Periodic vs. intermittent adaptive cycles in quasispecies co-evolution

We study an abstract model for the co-evolution between mutating viruses and the adaptive immune system. In sequence space, these two populations are localized around transiently dominant strains. Delocalization or error thresholds exhibit a novel interdependence because immune response is conditional on the viral attack. An evolutionary chase is induced by stochastic fluctuations and can occur via periodic or intermittent cycles. Using simulations and stochastic analysis, we show how the transition between these two dynamic regimes depends on mutation rate, immune response, and population size.Comment: 5 pages, 3 figures, 11 pages supplementary material; updated formatting; accepted at Phys. Rev. Let

Continuous attractor working memory and provenance of channel models

The brain is a complex biological system composed of a multitude of microscopic processes, which together give rise to computational abilities observed in everyday behavior. Neuronal modeling, consisting of models of single neurons and neuronal networks at varying levels of biological detail, can synthesize the gaps currently hard to constrain in experiments and provide mechanistic explanations of how these computations might arise. In this thesis, I present two parallel lines of research on neuronal modeling, situated at varying levels of biological detail. First, I assess the provenance of voltage-gated ion channel models in an integrative meta-analysis that investigates a backlog of nearly 50 years of published research. To cope with the ever-increasing volume of research produced in the field of neuroscience, we need to develop methods for the systematic assessment and comparison of published work. As we demonstrate, neuronal models offer the intriguing possibility of performing automated quantitative analyses across studies, by standardized simulated experiments. We developed protocols for the quantitative comparison of voltage-gated ion channels, and applied them to a large body of published models, allowing us to assess the variety and temporal development of different models for the same ion channels over the time scale of years of research. Beyond a systematic classification of the existing body of research made available in an online platform, we show that our approach extends to large-scale comparisons of ion channel models to experimental data, thereby facilitating field-wide standardization of experimentally-constrained modeling. Second, I investigate neuronal models of working memory (WM). How can cortical networks bridge the short time scales of their microscopic components, which operate on the order of milliseconds, to the behaviorally relevant time scales of seconds observed in WM experiments? I consider here a candidate model: continuous attractor networks. These can implement WM for a continuum of possible spatial locations over several seconds and have been proposed for the organization of prefrontal cortical networks. I first present a novel method for the efficient prediction of the network-wide steady states from the underlying microscopic network properties. The method can be applied to predict and tune the "bump" shapes of continuous attractors implemented in networks of spiking neuron models connected by nonlinear synapses, which we demonstrate for saturating synapses involving NMDA receptors. In a second part, I investigate the computational role of short-term synaptic plasticity as a synaptic nonlinearity. Continuous attractor models are sensitive to the inevitable variability of biological neurons: variable neuronal firing and heterogeneous networks decrease the time that memories are accurately retained, eventually leading to a loss of memory functionality on behaviorally relevant time scales. In theory and simulations, I show that short-term plasticity can control the time scale of memory retention, with facilitation and depression playing antagonistic roles in controlling the drift and diffusion of locations in memory. Finally, we place quantitative constraints on the combination of synaptic and network parameters under which continuous attractors networks can implement reliable WM in cortical settings

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

Leveraging heterogeneity for neural computation with fading memory in layer 2/3 cortical microcircuits

Computational studies addressing the dynamics and computational properties of biologically inspired spiking neurons and networks tend to assume (often for the sake of analytical tractability) a great degree of homogeneity in both neuronal and connectivity parameters. The biophysical reality, however, is radically different from a homogeneous system and multiple levels of complex heterogeneous properties co-exist and shape a local circuit's emergent collective dynamics and information processing properties. Despite their varying molecular, morphological and physiological features, cortical modules can be seen as variations on a common theme. The combined complexity of the circuit's heterogeneous building blocks can be used to provide a rich dynamical space, suitable for online information processing.In this study, we set out to systematically evaluate the role played by different sources of heterogeneity (structural, neuronal and synaptic) in the characteristics of population dynamics and the circuit's capacity for online stimulus processing with fading memory, using cortical layer 2/3 microcircuits as a core inspiration for the circuit specification. We cross-reference various sources of experimental data regarding the composition and patterning of these microcircuits, accounting for different phenomena of interest (e.g. neuron types and corresponding sub-threshold characteristics, conductance properties of different receptor types, circuit-level connectivity and activity statistics, etc.), across different cortical regions, assuming a certain degree of generalization is possible. The methods applied in this study to quantify the dynamics and generic processing properties, being system-independent, can provide a valuable set of tools for microcircuit benchmarking. As carefully curated and organized datasets become increasingly available, it will become possible in the near future to apply increasingly realistic constrains and comparatively study the properties of realistic microcircuits, built to model specific cortical regions and input-output relations

Stability of working memory in continuous attractor networks under the control of short-term plasticity

Continuous attractor models of working-memory store continuous-valued information in continuous state-spaces, but are sensitive to noise processes that degrade memory retention. Short-term synaptic plasticity of recurrent synapses has previously been shown to affect continuous attractor systems: short-term facilitation can stabilize memory retention, while short-term depression possibly increases continuous attractor volatility. Here, we present a comprehensive description of the combined effect of both short-term facilitation and depression on noise-induced memory degradation in one-dimensional continuous attractor models. Our theoretical description, applicable to rate models as well as spiking networks close to a stationary state, accurately describes the slow dynamics of stored memory positions as a combination of two processes: (i) diffusion due to variability caused by spikes; and (ii) drift due to random connectivity and neuronal heterogeneity. We find that facilitation decreases both diffusion and directed drifts, while short-term depression tends to increase both. Using mutual information, we evaluate the combined impact of short-term facilitation and depression on the ability of networks to retain stable working memory. Finally, our theory predicts the sensitivity of continuous working memory to distractor inputs and provides conditions for stability of memory. Author summary The ability to transiently memorize positions in the visual field is crucial for behavior. Models and experiments have shown that such memories can be maintained in networks of cortical neurons with a continuum of possible activity states, that reflects the continuum of positions in the environment. However, the accuracy of positions stored in such networks will degrade over time due to the noisiness of neuronal signaling and imperfections of the biological substrate. Previous work in simplified models has shown that synaptic short-term plasticity could stabilize this degradation by dynamically up- or down-regulating the strength of synaptic connections, thereby pinning down memorized positions. Here, we present a general theory that accurately predicts the extent of this pinning down by short-term plasticity in a broad class of biologically plausible network models, thereby untangling the interplay of varying biological sources of noise with short-term plasticity. Importantly, our work provides a novel theoretical link from the microscopic substrate of working memoryneurons and synaptic connectionsto observable behavioral correlates, for example the susceptibility to distracting stimuli

Multicontact Co-operativity in Spike-Timing-Dependent Structural Plasticity Stabilizes Networks

Excitatory synaptic connections in the adult neocortex consist of multiple synaptic contacts, almost exclusively formed on dendritic spines. Changes of spine volume, a correlate of synaptic strength, can be tracked in vivo for weeks. Here, we present a combined model of structural and spike-timing-dependent plasticity that explains the multicontact configuration of synapses in adult neocortical networks under steady-state and lesion-induced conditions. Our plasticity rule with Hebbian and anti-Hebbian terms stabilizes both the postsynaptic firing rate and correlations between the pre- and postsynaptic activity at an active synaptic contact. Contacts appear spontaneously at a low rate and disappear if their strength approaches zero. Many presynaptic neurons compete to make strong synaptic connections onto a postsynaptic neuron, whereas the synaptic contacts of a given presynaptic neuron co-operate via postsynaptic firing. We find that co-operation of multiple synaptic contacts is crucial for stable, long-term synaptic memories. In simulations of a simplified network model of barrel cortex, our plasticity rule reproduces whisker-trimming-induced rewiring of thalamocortical and recurrent synaptic connectivity on realistic time scales

Synaptic patterning and the timescales of cortical dynamics

Neocortical circuits, as large heterogeneous recurrent networks, can potentially operate and process signals at multiple timescales, but appear to be differentially tuned to operate within certain temporal receptive windows. The modular and hierarchical organization of this selectivity mirrors anatomical and physiological relations throughout the cortex and is likely determined by the regional electrochemical composition. Being consistently patterned and actively regulated, the expression of molecules involved in synaptic transmission constitutes the most significant source of laminar and regional variability. Due to their complex kinetics and adaptability, synapses form a natural primary candidate underlying this regional temporal selectivity. The ability of cortical networks to reflect the temporal structure of the sensory environment can thus be regulated by evolutionary and experience-dependent processes

Mapping the function of neuronal ion channels in model and experiment

Ion channel models are the building blocks of computational neuron models. Their biological fidelity is therefore crucial for the interpretation of simulations. However, the number of published models, and the lack of standardization, make the comparison of ion channel models with one another and with experimental data difficult. Here, we present a framework for the automated large-scale classification of ion channel models. Using annotated metadata and responses to a set of voltage-clamp protocols, we assigned 2378 models of voltage- and calcium-gated ion channels coded in NEURON to 211 clusters. The IonChannelGenealogy (ICGenealogy) web interface provides an interactive resource for the categorization of new and existing models and experimental recordings. It enables quantitative comparisons of simulated and/or measured ion channel kinetics, and facilitates field-wide standardization of experimentally-constrained modeling