems.     

Bifurcation, Bursting, and Spike Frequency Adaptation

Many neural systems display adaptive properties that occur on timescales that are slower than the time scales associated withrepetitive firing of action potentials or bursting oscillations. Spike frequency adaptation is the name givento processes thatreduce the frequency of rhythmic tonic firing of action potentials,sometimes leading to the termination of spiking and the cell becomingquiescent. This article examines these processes mathematically,within the context of singularly perturbed dynamical systems.We place emphasis on the lengths of successive interspikeintervals during adaptation. Two different bifurcation mechanisms insingularly perturbed systems that correspond to the termination offiring are distinguished by the rate at which interspike intervalsslow near the termination of firing. We compare theoreticalpredictions to measurement of spike frequency adaptation in a modelof the LP cell of the lobster stomatogastric ganglion.     

Biases,gaps, and opportunities in mammalian extinction risk research

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Biases in Visual,Auditory, and Audiovisual Perception of Space

Localization of objects and events in the environment is critical for survival, as many perceptual and motor tasks rely on estimation of spatial location. Therefore, it seems reasonable to assume that spatial localizations should generally be accurate. Curiously, some previous studies have reported biases in visual and auditory localizations, but these studies have used small sample sizes and the results have been mixed. Therefore, it is not clear (1) if the reported biases in localization responses are real (or due to outliers, sampling bias, or other factors), and (2) whether these putative biases reflect a bias in sensory representations of space or a priori expectations (which may be due to the experimental setup, instructions, or distribution of stimuli). Here, to address these questions, a dataset of unprecedented size (obtained from 384 observers) was analyzed to examine presence, direction, and magnitude of sensory biases, and quantitative computational modeling was used to probe the underlying mechanism(s) driving these effects. Data revealed that, on average, observers were biased towards the center when localizing visual stimuli, and biased towards the periphery when localizing auditory stimuli. Moreover, quantitative analysis using a Bayesian Causal Inference framework suggests that while pre-existing spatial biases for central locations exert some influence, biases in the sensory representations of both visual and auditory space are necessary to fully explain the behavioral data. How are these opposing visual and auditory biases reconciled in conditions in which both auditory and visual stimuli are produced by a single event? Potentially, the bias in one modality could dominate, or the biases could interact/cancel out. The data revealed that when integration occurred in these conditions, the visual bias dominated, but the magnitude of this bias was reduced compared to unisensory conditions. Therefore, multisensory integration not only improves the precision of perceptual estimates, but also the accuracy.     

Spike timing,calcium signals and synaptic plasticity

Plasticity at central synapses depends critically on the timing of presynaptic and postsynaptic action potentials. Key initial steps in synaptic plasticity involve the back-propagation of action potentials into the dendritic tree and calcium influx that depends nonlinearly on the action potential and synaptic input. These initial steps are now better understood. In addition, recent studies of processes as diverse as gene expression and channel inactivation suggest that responses to calcium transients depend not only their amplitude, but on their time course and on the location of their origin.     

Kin Relationships and the Caregiving Biases of Grandparents, Aunts, and Uncles

Paternity certainty and matrilineal family ties have been used to explain the asymmetric caregiving of grandparents and aunts and uncles. The proximate mechanisms underlying biased kin investment, however, remain unclear. A central question of the study presented here was whether the parent-kin relationship is an important link in the caregiving. In a two-generational questionnaire study, we asked subjects to estimate the intensity of their relationships to parents, grandparents, aunts, and uncles (emotional closeness, investment received in childhood). In addition, the subjects’ parents rated their emotional closeness to their parents and siblings. We found that the parent-kin relationship was closely linked to the relatives’ child care and could partly explain asymmetric caregiving. Maternal aunts played a special role as caregivers. Especially the mother’s younger or last-born sister cared intensively for nieces and nephews, regardless of her closeness to the subjects’ mother.     

Species Richness and Invasion Vectors: Sampling Techniques and Biases

During a European Union Concerted Action study on species introductions, an intercalibration workshop on ship ballast water sampling techniques considered various phytoplankton and zooplankton sampling methods. For the first time, all the techniques presently in use worldwide were compared using a plankton tower as a model ballast tank spiked with the brine shrimp and oyster larvae while phytoplankton samples were taken simultaneously in the field (Helgoland Harbour, Germany). Three cone-shaped and 11 non-cone shaped plankton nets of different sizes and designs were employed. Net lengths varied from 50 to 300 cm, diameters 9.7–50 cm, and mesh sizes 10–100 μm. Three pumps, a Ruttner sampler, and a bucket previously used in ballast water sampling studies were also compared. This first assessment indicates that for sampling ballast water a wide range of techniques may be needed. Each method showed different results in efficiency and it is unlikely that any of the methods will sample all taxa. Although several methods proved to be valid elements of a hypothetical `tool box' of effective ship sampling techniques. The Ruttner water sampler and the pump P30 provide suitable means for the quantitative phytoplankton sampling, whereas other pumps prevailed during the qualitative trial. Pump P15 and cone-shaped nets were the best methods used for quantitative zooplankton sampling. It is recommended that a further exercise involving a wider range of taxa be examined in a larger series of mesocosms in conjunction with promising treatment measures for managing ballast water. This revised version was published online in July 2006 with corrections to the Cover Date.     

Oscillations, resonances and noise: basis of flexible neuronal pattern generation

Modulation of neuronal impulse pattern is examined by means of a simplified Hodgkin-Huxley type computer model which refers to experimental recordings of cold receptor discharges. This model essentially consists of two potentially oscillating subsystems: a spike generator and a subthreshold oscillator. With addition of noise the model successfully mimics the major types of experimentally recorded impulse patterns and thereby elucidate different resonance behaviors. (1) There is a range of rhythmic spiking or bursting where the spike generator is strongly coupled to the subthreshold oscillator. (2) There is a pacemaker activity of more complex interactions where the spike generator has overtaken part of the control. (3) There is a situation where the two subsystems are decoupled and only resonate with the help of noise.     

The Sicker Sex: Understanding Male Biases in Parasitic Infection,Resource Allocation and Fitness

The “sicker sex” idea summarizes our knowledge of sex biases in parasite burden and immune ability whereby males fare worse than females. The theoretical basis of this is that because males invest more on mating effort than females, the former pay the costs by having a weaker immune system and thus being more susceptible to parasites. Females, conversely, have a greater parental investment. Here we tested the following: a) whether both sexes differ in their ability to defend against parasites using a natural host-parasite system; b) the differences in resource allocation conflict between mating effort and parental investment traits between sexes; and, c) effect of parasitism on survival for both sexes. We used a number of insect damselfly species as study subjects. For (a), we quantified gregarine and mite parasites, and experimentally manipulated gregarine levels in both sexes during adult ontogeny. For (b), first, we manipulated food during adult ontogeny and recorded thoracic fat gain (a proxy of mating effort) and abdominal weight (a proxy of parental investment) in both sexes. Secondly for (b), we manipulated food and gregarine levels in both sexes when adults were about to become sexually mature, and recorded gregarine number. For (c), we infected male and female adults of different ages and measured their survival. Males consistently showed more parasites than females apparently due to an increased resource allocation to fat production in males. Conversely, females invested more on abdominal weight. These differences were independent of how much food/infecting parasites were provided. The cost of this was that males had more parasites and reduced survival than females. Our results provide a resource allocation mechanism for understanding sexual differences in parasite defense as well as survival consequences for each sex.     

Quantifying asymmetry: Ratios and alternatives

Traditionally, the study of metric skeletal asymmetry has relied largely on univariate analyses, utilizing ratio transformations when the goal is comparing asymmetries in skeletal elements or populations of dissimilar dimensions. Under this approach, raw asymmetries are divided by a size marker, such as a bilateral average, in an attempt to produce size‐free asymmetry indices. Henceforth, this will be referred to as “controlling for size” (see Smith: Curr Anthropol 46 (2005) 249‐273). Ratios obtained in this manner often require further transformations to interpret the meaning and sources of asymmetry. This model frequently ignores the fundamental assumption of ratios: the relationship between the variables entered in the ratio must be isometric. Violations of this assumption can obscure existing asymmetries and render spurious results. In this study, we examined the performance of the classic indices in detecting and portraying the asymmetry patterns in four human appendicular bones and explored potential methodological alternatives. Examination of the ratio model revealed that it does not fulfill its intended goals in the bones examined, as the numerator and denominator are independent in all cases. The ratios also introduced strong biases in the comparisons between different elements and variables, generating spurious asymmetry patterns. Multivariate analyses strongly suggest that any transformation to control for overall size or variable range must be conducted before, rather than after, calculating the asymmetries. A combination of exploratory multivariate techniques, such as Principal Components Analysis, and confirmatory linear methods, such as regression and analysis of covariance, appear as a promising and powerful alternative to the use of ratios. Am J Phys Anthropol 154:498–511, 2014. © 2014 Wiley Periodicals, Inc.     

Variation in Reproductive Success Across Captive Populations: Methodological Differences,Potential Biases and Opportunities

Our understanding of fundamental organismal biology has been disproportionately influenced by studies of a relatively small number of ‘model’ species extensively studied in captivity. Laboratory populations of model species are commonly subject to a number of forms of past and current selection that may affect experimental outcomes. Here, we examine these processes and their outcomes in one of the most widely used vertebrate species in the laboratory – the zebra finch (Taeniopygia guttata). This important model species is used for research across a broad range of fields, partly due to the ease with which it can be bred in captivity. However despite this perceived amenability, we demonstrate extensive variation in the success with which different laboratories and studies bred their subjects, and overall only 64% of all females that were given the opportunity, bred successfully in the laboratory. We identify and review several environmental, husbandry, life‐history and behavioural factors that potentially contribute to this variation. The variation in reproductive success across individuals could lead to biases in experimental outcomes and drive some of the heterogeneity in research outcomes across studies. The zebra finch remains an excellent captive animal system and our aim is to sharpen the insight that future studies of this species can provide, both to our understanding of this species and also with respect to the reproduction of captive animals more widely. We hope to improve systematic reporting methods and that further investigation of the issues we raise will lead both to advances in our fundamental understanding of avian reproduction as well as to improvements in future welfare and experimental efficiency.     

Replication Dynamics: Biases and Robustness of DNA Fiber Analysis

The factors that govern replication programs are still poorly identified in metazoans, especially in mammalian cells. Thanks to molecular combing, the dynamics of DNA replication can be assessed at the genome-scale level from the cumulative analysis of single DNA fibers. This technique notably enables measurement of replication fork speed and fork asymmetry and that of distances separating either initiation or termination events. The results presented here aim to evaluate requirements critical to accurate measurement of replication parameters by molecular combing. We show that sample size, fiber length and DNA counterstaining are crucial to gain robust information concerning replication dynamics. Our results thus provide a methodological frame to investigate the DNA replication program through molecular combing analyses.     

Slow Rhythmic Oscillations within the Human Cranium: Phenomenology, Origin, and Informational Significance

Slow rhythmic oscillations in the human cranial cavity were studied using two noninvasive methods: the bioimpedance method (volume ratios between liquid media in the cranial cavity) and transcranial ultrasound Doppler echography (variation in the blood flow in the middle cerebral artery). The combination of these methods made it possible to estimate the intracranial hemodynamics. Simultaneous recording of these parameters and their spectral analysis were carried out in healthy subjects and patients with intracranial hypertension syndrome and disturbed cerebrospinal fluid (CSF) flow. The parameters were recorded at rest and immediately after manual (osteopathic) correction. The recording and analysis were performed using a Macintosh-IIsi PC and the Chart-3.52, Cricket Graph-3.32, and Canvas-3.5 software. It was found that slow oscillations of the bioimpedance (BIM) in the frequency range 0.08–0.2 Hz were of intracranial origin and were related to the mechanisms of regulation of the blood supply to and oxygen consumption by cerebral tissue, as well as with the dynamics of the CSF circulation.