Network motifs in cellular neurophysiology.

Concepts from network science and graph theory, including the framework of network motifs, have been frequently applied in studying neuronal networks and other biological complex systems. Network-based approaches can also be used to study the functions of individual neurons, where cellular elements such as ion channels and membrane voltage are conceptualized as nodes within a network, and their interactions are denoted by edges. Network motifs in this context provide functional building blocks that help to illuminate the principles of cellular neurophysiology. In this review we build a case that network motifs operating within neurons provide tools for defining the functional architecture of single-neuron physiology and neuronal adaptations. We highlight the presence of such computational motifs in the cellular mechanisms underlying action potential generation, neuronal oscillations, dendritic integration, and neuronal plasticity. Future work applying the network motifs perspective may help to decipher the functional complexities of neurons and their adaptation during health and disease.

Heterogeneous stochastic bifurcations explain intrinsic oscillatory patterns in entorhinal cortical stellate cells.

Stellate cells (SC) in the medial entorhinal cortex manifest intrinsic membrane potential oscillatory patterns. Although different theoretical frameworks have been proposed to explain these patterns, a robust unifying framework that jointly accounts for intrinsic heterogeneities and stochasticity is missing. Here, we first performed in vitro patch-clamp electrophysiological recordings from rat SCs and found pronounced cell-to-cell variability in their characteristic physiological properties, including peri-threshold oscillatory patterns. We demonstrate that noise introduced into two independent populations (endowed with deterministic or stochastic ion-channel gating kinetics) of heterogeneous biophysical models yielded activity patterns that were qualitatively similar to electrophysiological peri-threshold oscillatory activity in SCs. We developed spectrogram-based quantitative metrics for the identification of valid oscillations and confirmed that these metrics reliably captured the variable-amplitude and arhythmic oscillatory patterns observed in electrophysiological recordings. Using these quantitative metrics, we validated activity patterns from both heterogeneous populations of SC models, with each model assessed with multiple trials of different levels of noise at distinct membrane depolarizations. Our analyses unveiled the manifestation of stochastic resonance (detection of the highest number of valid oscillatory traces at an optimal level of noise) in both heterogeneous populations of SC models. Finally, we show that a generalized network motif comprised of a slow negative feedback loop amplified by a fast positive feedback loop manifested stochastic bifurcations and stochastic resonance in the emergence of oscillations. Together, through a unique convergence of the degeneracy and stochastic resonance frameworks, our unifying framework centered on heterogeneous stochastic bifurcations argues for state-dependent emergence of SC oscillations.

eLife's new model and its impact on science communication.

The eLife Early-Career Advisory Group discusses eLife's new peer review and publishing model, and how the whole process of scientific communication could be improved for the benefit of early-career researchers and the entire scientific community.

Resonating neurons stabilize heterogeneous grid-cell networks.

A central theme that governs the functional design of biological networks is their ability to sustain stable function despite widespread parametric variability. Here, we investigated the impact of distinct forms of biological heterogeneities on the stability of a two-dimensional continuous attractor network (CAN) implicated in grid-patterned activity generation. We show that increasing degrees of biological heterogeneities progressively disrupted the emergence of grid-patterned activity and resulted in progressively large perturbations in low-frequency neural activity. We postulated that targeted suppression of low-frequency perturbations could ameliorate heterogeneity-induced disruptions of grid-patterned activity. To test this, we introduced intrinsic resonance, a physiological mechanism to suppress low-frequency activity, either by adding an additional high-pass filter (phenomenological) or by incorporating a slow negative feedback loop (mechanistic) into our model neurons. Strikingly, CAN models with resonating neurons were resilient to the incorporation of heterogeneities and exhibited stable grid-patterned firing. We found CAN models with mechanistic resonators to be more effective in targeted suppression of low-frequency activity, with the slow kinetics of the negative feedback loop essential in stabilizing these networks. As low-frequency perturbations (1/f noise) are pervasive across biological systems, our analyses suggest a universal role for mechanisms that suppress low-frequency activity in stabilizing heterogeneous biological networks.

Biomimetic FPGA-based spatial navigation model with grid cells and place cells.

The mammalian spatial navigation system is characterized by an initial divergence of internal representations, with disparate classes of neurons responding to distinct features including location, speed, borders and head direction; an ensuing convergence finally enables navigation and path integration. Here, we report the algorithmic and hardware implementation of biomimetic neural structures encompassing a feed-forward trimodular, multi-layer architecture representing grid-cell, place-cell and decoding modules for navigation. The grid-cell module comprised of neurons that fired in a grid-like pattern, and was built of distinct layers that constituted the dorsoventral span of the medial entorhinal cortex. Each layer was built as an independent continuous attractor network with distinct grid-field spatial scales. The place-cell module comprised of neurons that fired at one or few spatial locations, organized into different clusters based on convergent modular inputs from different grid-cell layers, replicating the gradient in place-field size along the hippocampal dorso-ventral axis. The decoding module, a two-layer neural network that constitutes the convergence of the divergent representations in preceding modules, received inputs from the place-cell module and provided specific coordinates of the navigating object. After vital design optimizations involving all modules, we implemented the tri-modular structure on Zynq Ultrascale+ field-programmable gate array silicon chip, and demonstrated its capacity in precisely estimating the navigational trajectory with minimal overall resource consumption involving a mere 2.92% Look Up Table utilization. Our implementation of a biomimetic, digital spatial navigation system is stable, reliable, reconfigurable, real-time with execution time of about 32 s for 100k input samples (in contrast to 40 minutes on Intel Core i7-7700 CPU with 8 cores clocking at 3.60 GHz) and thus can be deployed for autonomous-robotic navigation without requiring additional sensors.

Degeneracy in the robust expression of spectral selectivity, subthreshold oscillations, and intrinsic excitability of entorhinal stellate cells.

Biological heterogeneities are ubiquitous and play critical roles in the emergence of physiology at multiple scales. Although neurons in layer II (LII) of the medial entorhinal cortex (MEC) express heterogeneities in channel properties, the impact of such heterogeneities on the robustness of their cellular-scale physiology has not been assessed. Here, we performed a 55-parameter stochastic search spanning nine voltage- or calcium-activated channels to assess the impact of channel heterogeneities on the concomitant emergence of 10 in vitro electrophysiological characteristics of LII stellate cells (SCs). We generated 150,000 models and found a heterogeneous subpopulation of 449 valid models to robustly match all electrophysiological signatures. We employed this heterogeneous population to demonstrate the emergence of cellular-scale degeneracy in SCs, whereby disparate parametric combinations expressing weak pairwise correlations resulted in similar models. We then assessed the impact of virtually knocking out each channel from all valid models and demonstrate that the mapping between channels and measurements was many-to-many, a critical requirement for the expression of degeneracy. Finally, we quantitatively predict that the spike-triggered average of SCs should be endowed with theta-frequency spectral selectivity and coincidence detection capabilities in the fast gamma-band. We postulate this fast gamma-band coincidence detection as an instance of cellular-scale-efficient coding, whereby SC response characteristics match the dominant oscillatory signals in LII MEC. The heterogeneous population of valid SC models built here unveils the robust emergence of cellular-scale physiology despite significant channel heterogeneities, and forms an efficacious substrate for evaluating the impact of biological heterogeneities on entorhinal network function. NEW & NOTEWORTHY We assessed the impact of heterogeneities in channel properties on the robustness of cellular-scale physiology of medial entorhinal cortical stellate neurons. We demonstrate that neuronal models with disparate channel combinations were endowed with similar physiological characteristics, as a consequence of the many-to-many mapping between channel properties and the physiological characteristics that they modulate. We predict that the spike-triggered average of stellate cells should be endowed with theta-frequency spectral selectivity and fast gamma-band coincidence detection capabilities.