Impact on backpropagation of the spatial heterogeneity of sodium channel kinetics in the axon initial segment.

In a variety of neurons, action potentials (APs) initiate at the proximal axon, within a region called the axon initial segment (AIS), which has a high density of voltage-gated sodium channels (NaVs) on its membrane. In pyramidal neurons, the proximal AIS has been reported to exhibit a higher proportion of NaVs with gating properties that are "right-shifted" to more depolarized voltages, compared to the distal AIS. Further, recent experiments have revealed that as neurons develop, the spatial distribution of NaV subtypes along the AIS can change substantially, suggesting that neurons tune their excitability by modifying said distribution. When neurons are stimulated axonally, computational modelling has shown that this spatial separation of gating properties in the AIS enhances the backpropagation of APs into the dendrites. In contrast, in the more natural scenario of somatic stimulation, our simulations show that the same distribution can impede backpropagation, suggesting that the choice of orthodromic versus antidromic stimulation can bias or even invert experimental findings regarding the role of NaV subtypes in the AIS. We implemented a range of hypothetical NaV distributions in the AIS of three multicompartmental pyramidal cell models and investigated the precise kinetic mechanisms underlying such effects, as the spatial distribution of NaV subtypes is varied. With axonal stimulation, proximal NaV availability dominates, such that concentrating right-shifted NaVs in the proximal AIS promotes backpropagation. However, with somatic stimulation, the models are insensitive to availability kinetics. Instead, the higher activation threshold of right-shifted NaVs in the AIS impedes backpropagation. Therefore, recently observed developmental changes to the spatial separation and relative proportions of NaV1.2 and NaV1.6 in the AIS differentially impact activation and availability. The observed effects on backpropagation, and potentially learning via its putative role in synaptic plasticity (e.g. through spike-timing-dependent plasticity), are opposite for orthodromic versus antidromic stimulation, which should inform hypotheses about the impact of the developmentally regulated subcellular localization of these NaV subtypes.

Adaptive spike threshold dynamics associated with sparse spiking of hilar mossy cells are captured by a simple model.

Hilar mossy cells (hMCs) in the dentate gyrus (DG) receive inputs from DG granule cells (GCs), CA3 pyramidal cells and inhibitory interneurons, and provide feedback input to GCs. Behavioural and in vivo recording experiments implicate hMCs in pattern separation, navigation and spatial learning. Our experiments link hMC intrinsic excitability to their synaptically evoked in vivo spiking outputs. We performed electrophysiological recordings from DG neurons and found that hMCs displayed an adaptative spike threshold that increased both in proportion to the intensity of injected currents, and in response to spiking itself, returning to baseline over a long time scale, thereby instantaneously limiting their firing rate responses. The hMC activity is additionally limited by a prominent medium after-hyperpolarizing potential (AHP) generated by small conductance K+ channels. We hypothesize that these intrinsic hMC properties are responsible for their low in vivo firing rates. Our findings extend previous studies that compare hMCs, CA3 pyramidal cells and hilar inhibitory cells and provide novel quantitative data that contrast the intrinsic properties of these cell types. We developed a phenomenological exponential integrate-and-fire model that closely reproduces the hMC adaptive threshold nonlinearities with respect to their threshold dependence on input current intensity, evoked spike latency and long-lasting spike-induced increase in spike threshold. Our robust and computationally efficient model is amenable to incorporation into large network models of the DG that will deepen our understanding of the neural bases of pattern separation, spatial navigation and learning. KEY POINTS: Previous studies have shown that hilar mossy cells (hMCs) are implicated in pattern separation and the formation of spatial memory, but how their intrinsic properties relate to their in vivo spiking patterns is still unknown. Here we show that the hMCs display electrophysiological properties that distinguish them from the other hilar cell types including a highly adaptive spike threshold that decays slowly. The spike-dependent increase in threshold combined with an after-hyperpolarizing potential mediated by a slow K+ conductance is hypothesized to be responsible for the low-firing rate of the hMC observed in vivo. The hMC's features are well captured by a modified stochastic exponential integrate-and-fire model that has the unique feature of a threshold intrinsically dependant on both the stimulus intensity and the spiking history. This computational model will allow future work to study how the hMCs can contribute to spatial memory formation and navigation.

Continuous Monitoring of Entropy Production and Entropy Flow in Humans Exercising under Heat Stress.

Complex living systems, such as the human organism, are characterized by their self-organized and dissipative behaviors, where irreversible processes continuously produce entropy internally and export it to the environment; however, a means by which to measure human entropy production and entropy flow over time is not well-studied. In this article, we leverage prior experimental data to introduce an experimental approach for the continuous measurement of external entropy flow (released to the environment) and internal entropy production (within the body), using direct and indirect calorimetry, respectively, for humans exercising under heat stress. Direct calorimetry, performed with a whole-body modified Snellen calorimeter, was used to measure the external heat dissipation from the change in temperature and relative humidity between the air outflow and inflow, from which was derived the rates of entropy flow of the body. Indirect calorimetry, which measures oxygen consumption and carbon dioxide production from inspired and expired gases, was used to monitor internal entropy production. A two-compartment entropy flow model was used to calculate the rates of internal entropy production and external entropy flow for 11 middle-aged men during a schedule of alternating exercise and resting bouts at a fixed metabolic heat production rate. We measured a resting internal entropy production rate of (0.18 ± 0.01) W/(K·m2) during heat stress only, which is in agreement with published measurements. This research introduces an approach for the real-time monitoring of entropy production and entropy flow in humans, and aims for an improved understanding of human health and illness based on non-equilibrium thermodynamics.

Mutual information resonances in delay-coupled limit cycle and quasi-cycle brain rhythms.

We elucidate how coupling delays and noise impact phase and mutual information relationships between two stochastic brain rhythms. This impact depends on the dynamical regime of each PING-based rhythm, as well as on network heterogeneity and coupling asymmetry. The number of peaks at positive and negative time lags in the delayed mutual information between the two bi-directionally communicating rhythms defines our measure of flexibility of information sharing and reflects the number of ways in which the two networks can alternately lead one another. We identify two distinct mechanisms for the appearance of qualitatively similar flexible information sharing. The flexibility in the quasi-cycle regime arises from the coupling delay-induced bimodality of the phase difference distribution, and the related bimodal mutual information. It persists in the presence of asymmetric coupling and heterogeneity but is limited to two routes of information sharing. The second mechanism in noisy limit cycle regime is not induced by the delay. However, delay-coupling and heterogeneity enable communication routes at multiple time lags. Noise disrupts the shared compromise frequency, allowing the expression of individual network frequencies which leads to a slow beating pattern. Simulations of an envelope-phase description for delay-coupled quasi-cycles yield qualitatively similar properties as for the full system. Near the bifurcation from in-phase to out-of-phase behaviour, a single preferred phase difference can coexist with two information sharing routes; further, the phase laggard can be the mutual information leader, or vice versa. Overall, the coupling delay endows a two-rhythm system with an array of lead-lag relationships and mutual information resonances that exist in spite of the noise and across the Hopf bifurcation. These beg to be mapped out experimentally with the help of our predictions.

Controlling the spontaneous firing behavior of a neuron with astrocyte.

Mounting evidence in recent years suggests that astrocytes, a sub-type of glial cells, not only serve metabolic and structural support for neurons and synapses but also play critical roles in the regulation of proper functioning of the nervous system. In this work, we investigate the effect of astrocytes on the spontaneous firing activity of a neuron through a combined model that includes a neuron-astrocyte pair. First, we show that an astrocyte may provide a kind of multistability in neuron dynamics by inducing different firing modes such as random and bursty spiking. Then, we identify the underlying mechanism of this behavior and search for the astrocytic factors that may have regulatory roles in different firing regimes. More specifically, we explore how an astrocyte can participate in the occurrence and control of spontaneous irregular spiking activity of a neuron in random spiking mode. Additionally, we systematically investigate the bursty firing regime dynamics of the neuron under the variation of biophysical facts related to the intracellular environment of the astrocyte. It is found that an astrocyte coupled to a neuron can provide a control mechanism for both spontaneous firing irregularity and burst firing statistics, i.e., burst regularity and size.

Prestimulus dynamics blend with the stimulus in neural variability quenching.

Neural responses to the same stimulus show significant variability over trials, with this variability typically reduced (quenched) after a stimulus is presented. This trial-to-trial variability (TTV) has been much studied, however how this neural variability quenching is influenced by the ongoing dynamics of the prestimulus period is unknown. Utilizing a human intracranial stereo-electroencephalography (sEEG) data set, we investigate how prestimulus dynamics, as operationalized by standard deviation (SD), shapes poststimulus activity through trial-to-trial variability (TTV). We first observed greater poststimulus variability quenching in those real trials exhibiting high prestimulus variability as observed in all frequency bands. Next, we found that the relative effect of the stimulus was higher in the later (300-600ms) than the earlier (0-300ms) poststimulus period. Lastly, we replicate our findings in a separate EEG dataset and extend them by finding that trials with high prestimulus variability in the theta and alpha bands had faster reaction times. Together, our results demonstrate that stimulus-related activity, including its variability, is a blend of two factors: 1) the effects of the external stimulus itself, and 2) the effects of the ongoing dynamics spilling over from the prestimulus period - the state at stimulus onset - with the second dwarfing the influence of the first.

Enhanced Signal Detection by Adaptive Decorrelation of Interspike Intervals.

Spike trains with negative interspike interval (ISI) correlations, in which long/short ISIs are more likely followed by short/long ISIs, are common in many neurons. They can be described by stochastic models with a spike-triggered adaptation variable. We analyze a phenomenon in these models where such statistically dependent ISI sequences arise in tandem with quasi-statistically independent and identically distributed (quasi-IID) adaptation variable sequences. The sequences of adaptation states and resulting ISIs are linked by a nonlinear decorrelating transformation. We establish general conditions on a family of stochastic spiking models that guarantee this quasi-IID property and establish bounds on the resulting baseline ISI correlations. Inputs that elicit weak firing rate changes in samples with many spikes are known to be more detectible when negative ISI correlations are present because they reduce spike count variance; this defines a variance-reduced firing rate coding benchmark. We performed a Fisher information analysis on these adapting models exhibiting ISI correlations to show that a spike pattern code based on the quasi-IID property achieves the upper bound of detection performance, surpassing rate codes with the same mean rate-including the variance-reduced rate code benchmark-by 20% to 30%. The information loss in rate codes arises because the benefits of reduced spike count variance cannot compensate for the lower firing rate gain due to adaptation. Since adaptation states have similar dynamics to synaptic responses, the quasi-IID decorrelation transformation of the spike train is plausibly implemented by downstream neurons through matched postsynaptic kinetics. This provides an explanation for observed coding performance in sensory systems that cannot be accounted for by rate coding, for example, at the detection threshold where rate changes can be insignificant.

Vibrational resonance in a neuron-astrocyte coupled model.

Recent findings have revealed that not only neurons but also astrocytes, a special type of glial cells, are major players of neuronal information processing. It is now widely accepted that they contribute to the regulation of their microenvironment by cross-talking with neurons via gliotransmitters. In this context, we here study the phenomenon of vibrational resonance in neurons by considering their interaction with astrocytes. Our analysis of a neuron-astrocyte pair reveals that intracellular dynamics of astrocytes can induce a double vibrational resonance effect in the weak signal detection performance of a neuron, exhibiting two distinct wells centred at different high-frequency driving amplitudes. We also identify the underlying mechanism of this behaviour, showing that the interaction of widely separated time scales of neurons, astrocytes and driving signals is the key factor for the emergence and control of double vibrational resonance. This article is part of the theme issue 'Vibrational and stochastic resonance in driven nonlinear systems (part 2)'.

Dynamical invariants and inverse period-doubling cascades in multi-delay systems.

We investigate transitions to simple dynamics in first-order nonlinear differential equations with multiple delays. With a proper choice of parameters, a single delay can destabilize a fixed point. In contrast, multiple delays can both destabilize fixed points and promote high-dimensional chaos but also induce stabilization onto simpler dynamics. We show that the dynamics of these systems depend on the precise distribution of the delays. Narrow spacing between individual delays induces chaotic behavior, while a lower density of delays enables stable periodic or fixed point behavior. As the dynamics become simpler, the number of unstable roots of the characteristic equation around the fixed point decreases. In fact, the behavior of these roots exhibits an astonishing parallel with that of the Lyapunov exponents and the Kolmogorov-Sinai entropy for these multi-delay systems. A theoretical analysis shows how these roots move back toward stability as the number of delays increases. Our results are based on numerical determination of the Lyapunov spectrum for these multi-delay systems as well as on permutation entropy computations. Finally, we report how complexity reduction upon adding more delays can occur through an inverse period-doubling sequence.

Brain rhythm bursts are enhanced by multiplicative noise.

Many healthy and pathological brain rhythms, including beta and gamma rhythms and essential tremor, are suspected to be induced by noise. This yields randomly occurring, brief epochs of higher amplitude oscillatory activity known as "bursts," the statistics of which are important for proper neural function. Here, we consider a more realistic model with both multiplicative and additive noise instead of only additive noise, to understand how state-dependent fluctuations further affect rhythm induction. For illustrative purposes, we calibrate the model at the lower end of the beta band that relates to movement; parameter tuning can extend the relevance of our analysis to the higher frequency gamma band or to lower frequency essential tremors. A stochastic Wilson-Cowan model for reciprocally as well as self-coupled excitatory (E) and inhibitory (I) populations is analyzed in the parameter regime where the noise-free dynamics spiral in to a fixed point. Noisy oscillations known as quasi-cycles are then generated by stochastic synaptic inputs. The corresponding dynamics of E and I local field potentials can be studied using linear stochastic differential equations subject to both additive and multiplicative noises. As the prevalence of bursts is proportional to the slow envelope of the E and I firing activities, we perform an envelope-phase decomposition using the stochastic averaging method. The resulting envelope dynamics are uni-directionally coupled to the phase dynamics as in the case of additive noise alone but both dynamics involve new noise-dependent terms. We derive the stationary probability and compute power spectral densities of envelope fluctuations. We find that multiplicative noise can enhance network synchronization by reducing the magnitude of the negative real part of the complex conjugate eigenvalues. Higher noise can lead to a "virtual limit cycle," where the deterministically stable eigenvalues around the fixed point acquire a positive real part, making the system act more like a noisy limit cycle rather than a quasi-cycle. Multiplicative noise can thus exacerbate synchronization and possibly contribute to the onset of symptoms in certain motor diseases.

Contrast coding in the electrosensory system: parallels with visual computation.

To identify and interact with moving objects, including other members of the same species, an animal's nervous system must correctly interpret patterns of contrast in the physical signals (such as light or sound) that it receives from the environment. In weakly electric fish, the motion of objects in the environment and social interactions with other fish create complex patterns of contrast in the electric fields that they produce and detect. These contrast patterns can extend widely over space and time and represent a multitude of relevant features, as is also true for other sensory systems. Mounting evidence suggests that the computational principles underlying contrast coding in electrosensory neural networks are conserved elements of spatiotemporal processing that show strong parallels with the vertebrate visual system.

Inference of a Mesoscopic Population Model from Population Spike Trains.

Understanding how rich dynamics emerge in neural populations requires models exhibiting a wide range of behaviors while remaining interpretable in terms of connectivity and single-neuron dynamics. However, it has been challenging to fit such mechanistic spiking networks at the single-neuron scale to empirical population data. To close this gap, we propose to fit such data at a mesoscale, using a mechanistic but low-dimensional and, hence, statistically tractable model. The mesoscopic representation is obtained by approximating a population of neurons as multiple homogeneous pools of neurons and modeling the dynamics of the aggregate population activity within each pool. We derive the likelihood of both single-neuron and connectivity parameters given this activity, which can then be used to optimize parameters by gradient ascent on the log likelihood or perform Bayesian inference using Markov chain Monte Carlo (MCMC) sampling. We illustrate this approach using a model of generalized integrate-and-fire neurons for which mesoscopic dynamics have been previously derived and show that both single-neuron and connectivity parameters can be recovered from simulated data. In particular, our inference method extracts posterior correlations between model parameters, which define parameter subsets able to reproduce the data. We compute the Bayesian posterior for combinations of parameters using MCMC sampling and investigate how the approximations inherent in a mesoscopic population model affect the accuracy of the inferred single-neuron parameters.

The temporal signature of self: Temporal measures of resting-state EEG predict self-consciousness.

The self is the core of our mental life. Previous investigations have demonstrated a strong neural overlap between self-related activity and resting state activity. This suggests that information about self-relatedness is encoded in our brain's spontaneous activity. The exact neuronal mechanisms of such "rest-self containment," however, remain unclear. The present EEG study investigated temporal measures of resting state EEG to relate them to self-consciousness. This was obtained with the self-consciousness scale (SCS) which measures Private, Public, and Social dimensions of self. We demonstrate positive correlations between Private self-consciousness and three temporal measures of resting state activity: scale-free activity as indexed by the power-law exponent (PLE), the auto-correlation window (ACW), and modulation index (MI). Specifically, higher PLE, longer ACW, and stronger MI were related to higher degrees of Private self-consciousness. Finally, conducting eLORETA for spatial tomography, we found significant correlation of Private self-consciousness with activity in cortical midline structures such as the perigenual anterior cingulate cortex and posterior cingulate cortex. These results were reinforced with a data-driven analysis; a machine learning algorithm accurately predicted an individual as having a "high" or "low" Private self-consciousness score based on these measures of the brain's spatiotemporal structure. In conclusion, our results demonstrate that Private self-consciousness is related to the temporal structure of resting state activity as featured by temporal nestedness (PLE), temporal continuity (ACW), and temporal integration (MI). Our results support the hypothesis that self-related information is temporally contained in the brain's resting state. "Rest-self containment" can thus be featured by a temporal signature.

A stochastic-field description of finite-size spiking neural networks.

Neural network dynamics are governed by the interaction of spiking neurons. Stochastic aspects of single-neuron dynamics propagate up to the network level and shape the dynamical and informational properties of the population. Mean-field models of population activity disregard the finite-size stochastic fluctuations of network dynamics and thus offer a deterministic description of the system. Here, we derive a stochastic partial differential equation (SPDE) describing the temporal evolution of the finite-size refractory density, which represents the proportion of neurons in a given refractory state at any given time. The population activity-the density of active neurons per unit time-is easily extracted from this refractory density. The SPDE includes finite-size effects through a two-dimensional Gaussian white noise that acts both in time and along the refractory dimension. For an infinite number of neurons the standard mean-field theory is recovered. A discretization of the SPDE along its characteristic curves allows direct simulations of the activity of large but finite spiking networks; this constitutes the main advantage of our approach. Linearizing the SPDE with respect to the deterministic asynchronous state allows the theoretical investigation of finite-size activity fluctuations. In particular, analytical expressions for the power spectrum and autocorrelation of activity fluctuations are obtained. Moreover, our approach can be adapted to incorporate multiple interacting populations and quasi-renewal single-neuron dynamics.

Non-monotonic accumulation of spike time variance during membrane potential oscillations.

A spike-phase neural code has been proposed as a mechanism to encode stimuli based on the precise timing of spikes relative to the phase of membrane potential oscillations. This form of coding has been reported in both in vivo and in vitro experiments across several regions of the brain, yet there are concerns that such precise timing may be compromised by an effect referred to as variance accumulation, wherein spike timing variance increases over the phase of an oscillation. Here, we provide a straightforward explanation of this effect based on the theoretical spike time variance. The proposed theory is consistent with recordings of mitral neurons. It shows that spike time variance can increase in a nonlinear fashion with spike number, in a way that is dependent upon the frequency and amplitude of the oscillation. Further, non-monotonic accumulation of variance can arise from different combinations of oscillation parameters. Nonlinear accumulation sometimes leads to lower variance than that of a mean rate-matched homogeneous Poisson process, particularly for spikes that occur in later phases of oscillation. However, such an advantage is limited to a narrow range of oscillation amplitudes and frequencies. These results suggest fundamental constraints on spike-phase coding, and reveal how certain spikes in a sequence may exhibit increased firing time precision relative to their neighbors.

Is There a Nonadditive Interaction Between Spontaneous and Evoked Activity? Phase-Dependence and Its Relation to the Temporal Structure of Scale-Free Brain Activity.

The aim of our study was to use functional magnetic resonance imaging to investigate how spontaneous activity interacts with evoked activity, as well as how the temporal structure of spontaneous activity, that is, long-range temporal correlations, relate to this interaction. Using an extremely sparse event-related design (intertrial intervals: 52-60 s), a novel blood oxygen level-dependent signal correction approach (accounting for spontaneous fluctuations using pseudotrials) and phase analysis, we provided direct evidence for a nonadditive interaction between spontaneous and evoked activity. We demonstrated the discrepancy between the present and previous observations on why a linear superposition between spontaneous and evoked activity can be seen by using co-occurring signals from homologous brain regions. Importantly, we further demonstrated that the nonadditive interaction can be characterized by phase-dependent effects of spontaneous activity, which is closely related to the degree of long-range temporal correlations in spontaneous activity as indexed by both power-law exponent and phase-amplitude coupling. Our findings not only contribute to the understanding of spontaneous brain activity and its scale-free properties, but also bear important implications for our understanding of neural activity in general.

Mean, covariance, and effective dimension of stochastic distributed delay dynamics.

Dynamical models are often required to incorporate both delays and noise. However, the inherently infinite-dimensional nature of delay equations makes formal solutions to stochastic delay differential equations (SDDEs) challenging. Here, we present an approach, similar in spirit to the analysis of functional differential equations, but based on finite-dimensional matrix operators. This results in a method for obtaining both transient and stationary solutions that is directly amenable to computation, and applicable to first order differential systems with either discrete or distributed delays. With fewer assumptions on the system's parameters than other current solution methods and no need to be near a bifurcation, we decompose the solution to a linear SDDE with arbitrary distributed delays into natural modes, in effect the eigenfunctions of the differential operator, and show that relatively few modes can suffice to approximate the probability density of solutions. Thus, we are led to conclude that noise makes these SDDEs effectively low dimensional, which opens the possibility of practical definitions of probability densities over their solution space.

Active sensing associated with spatial learning reveals memory-based attention in an electric fish.

Active sensing behaviors reveal what an animal is attending to and how it changes with learning. Gymnotus sp, a gymnotiform weakly electric fish, generates an electric organ discharge (EOD) as discrete pulses to actively sense its surroundings. We monitored freely behaving gymnotid fish in a large dark "maze" and extracted their trajectories and EOD pulse pattern and rate while they learned to find food with electrically detectable landmarks as cues. After training, they more rapidly found food using shorter, more stereotyped trajectories and spent more time near the food location. We observed three forms of active sensing: sustained high EOD rates per unit distance (sampling density), transient large increases in EOD rate (E-scans) and stereotyped scanning movements (B-scans) were initially strong at landmarks and food, but, after learning, intensified only at the food location. During probe (no food) trials, after learning, the fish's search area and intense active sampling was still centered on the missing food location, but now also increased near landmarks. We hypothesize that active sensing is a behavioral manifestation of attention and essential for spatial learning; the fish use spatial memory of landmarks and path integration to reach the expected food location and confine their attention to this region.

Weak signal amplification and detection by higher-order sensory neurons.

Sensory systems must extract behaviorally relevant information and therefore often exhibit a very high sensitivity. How the nervous system reaches such high sensitivity levels is an outstanding question in neuroscience. Weakly electric fish (Apteronotus leptorhynchus/albifrons) are an excellent model system to address this question because detailed background knowledge is available regarding their behavioral performance and its underlying neuronal substrate. Apteronotus use their electrosense to detect prey objects. Therefore, they must be able to detect electrical signals as low as 1 µV while using a sensory integration time of <200 ms. How these very weak signals are extracted and amplified by the nervous system is not yet understood. We studied the responses of cells in the early sensory processing areas, namely, the electroreceptor afferents (EAs) and pyramidal cells (PCs) of the electrosensory lobe (ELL), the first-order electrosensory processing area. In agreement with previous work we found that EAs cannot encode very weak signals with a spike count code. However, PCs can encode prey mimic signals by their firing rate, revealing a huge signal amplification between EAs and PCs and also suggesting differences in their stimulus encoding properties. Using a simple leaky integrate-and-fire (LIF) model we predict that the target neurons of PCs in the midbrain torus semicircularis (TS) are able to detect very weak signals. In particular, TS neurons could do so by assuming biologically plausible convergence rates as well as very simple decoding strategies such as temporal integration, threshold crossing, and combining the inputs of PCs.