Transmission of temporally correlated spike trains through synapses with short-term depression

Short-term synaptic depression, caused by depletion of releasable neurotransmitter, modulates the strength of neuronal connections in a history-dependent manner. Quantifying the statistics of synaptic transmission requires stochastic models that link probabilistic neurotransmitter release with presynaptic spike-train statistics. Common approaches are to model the presynaptic spike train as either regular or a memory-less Poisson process: few analytical results are available that describe depressing synapses when the afferent spike train has more complex, temporally correlated statistics such as bursts. Here we present a series of analytical results—from vesicle release-site occupancy statistics, via neurotransmitter release, to the post-synaptic voltage mean and variance—for depressing synapses driven by correlated presynaptic spike trains. The class of presynaptic drive considered is that fully characterised by the inter-spike-interval distribution and encompasses a broad range of models used for neuronal circuit and network analyses, such as integrate-and-fire models with a complete post-spike reset and receiving sufficiently short-time correlated drive. We further demonstrate that the derived post-synaptic voltage mean and variance allow for a simple and accurate approximation of the firing rate of the post-synaptic neuron, using the exponential integrate-and-fire model as an example. These results extend the level of biological detail included in models of synaptic transmission and will allow for the incorporation of more complex and physiologically relevant firing patterns into future studies of neuronal networks

Temporal and spatial factors affecting synaptic transmission in cortex

Synaptic transmission in cortex depends on both the history of synaptic activity and the location of individual anatomical contacts within the dendritic tree. This thesis analyses key aspects of the roles of both these factors and, in particular, extends many of the results for deterministic synaptic transmission to a more naturalistic stochastic framework. Firstly, I consider how correlations in neurotransmitter vesicle occupancy arising from synchronous activity in a presynaptic population interact with the number of independent release sites, a parameter recently shown to be modified during long-term plasticity. I study a model of multiple-release-site short-term plasticity and derive exact results for the postsynaptic voltage variance. Using approximate results for the postsynaptic firing rate in the limits of low and high correlations, I demonstrate that short-term depression leads to a maximum response for an intermediate number of presynaptic release sites, and that this in turn leads to a tuning-curve response peaked at an optimal presynaptic synchrony set by the number of neurotransmitter release sites per presynaptic neuron. As the nervous system operates under constraints of efficient metabolism it is likely that this phenomenon provides an activity-dependent constraint on network architecture. Secondly, I consider how synapses exhibiting short-term plasticity transmit spike trains when spike times are autocorrelated. I derive exact results for vesicle occupancy and postsynaptic voltage variance in the case that spiking is a renewal process, with uncorrelated interspike intervals (ISIs). The vesicle occupancy predictions are tested experimentally and shown to be in good agreement with the theory. I demonstrate that neurotransmitter is released at a higher rate when the presynaptic spike train is more regular, but that positively autocorrelated spike trains are better drivers of the postsynaptic voltage when the vesicle release probability is low. I provide accurate approximations to the postsynaptic firing rate, allowing future studies of neuronal circuits and networks with dynamic synapses to incorporate physiologically relevant spiking statistics. Thirdly, I develop a Bayesian inference method for synaptic parameters. This expands on recent Bayesian approaches in that the likelihood function is exact for both the quantal and dynamic synaptic parameters. This means that it can be used to directly estimate parameters for common synaptic models with few release sites. I apply the method to simulated and real data; demonstrating a substantial improvement over analysis techniques that are based around the mean and variance. Finally, I consider a spatially extended neuron model where the dendrites taper away from the soma. I derive an accurate asymptotic solution for the voltage profile in a dendritic cable of arbitrary radius profile and use this to determine the profile that optimally transfers voltages to the soma. I find a precise quadratic form that matches results from non-parametric numerical optimisation. The equation predicts diameter profiles from reconstructed cells, suggesting that dendritic diameters optimise passive transfer of synaptic currents

Bayesian Inference of Synaptic Quantal Parameters from Correlated Vesicle Release

Synaptic transmission is both history-dependent and stochastic, resulting in varying responses to presentations of the same presynaptic stimulus. This complicates attempts to infer synaptic parameters and has led to the proposal of a number of different strategies for their quantification. Recently Bayesian approaches have been applied to make more efficient use of the data collected in paired intracellular recordings. Methods have been developed that either provide a complete model of the distribution of amplitudes for isolated responses or approximate the amplitude distributions of a train of post-synaptic potentials, with correct short-term synaptic dynamics but neglecting correlations. In both cases the methods provided significantly improved inference of model parameters as compared to existing mean-variance fitting approaches. However, for synapses with high release probability, low vesicle number or relatively low restock rate and for data in which only one or few repeats of the same pattern are available, correlations between serial events can allow for the extraction of significantly more information from experiment: a more complete Bayesian approach would take this into account also. This has not been possible previously because of the technical difficulty in calculating the likelihood of amplitudes seen in correlated post-synaptic potential trains; however, recent theoretical advances have now rendered the likelihood calculation tractable for a broad class of synaptic dynamics models. Here we present a compact mathematical form for the likelihood in terms of a matrix product and demonstrate how marginals of the posterior provide information on covariance of parameter distributions. The associated computer code for Bayesian parameter inference for a variety of models of synaptic dynamics is provided in the supplementary material allowing for quantal and dynamical parameters to be readily inferred from experimental data sets

Dose-response relationship of ICS/fast-onset LABA as reliever therapy in asthma

The dose-response relationship of inhaled corticosteroid (ICS)/fast-onset long acting beta agonist (LABA) reliever therapy has not been formally addressed. The objective of this retrospective analysis is to ascertain from the available evidence whether ICS/fast-onset LABA administered as reliever therapy has a different dose-response relationship than maintenance fixed dose ICS/fast-onset LABA therapy in reducing risk of severe exacerbations

Nanorheology of viscoelastic shells: Applications to viral capsids

We study the microrheology of nanoparticle shells [Dinsmore et al. Science 298, 1006 (2002)] and viral capsids [Ivanovska et al. PNAS 101, 7600 (2004)] by computing the mechanical response function and thermal fluctuation spectrum of a viscoelastic spherical shell that is permeable to the surrounding solvent. We determine analytically the damped dynamics of the shear, bend, and compression modes of the shell coupled to the solvent both inside and outside the sphere in the zero Reynolds number limit. We identify fundamental length and time scales in the system, and compute the thermal correlation function of displacements of antipodal points on the sphere and the mechanical response to pinching forces applied at these points. We describe how such a frequency-dependent antipodal correlation and/or response function, which should be measurable in new AFM-based microrheology experiments, can probe the viscoelasticity of these synthetic and biological shells constructed of nanoparticles.Comment: 17 page

Chaotic flow and efficient mixing in a micro-channel with a polymer solution

Microscopic flows are almost universally linear, laminar and stationary because Reynolds number, $Re$, is usually very small. That impedes mixing in micro-fluidic devices, which sometimes limits their performance. Here we show that truly chaotic flow can be generated in a smooth micro-channel of a uniform width at arbitrarily low $Re$, if a small amount of flexible polymers is added to the working liquid. The chaotic flow regime is characterized by randomly fluctuating three-dimensional velocity field and significant growth of the flow resistance. Although the size of the polymer molecules extended in the flow may become comparable with the micro-channel width, the flow behavior is fully compatible with that in a table-top channel in the regime of elastic turbulence. The chaotic flow leads to quite efficient mixing, which is almost diffusion independent. For macromolecules, mixing time in this microscopic flow can be three to four orders of magnitude shorter than due to molecular diffusion.Comment: 8 pages,7 figure

Conjugated linoleic acid administration induces amnesia in male sprague dawley rats and exacerbates recovery from functional deficits induced by a controlled cortical impact injury

Long-chain polyunsaturated fatty acids like conjugated linoleic acids (CLA) are required for normal neural development and cognitive function and have been ascribed various beneficial functions. Recently, oral CLA also has been shown to increase testosterone (T) biosynthesis, which is known to diminish traumatic brain injury (TBI)-induced neuropathology and reduce deficits induced by stroke in adult rats. To test the impact of CLA on cognitive recovery following a TBI, 5–6 month old male Sprague Dawley rats received a focal injury (craniectomy + controlled cortical impact (CCI; n = 17)) or Sham injury (craniectomy alone; n = 12) and were injected with 25 mg/kg body weight of Clarinol® G-80 (80% CLA in safflower oil; n = 16) or saline (n = 13) every 48 h for 4 weeks. Sham surgery decreased baseline plasma progesterone (P4) by 64.2% (from 9.5 ± 3.4 ng/mL to 3.4 ± 0.5 ng/mL; p = 0.068), T by 74.6% (from 5.9 ± 1.2 ng/mL to 1.5 ± 0.3 ng/mL; p \u3c 0.05), 11-deoxycorticosterone (11-DOC) by 37.5% (from 289.3 ± 42.0 ng/mL to 180.7 ± 3.3 ng/mL), and corticosterone by 50.8% (from 195.1 ± 22.4 ng/mL to 95.9 ± 2.2 ng/mL), by post-surgery day 1. CCI injury induced similar declines in P4, T, 11-DOC and corticosterone (58.9%, 74.6%, 39.4% and 24.6%, respectively) by post-surgery day 1. These results suggest that both Sham surgery and CCI injury induce hypogonadism and hypoadrenalism in adult male rats. CLA treatment did not reverse hypogonadism in Sham (P4: 2.5 ± 1.0 ng/mL; T: 0.9 ± 0.2 ng/mL) or CCI-injured (P4: 2.2 ± 0.9 ng/mL; T: 1.0 ± 0.2 ng/mL, p \u3e 0.05) animals by post-injury day 29, but rapidly reversed by post-injury day 1 the hypoadrenalism in Sham (11-DOC: 372.6 ± 36.6 ng/mL; corticosterone: 202.6 ± 15.6 ng/mL) and CCI-injured (11-DOC: 384.2 ± 101.3 ng/mL; corticosterone: 234.6 ± 43.8 ng/mL) animals. In Sham surgery animals, CLA did not alter body weight, but did markedly increase latency to find the hidden Morris Water Maze platform (40.3 ± 13.0 s) compared to saline treated Sham animals (8.8 ± 1.7 s). In CCI injured animals, CLA did not alter CCI-induced body weight loss, CCI-induced cystic infarct size, or deficits in rotarod performance. However, like Sham animals, CLA injections exacerbated the latency of CCI-injured rats to find the hidden MWM platform (66.8 ± 10.6 s) compared to CCI-injured rats treated with saline (30.7 ± 5.5 s, p \u3c 0.05). These results indicate that chronic treatment of CLA at a dose of 25 mg/kg body weight in adult male rats over 1-month 1) does not reverse craniectomy- and craniectomy + CCI-induced hypogonadism, but does reverse craniectomy- and craniectomy + CCI-induced hypoadrenalism, 2) is detrimental to medium- and long-term spatial learning and memory in craniectomized uninjured rats, 3) limits cognitive recovery following a moderate-severe CCI injury, and 4) does not alter body weight

Diversity of Tanaidacea (Crustacea: Peracarida) in the World's Oceans – How Far Have We Come?

Tanaidaceans are small peracarid crustaceans which occur in all marine habitats, over the full range of depths, and rarely into fresh waters. Yet they have no obligate dispersive phase in their life-cycle. Populations are thus inevitably isolated, and allopatric speciation and high regional diversity are inevitable; cosmopolitan distributions are considered to be unlikely or non-existent. Options for passive dispersion are discussed. Tanaidaceans appear to have first evolved in shallow waters, the region of greatest diversification of the Apseudomorpha and some tanaidomorph families, while in deeper waters the apseudomorphs have subsequently evolved two or three distinct phyletic lines. The Neotanaidomorpha has evolved separately and diversified globally in deep waters, and the Tanaidomorpha has undergone the greatest evolution, diversification and adaptation, to the point where some of the deep-water taxa are recolonizing shallow waters. Analysis of their geographic distribution shows some level of regional isolation, but suffers from inclusion of polyphyletic taxa and a general lack of data, particularly for deep waters. It is concluded that the diversity of the tanaidomorphs in deeper waters and in certain ocean regions remains to be discovered; that the smaller taxa are largely understudied; and that numerous cryptic species remain to be distinguished. Thus the number of species currently recognized is likely to be an order of magnitude too low, and globally the Tanaidacea potentially rival the Amphipoda and Isopoda in diversity