Where Top-Down Meets Bottom-Up: Cell-Type Specific Connectivity Map of the Whisker System.

Sensorimotor computation integrates bottom-up world state information with top-down knowledge and task goals to form action plans. In the rodent whisker system, a prime model of active sensing, evidence shows neuromodulatory neurotransmitters shape whisker control, affecting whisking frequency and amplitude. Since neuromodulatory neurotransmitters are mostly released from subcortical nuclei and have long-range projections that reach the rest of the central nervous system, mapping the circuits of top-down neuromodulatory control of sensorimotor nuclei will help to systematically address the mechanisms of active sensing. Therefore, we developed a neuroinformatic target discovery pipeline to mine the Allen Institute's Mouse Brain Connectivity Atlas. Using network connectivity analysis, we identified new putative connections along the whisker system and anatomically confirmed the existence of 42 previously unknown monosynaptic connections. Using this data, we updated the sensorimotor connectivity map of the mouse whisker system and developed the first cell-type-specific map of the network. The map includes 157 projections across 18 principal nuclei of the whisker system and neuromodulatory neurotransmitter-releasing. Performing a graph network analysis of this connectome, we identified cell-type specific hubs, sources, and sinks, provided anatomical evidence for monosynaptic inhibitory projections into all stages of the ascending pathway, and showed that neuromodulatory projections improve network-wide connectivity. These results argue that beyond the modulatory chemical contributions to information processing and transfer in the whisker system, the circuit connectivity features of the neuromodulatory networks position them as nodes of sensory and motor integration.

The tuning of tuning: How adaptation influences single cell information transfer.

Sensory neurons reconstruct the world from action potentials (spikes) impinging on them. To effectively transfer information about the stimulus to the next processing level, a neuron needs to be able to adapt its working range to the properties of the stimulus. Here, we focus on the intrinsic neural properties that influence information transfer in cortical neurons and how tightly their properties need to be tuned to the stimulus statistics for them to be effective. We start by measuring the intrinsic information encoding properties of putative excitatory and inhibitory neurons in L2/3 of the mouse barrel cortex. Excitatory neurons show high thresholds and strong adaptation, making them fire sparsely and resulting in a strong compression of information, whereas inhibitory neurons that favour fast spiking transfer more information. Next, we turn to computational modelling and ask how two properties influence information transfer: 1) spike-frequency adaptation and 2) the shape of the IV-curve. We find that a subthreshold (but not threshold) adaptation, the 'h-current', and a properly tuned leak conductance can increase the information transfer of a neuron, whereas threshold adaptation can increase its working range. Finally, we verify the effect of the IV-curve slope in our experimental recordings and show that excitatory neurons form a more heterogeneous population than inhibitory neurons. These relationships between intrinsic neural features and neural coding that had not been quantified before will aid computational, theoretical and systems neuroscientists in understanding how neuronal populations can alter their coding properties, such as through the impact of neuromodulators. Why the variability of intrinsic properties of excitatory neurons is larger than that of inhibitory ones is an exciting question, for which future research is needed.

Nonlinear super-resolution signal processing allows intracellular tracking of calcium dynamics.

Objective.Traditional quantification of fluorescence signals, such asΔF/F, relies on ratiometric measures that necessitate a baseline for comparison, limiting their applicability in dynamic analyses. Our goal here is to develop a baseline-independent method for analyzing fluorescence data that fully exploits temporal dynamics to introduce a novel approach for dynamical super-resolution analysis, including in subcellular resolution.Approach.We introduce ARES (Autoregressive RESiduals), a novel method that leverages the temporal aspect of fluorescence signals. By focusing on the quantification of residuals following linear autoregression, ARES obviates the need for a predefined baseline, enabling a more nuanced analysis of signal dynamics.Main result.We delineate the foundational attributes of ARES, illustrating its capability to enhance both spatial and temporal resolution of calcium fluorescence activity beyond the conventional ratiometric measure (ΔF/F). Additionally, we demonstrate ARES's utility in elucidating intracellular calcium dynamics through the detailed observation of calcium wave propagation within a dendrite.Significance.ARES stands out as a robust and precise tool for the quantification of fluorescence signals, adept at analyzing both spontaneous and evoked calcium dynamics. Its ability to facilitate the subcellular localization of calcium signals and the spatiotemporal tracking of calcium dynamics-where traditional ratiometric measures falter-underscores its potential to revolutionize baseline-independent analyses in the field.

Cortical Representation of Touch in Silico.

With its six layers and ~ 12,000 neurons, a cortical column is a complex network whose function is plausibly greater than the sum of its constituents'. Functional characterization of its network components will require going beyond the brute-force modulation of the neural activity of a small group of neurons. Here we introduce an open-source, biologically inspired, computationally efficient network model of the somatosensory cortex's granular and supragranular layers after reconstructing the barrel cortex in soma resolution. Comparisons of the network activity to empirical observations showed that the in silico network replicates the known properties of touch representations and whisker deprivation-induced changes in synaptic strength induced in vivo. Simulations show that the history of the membrane potential acts as a spatial filter that determines the presynaptic population of neurons contributing to a post-synaptic action potential; this spatial filtering might be critical for synaptic integration of top-down and bottom-up information.

Efficient and robust coding in heterogeneous recurrent networks.

Cortical networks show a large heterogeneity of neuronal properties. However, traditional coding models have focused on homogeneous populations of excitatory and inhibitory neurons. Here, we analytically derive a class of recurrent networks of spiking neurons that close to optimally track a continuously varying input online, based on two assumptions: 1) every spike is decoded linearly and 2) the network aims to reduce the mean-squared error between the input and the estimate. From this we derive a class of predictive coding networks, that unifies encoding and decoding and in which we can investigate the difference between homogeneous networks and heterogeneous networks, in which each neurons represents different features and has different spike-generating properties. We find that in this framework, 'type 1' and 'type 2' neurons arise naturally and networks consisting of a heterogeneous population of different neuron types are both more efficient and more robust against correlated noise. We make two experimental predictions: 1) we predict that integrators show strong correlations with other integrators and resonators are correlated with resonators, whereas the correlations are much weaker between neurons with different coding properties and 2) that 'type 2' neurons are more coherent with the overall network activity than 'type 1' neurons.

A databank for intracellular electrophysiological mapping of the adult somatosensory cortex.

Background: Neurons in the supragranular layers of the somatosensory cortex integrate sensory (bottom-up) and cognitive/perceptual (top-down) information as they orchestrate communication across cortical columns. It has been inferred, based on intracellular recordings from juvenile animals, that supragranular neurons are electrically mature by the fourth postnatal week. However, the dynamics of the neuronal integration in adulthood is largely unknown. Electrophysiological characterization of the active properties of these neurons throughout adulthood will help to address the biophysical and computational principles of the neuronal integration. Findings: Here, we provide a database of whole-cell intracellular recordings from 315 neurons located in the supragranular layers (L2/3) of the primary somatosensory cortex in adult mice (9-45 weeks old) from both sexes (females, N = 195; males, N = 120). Data include 361 somatic current-clamp (CC) and 476 voltage-clamp (VC) experiments, recorded using a step-and-hold protocol (CC, N = 257; VC, N = 46), frozen noise injections (CC, N = 104) and triangular voltage sweeps (VC, 10 (N = 132), 50 (N = 146) and 100 ms (N = 152)), from regular spiking (N = 169) and fast-spiking neurons (N = 66). Conclusions: The data can be used to systematically study the properties of somatic integration and the principles of action potential generation across sexes and across electrically characterized neuronal classes in adulthood. Understanding the principles of the somatic transformation of postsynaptic potentials into action potentials will shed light onto the computational principles of intracellular information transfer in single neurons and information processing in neuronal networks, helping to recreate neuronal functions in artificial systems.

Neural coding: A single neuron's perspective.

What any sensory neuron knows about the world is one of the cardinal questions in Neuroscience. Information from the sensory periphery travels across synaptically coupled neurons as each neuron encodes information by varying the rate and timing of its action potentials (spikes). Spatiotemporally correlated changes in this spiking regimen across neuronal populations are the neural basis of sensory representations. In the somatosensory cortex, however, spiking of individual (or pairs of) cortical neurons is only minimally informative about the world. Recent studies showed that one solution neurons implement to counteract this information loss is adapting their rate of information transfer to the ongoing synaptic activity by changing the membrane potential at which spike is generated. Here we first introduce the principles of information flow from the sensory periphery to the primary sensory cortex in a model sensory (whisker) system, and subsequently discuss how the adaptive spike threshold gates the intracellular information transfer from the somatic post-synaptic potential to action potentials, controlling the information content of communication across somatosensory cortical neurons.

Neural Coding With Bursts-Current State and Future Perspectives.

Neuronal action potentials or spikes provide a long-range, noise-resistant means of communication between neurons. As point processes single spikes contain little information in themselves, i.e., outside the context of spikes from other neurons. Moreover, they may fail to cross a synapse. A burst, which consists of a short, high frequency train of spikes, will more reliably cross a synapse, increasing the likelihood of eliciting a postsynaptic spike, depending on the specific short-term plasticity at that synapse. Both the number and the temporal pattern of spikes in a burst provide a coding space that lies within the temporal integration realm of single neurons. Bursts have been observed in many species, including the non-mammalian, and in brain regions that range from subcortical to cortical. Despite their widespread presence and potential relevance, the uncertainties of how to classify bursts seems to have limited the research into the coding possibilities for bursts. The present series of research articles provides new insights into the relevance and interpretation of bursts across different neural circuits, and new methods for their analysis. Here, we provide a succinct introduction to the history of burst coding and an overview of recent work on this topic.

Spike and burst coding in thalamocortical relay cells.

Mammalian thalamocortical relay (TCR) neurons switch their firing activity between a tonic spiking and a bursting regime. In a combined experimental and computational study, we investigated the features in the input signal that single spikes and bursts in the output spike train represent and how this code is influenced by the membrane voltage state of the neuron. Identical frozen Gaussian noise current traces were injected into TCR neurons in rat brain slices as well as in a validated three-compartment TCR model cell. The resulting membrane voltage traces and spike trains were analyzed by calculating the coherence and impedance. Reverse correlation techniques gave the Event-Triggered Average (ETA) and the Event-Triggered Covariance (ETC). This demonstrated that the feature selectivity started relatively long before the events (up to 300 ms) and showed a clear distinction between spikes (selective for fluctuations) and bursts (selective for integration). The model cell was fine-tuned to mimic the frozen noise initiated spike and burst responses to within experimental accuracy, especially for the mixed mode regimes. The information content carried by the various types of events in the signal as well as by the whole signal was calculated. Bursts phase-lock to and transfer information at lower frequencies than single spikes. On depolarization the neuron transits smoothly from the predominantly bursting regime to a spiking regime, in which it is more sensitive to high-frequency fluctuations. The model was then used to elucidate properties that could not be assessed experimentally, in particular the role of two important subthreshold voltage-dependent currents: the low threshold activated calcium current (IT) and the cyclic nucleotide modulated h current (Ih). The ETAs of those currents and their underlying activation/inactivation states not only explained the state dependence of the firing regime but also the long-lasting concerted dynamic action of the two currents. Finally, the model was used to investigate the more realistic "high-conductance state", where fluctuations are caused by (synaptic) conductance changes instead of current injection. Under "standard" conditions bursts are difficult to initiate, given the high degree of inactivation of the T-type calcium current. Strong and/or precisely timed inhibitory currents were able to remove this inactivation.

Estimating the Information Extracted by a Single Spiking Neuron from a Continuous Input Time Series.

Understanding the relation between (sensory) stimuli and the activity of neurons (i.e., "the neural code") lies at heart of understanding the computational properties of the brain. However, quantifying the information between a stimulus and a spike train has proven to be challenging. We propose a new (in vitro) method to measure how much information a single neuron transfers from the input it receives to its output spike train. The input is generated by an artificial neural network that responds to a randomly appearing and disappearing "sensory stimulus": the hidden state. The sum of this network activity is injected as current input into the neuron under investigation. The mutual information between the hidden state on the one hand and spike trains of the artificial network or the recorded spike train on the other hand can easily be estimated due to the binary shape of the hidden state. The characteristics of the input current, such as the time constant as a result of the (dis)appearance rate of the hidden state or the amplitude of the input current (the firing frequency of the neurons in the artificial network), can independently be varied. As an example, we apply this method to pyramidal neurons in the CA1 of mouse hippocampi and compare the recorded spike trains to the optimal response of the "Bayesian neuron" (BN). We conclude that like in the BN, information transfer in hippocampal pyramidal cells is non-linear and amplifying: the information loss between the artificial input and the output spike train is high if the input to the neuron (the firing of the artificial network) is not very informative about the hidden state. If the input to the neuron does contain a lot of information about the hidden state, the information loss is low. Moreover, neurons increase their firing rates in case the (dis)appearance rate is high, so that the (relative) amount of transferred information stays constant.

Measures of spike train synchrony for data with multiple time scales.

BACKGROUND: Measures of spike train synchrony are widely used in both experimental and computational neuroscience. Time-scale independent and parameter-free measures, such as the ISI-distance, the SPIKE-distance and SPIKE-synchronization, are preferable to time scale parametric measures, since by adapting to the local firing rate they take into account all the time scales of a given dataset. NEW METHOD: In data containing multiple time scales (e.g. regular spiking and bursts) one is typically less interested in the smallest time scales and a more adaptive approach is needed. Here we propose the A-ISI-distance, the A-SPIKE-distance and A-SPIKE-synchronization, which generalize the original measures by considering the local relative to the global time scales. For the A-SPIKE-distance we also introduce a rate-independent extension called the RIA-SPIKE-distance, which focuses specifically on spike timing. RESULTS: The adaptive generalizations A-ISI-distance and A-SPIKE-distance allow to disregard spike time differences that are not relevant on a more global scale. A-SPIKE-synchronization does not any longer demand an unreasonably high accuracy for spike doublets and coinciding bursts. Finally, the RIA-SPIKE-distance proves to be independent of rate ratios between spike trains. COMPARISON WITH EXISTING METHODS: We find that compared to the original versions the A-ISI-distance and the A-SPIKE-distance yield improvements for spike trains containing different time scales without exhibiting any unwanted side effects in other examples. A-SPIKE-synchronization matches spikes more efficiently than SPIKE-synchronization. CONCLUSIONS: With these proposals we have completed the picture, since we now provide adaptive generalized measures that are sensitive to firing rate only (A-ISI-distance), to timing only (ARI-SPIKE-distance), and to both at the same time (A-SPIKE-distance).

Reliability of spike and burst firing in thalamocortical relay cells.

The reliability and precision of the timing of spikes in a spike train is an important aspect of neuronal coding. We investigated reliability in thalamocortical relay (TCR) cells in the acute slice and also in a Morris-Lecar model with several extensions. A frozen Gaussian noise current, superimposed on a DC current, was injected into the TCR cell soma. The neuron responded with spike trains that showed trial-to-trial variability, due to amongst others slow changes in its internal state and the experimental setup. The DC current allowed to bring the neuron in different states, characterized by a well defined membrane voltage (between -80 and -50 mV) and by a specific firing regime that on depolarization gradually shifted from a predominantly bursting regime to a tonic spiking regime. The filtered frozen white noise generated a spike pattern output with a broad spike interval distribution. The coincidence factor and the Hunter and Milton measure were used as reliability measures of the output spike train. In the experimental TCR cell as well as the Morris-Lecar model cell the reliability depends on the shape (steepness) of the current input versus spike frequency output curve. The model also allowed to study the contribution of three relevant ionic membrane currents to reliability: a T-type calcium current, a cation selective h-current and a calcium dependent potassium current in order to allow bursting, investigate the consequences of a more complex current-frequency relation and produce realistic firing rates. The reliability of the output of the TCR cell increases with depolarization. In hyperpolarized states bursts are more reliable than single spikes. The analytically derived relations were capable to predict several of the experimentally recorded spike features.

Modulation of spike and burst rate in a minimal neuronal circuit with feed-forward inhibition.

Pyramidal cells perform computations on their inputs within the context of the local network. The present computational study investigates the consequences of feed-forward inhibition for the firing rate and reliability of a typical hippocampal pyramidal neuron that can respond with single spikes as well as bursts. A simple generic inhibitory interneuron is connected in a feed-forward mode to a pyramidal cell and this minimal circuit is activated with frozen noise. The properties (reversal potential, projection site, propagation delay, fast or slow kinetics) of the connecting synapse and the coupling strength between the interneuron and the pyramidal cell are varied. All forms of inhibition considered here decrease the burst rate, but the effects on the single spike (spikes that are not part of a burst) rate are more ambiguous. Slow dendritic shunting inhibition increases the single spike rate, but fast somatic inhibition does not. When a propagation delay is included in the slow dendritic synapse, the increase of the single spike rate is smaller, an effect that could also be obtained by lowering the reversal potential of the synaptic current. Cross-correlations, reverse correlation analysis and decorrelating the interneuron and pyramidal cell activity are used to demonstrate that these effects depend critically on the exact timing of inhibition, emphasizing the relevance of spatiotemporal organization. The reliability of the firing of the pyramidal cell is quantified with the Victor-Purpura measure. When burst and spikes together or spikes alone are taken into account, feed-forward inhibition makes firing more reliable. This is not the case when the analysis is restricted to bursts. A hyperpolarization-activated, non-specific cation current (Ih) is inserted into the dendritic membrane of the pyramidal cell, where it slightly depolarizes the membrane and reduces its time constant. This dendritic h-current increases the output frequency, makes inhibition less effective and introduces spike-spike interactions at a 40-140 ms time scale. Feed-forward inhibition always decreases the burst firing rate, but the effects on the single spike rate depended on the spatiotemporal organization of inhibition. Therefore, using different connection strategies, the spike and burst rate of such a minimal circuit can be modulated independently.

Two forms of feedback inhibition determine the dynamical state of a small hippocampal network.

Pyramidal cells in the hippocampus are part of a small neuronal network that performs computations on external input. The network consists of principal cells and various forms of feedback inhibition. Experimental evidence indicates at least two functionally distinct inhibitory feedback loops in the CA3 area of the hippocampus: (1) a loop in which O-LM interneurons project to the distal dendrites of pyramidal cells with synapses that have slow kinetics, and (2) a loop in which basket interneurons project to the somata of pyramidal cells with synapses that have fast kinetics. There is an interconnection between the two loops in the form of O-LM to basket interneuron inhibition and the configuration is further complicated by the presence of distinct propagation delays and short-term facilitation and depression of certain synapses in the two basic loops. In this study we investigated the consequences of various configurations of the circuit and modulations of the components of inhibition for the computation that the network can perform on its input. Gaussian noise was used as the input to the dendrite of the pyramidal cell and evoked two types of events: spikes or bursts. The event-triggered average (ETA) and the event-triggered covariance (ETC) were determined and the inter-event-intervals between spikes and bursts were analyzed. The ETA and ETC on the pyramidal cell show that this model behaves in first approximation as an activity integrator: with sufficient positive input, bursts as well as spikes are evoked. Which of the two is determined by the input just after the (first) spike: positive input results in a burst; negative input results in a spike. Stronger feedback inhibition, in the slow as well as in the fast loop, increases the event rate of the pyramidal cell. For a single input and large propagation delays, the interaction between the two feedback loops is not of great importance. The consequences of the presence of the slow and/or fast feedback inhibitory loop, with or without facilitation and depression, were analyzed in relation to synapse strength. Facilitation and depression are most relevant when their recovery time constant is of the same order as the mean inter-event interval. Short-term depression can stop activity in the fast loop after several fast spikes and can switch the network to a different state, thus functioning as a kind of 'brake' on the fast inhibitory feedback loop. Thus inhibition and the details of the microcircuit organization play an important role in the information processing of the small neuronal circuit.