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Differences in the apparent 1/f component of neural power spectra require correction depending on the underlying neural mechanisms, which remain incompletely understood. Past studies suggest that neuronal spiking produces broadband signals and shapes the spectral trend of invasive macroscopic recordings, but it is unclear to what extent action potentials (APs) influence scalp EEG. Here, we combined biophysical simulations with statistical modelling to examine the amplitude and spectral content of scalp potentials generated by the electric fields from spiking activity. In physiological parameter regimes, we found that APs contribute negligibly to the EEG spectral trend. Consistent with this, comparing our biophysical simulations with previously published data from pharmacologically paralyzed subjects suggested that the EEG spectral trend can be explained by a combination of synaptic timescales and electromyogram contamination. We also modelled rhythmic EEG generation, finding that APs can generate detectable narrowband power between approximately 60 and 1000 Hz, reaching frequencies much faster than would be possible from synaptic currents. Finally, we show that different spectral detrending strategies are required for AP generated oscillations compared to synaptically generated oscillations, suggesting that existing detrending methods for EEG spectra need to be modified for high frequency signals.

Electroencephalograms (EEGs) display a mixture of rhythmic and broadband fluctuations, the latter manifesting as an apparent 1/f spectral trend. While network oscillations are known to generate rhythmic EEG, the neural basis of broadband EEG remains unexplained. Here, we use biophysical modelling to show that aperiodic neural activity can generate detectable scalp potentials and shape broadband EEG features, but that these aperiodic signals do not significantly perturb brain rhythm quantification. Further model analysis demonstrated that rhythmic EEG signals are profoundly corrupted by shifts in synapse properties. To examine this scenario, we recorded EEGs of human subjects being administered propofol, a general anesthetic and GABA receptor agonist. Drug administration caused broadband EEG changes that quantitatively matched propofol’s known effects on GABA receptors. We used our model to correct for these confounding broadband changes, which revealed that delta power, uniquely, increased within seconds of individuals losing consciousness. Altogether, this work details how EEG signals are shaped by neurophysiological factors other than brain rhythms and elucidates how these signals can undermine traditional EEG interpretation. The neural mechanisms that give rise to aperiodic EEG signals remains unclear. Here the authors characterize EEG signals generated by neural processes other than brain rhythms, demonstrating that certain drugs alter EEG signals in ways that confound traditional interpretation.

Burst firing is an important property of neuronal activity, thought to enhance sensory encoding. While previous studies show significant differences in burst firing between in vivo and in vitro conditions, how burst firing contributes to neural coding in vivo and how it is modulated by underlying biophysical mechanisms when neurons are under active synaptic bombardments remains poorly understood. Here, we combined intracellular recordings and computational modeling to investigate how cellular and synaptic mechanisms can explain the in vivo firing activity of electrosensory lateral line lobe (ELL) pyramidal cells in Apteronotus leptorhynchus . We developed a biophysically detailed compartmental model incorporating voltage-gated currents, NMDA receptor-mediated calcium (Ca 2 +  ) influx, Ca 2 +  -activated SK channels, Ca 2 +  mobilization, and stochastic synaptic inputs to reproduce in vivo firing activities of ELL pyramidal cells. Specifically, using bifurcation analysis, we identified dynamical transitions between quiescent, tonic, and bursting regimes, governed by interactions among SK conductance, NMDA receptor activation, and applied current. Model parameters were optimized against in vivo data, accurately reproducing action potential waveforms and temporal dynamics, including characteristic bimodal interspike interval distributions reflecting intra- and inter-burst intervals. We further developed a modified Hindmarsh-Rose model incorporating dual adaptation variables and stochastic noise. This simplified phenomenological model successfully captured burst firing comparable to that observed in the biophysical model and recorded data, while replicating diverse firing patterns observed across the population. Finally, parameter sensitivity analysis revealed slow adaptation dynamics and noise intensity as key determinants of spiking variability within cells. Overall, our modeling results demonstrate that in vivo bursting arises from synergistic interactions between intrinsic conductances (e.g., NMDA-SK coupling), Ca 2 +  mobilization, and synaptic stochasticity, offering a potential reconciliation for discrepancies with in vitro firing activity. The models provide mechanistic insights into how background synaptic activity modulates burst firing.

The P2 purinergic receptor family implicated in many physiological processes, including neurotransmission, mechanical adaptation and inflammation, consists of ATP-gated non-specific cation channels P2XRs and G-protein coupled receptors P2YRs. Different cells, including bone forming osteoblasts, express multiple P2 receptors; however, how P2X and P2Y receptors interact in generating cellular responses to various doses of [ATP] remains poorly understood. Using primary bone marrow and compact bone derived osteoblasts and BMP2-expressing C2C12 osteoblastic cells, we demonstrated conserved features in the P2-mediated Ca 2+ responses to ATP, including a transition of Ca 2+ response signatures from transient at low [ATP] to oscillatory at moderate [ATP], and back to transient at high [ATP], and a non-monotonic changes in the response magnitudes which exhibited two troughs at 10 −4 and 10 −2 M [ATP]. We identified P2Y2 and P2X7 receptors as predominantly contributing to these responses and constructed a mathematical model of P2Y2R-induced inositol trisphosphate (IP 3 ) mediated Ca 2+ release coupled to a Markov model of P2X7R dynamics to study this system. Model predictions were validated using parental and CRISPR/Cas9-generated P2Y2 and P2Y7 knockouts in osteoblastic C2C12-BMP cells. Activation of P2Y2 by progressively increasing [ATP] induced a transition from transient to oscillatory to transient Ca 2+ responses due to the biphasic nature of IP 3 Rs and the interaction of SERCA pumps with IP 3 Rs. At high [ATP], activation of P2X7R modulated the response magnitudes through an interplay between the biphasic nature of IP 3 Rs and the desensitization kinetics of P2X7Rs. Moreover, we found that P2Y2 activity may alter the kinetics of P2X7 towards favouring naïve state activation. Finally, we demonstrated the functional consequences of lacking P2Y2 or P2X7 in osteoblast mechanotransduction. This study thus provides important insights into the biophysical mechanisms underlying ATP-dependent Ca 2+ response signatures, which are important in mediating bone mechanoadaptation.

The breadth of pathogens to which T cells can respond is determined by the T cell receptors (TCRs) present in an individual’s repertoire. Although more than 90% of the sequence diversity among TCRs is generated by terminal deoxynucleotidyl transferase (TdT)-mediated N-nucleotide addition during V(D)J recombination, the benefit of TdT-altered TCRs remains unclear. Here, we computationally and experimentally investigated whether TCRs with higher N-nucleotide diversity via TdT make distinct contributions to acute or chronic pathogen control specifically through the inclusion of TCRs with lower antigen binding strengths (i.e., lower reactivity to peptide-major histocompatibility complex (pMHC)). When T cells with high pMHC reactivity have a greater propensity to become functionally exhausted than those of low pMHC reactivity, our computational model predicts a shift toward T cells with low pMHC reactivity over time during chronic, but not acute, infections. This TCR-affinity shift is critical, as the elimination of T cells with lower pMHC reactivity in silico substantially increased the time to clear a chronic infection, while acute infection control remained largely unchanged. Corroborating an affinity-centric benefit for TCR diversification via TdT, we found evidence that TdT-deficient TCR repertoires possess fewer T cells with weaker pMHC binding strengths in vivo and showed that TdT-deficient mice infected with a chronic, but not an acute, viral pathogen led to protracted viral clearance. In contrast, in the case of a chronic fungal pathogen where T cells fail to clear the infection, both our computational model and experimental data showed that TdT-diversified TCR repertoires conferred no additional protection to the hosts. Taken together, our in silico and in vivo data suggest that TdT-mediated TCR diversity is of particular benefit for the eventual resolution of prolonged pathogen replication through the inclusion of TCRs with lower foreign antigen binding strengths.

Cerebellar stellate cells (CSCs) are spontaneously active, tonically firing (5-30 Hz), inhibitory interneurons that synapse onto Purkinje cells. We previously analyzed the excitability properties of CSCs, focusing on four key features: type I excitability, non-monotonic first-spike latency, switching in responsiveness and runup (i.e., temporal increase in excitability during whole-cell configuration). In this study, we extend this analysis by using whole-cell configuration to show that these neurons can also burst when treated with certain pharmacological agents separately or jointly. Indeed, treatment with 4-Aminopyridine (4-AP), a partial blocker of delayed rectifier and A-type K + channels, at low doses induces a bursting profile in CSCs significantly different than that produced at high doses or when it is applied at low doses but with cadmium (Cd 2+ ), a blocker of high voltage-activated (HVA) Ca 2+ channels. By expanding a previously revised Hodgkin–Huxley type model, through the inclusion of Ca 2+ -activated K + (K(Ca)) and HVA currents, we explain how these bursts are generated and what their underlying dynamics are. Specifically, we demonstrate that the expanded model preserves the four excitability features of CSCs, as well as captures their bursting patterns induced by 4-AP and Cd 2+ . Model investigation reveals that 4-AP is potentiating HVA, inducing square-wave bursting at low doses and pseudo-plateau bursting at high doses, whereas Cd 2+ is potentiating K(Ca), inducing pseudo-plateau bursting when applied in combination with low doses of 4-AP. Using bifurcation analysis, we show that spike adding in square-wave bursts is non-sequential when gradually changing HVA and K(Ca) maximum conductances, delayed Hopf is responsible for generating the plateau segment within the active phase of pseudo-plateau bursts, and bursting can become “chaotic” when HVA and K(Ca) maximum conductances are made low and high, respectively. These results highlight the secondary effects of the drugs applied and suggest that CSCs have all the ingredients needed for bursting.

In mesenchymal cell motility, several migration patterns have been observed, including directional, exploratory and stationary. Two key members of the Rho-family of GTPases, Rac and Rho, along with an adaptor protein called paxillin, have been particularly implicated in the formation of such migration patterns and in regulating adhesion dynamics. Together, they form a key regulatory network that involves the mutual inhibition exerted by Rac and Rho on each other and the promotion of Rac activation by phosphorylated paxillin. Although this interaction is sufficient in generating wave-pinning that underscores cellular polarization comprised of cellular front (high active Rac) and back (high active Rho), it remains unclear how they interact collectively to induce other modes of migration detected in Chinese hamster Ovary (CHO-K1) cells. We previously developed a six-variable (6V) reaction–diffusion model describing the interactions of these three proteins (in their active/phosphorylated and inactive/unphosphorylated forms) along with other auxiliary proteins, to decipher their role in generating wave-pinning. In this study, we explored, through computational modeling and image analysis, how differences in timescales within this molecular network can potentially produce the migration patterns in CHO-K1 cells and how switching between migration modes could occur. To do so, the 6V model was reduced to an excitable 4V spatiotemporal model possessing three different timescales. The model produced not only wave-pinning in the presence of diffusion, but also mixed-mode oscillations (MMOs) and relaxation oscillations (ROs). Implementing the model using the Cellular Potts Model (CPM) produced outcomes in which protrusions in the cell membrane changed Rac–Rho localization, resulting in membrane oscillations and fast directionality variations similar to those observed experimentally in CHO-K1 cells. The latter was assessed by comparing the migration patterns of experimental with CPM cells using four metrics: instantaneous cell speed, exponent of mean-square displacement ( α -value), directionality ratio and protrusion rate. Variations in migration patterns induced by mutating paxillin’s serine 273 residue were also captured by the model and detected by a machine classifier, revealing that this mutation alters the dynamics of the system from MMOs to ROs or nonoscillatory behaviour through variation in the scaled concentration of an active form of an adhesion protein called p21-Activated Kinase 1 (PAK). These results thus suggest that MMOs and adhesion dynamics are the key mechanisms regulating CHO-K1 cell motility.

Focal adhesions are protein complexes that anchor cells to the extracellular matrix. During migration, the growth and disassembly of these structures are spatiotemporally regulated, with new adhesions forming at the leading edge of the cell and mature adhesions disassembling at the rear. Signalling proteins and structural cytoskeletal components tightly regulate adhesion dynamics. Paxillin, an adaptor protein within adhesions, is one of these proteins. Its phosphorylation at serine 273 (S273) is crucial for maintaining fast adhesion assembly and disassembly. Paxillin is known to bind to a GIT1-βPIX-PAK1 complex, which increases the local activation of the small GTPase Rac. To understand quantitatively the behaviour of this system and how it relates to adhesion assembly/disassembly, we developed a mathematical model describing the dynamics of the small GTPases Rac and Rho as determined by paxillin S273 phosphorylation. Our model revealed that the system possesses bistability, where switching between uninduced (active Rho) and induced (active Rac) states can occur through a change in rate of paxillin phosphorylation or PAK1 activation. The bistable switch is characterized by the presence of memory, minimal change in the levels of active Rac and Rho within the induced and uninduced states, respectively, and the limited regime of monostability associated with the uninduced state. These results were validated experimentally by showing the presence of bimodality in adhesion assembly and disassembly rates, and demonstrating that Rac activity increases after treating Chinese Hamster Ovary cells with okadaic acid (a paxillin phosphatase inhibitor), followed by a modest recovery after 20 min washout. Spatial gradients of phosphorylated paxillin in a reaction-diffusion model gave rise to distinct regions of Rac and Rho activities, resembling polarization of a cell into front and rear. Perturbing several parameters of the model also revealed important insights into how signalling components upstream and downstream of paxillin phosphorylation affect dynamics.

Defining the role of T-cell avidity and killing efficacy in forming immunological response(s), leading to relapse-remission and autoantibody release in autoimmune type 1 diabetes (T1D), remains incompletely understood. Using competition-based population models of T- and B-cells, we provide a predictive tool to determine how these two parametric quantities, namely, avidity and killing efficacy, affect disease outcomes. We show that, in the presence of T-cell competition, successive waves along with cyclic fluctuations in the number of T-cells are exhibited by the model, with the former induced by transient bistability and the latter by transient periodic orbits. We hypothesize that these two immunological processes are responsible for making T1D a relapsing-remitting disease within prolonged but limited durations. The period and the number of peaks of these two processes differ, making them potential candidates to determine how plausible waves and cyclic fluctuations are in producing such effects. By assuming that T-cell and B-cell avidities are correlated, we demonstrate that autoantibodies associated with the higher avidity T-cell clones are first to be detected, and they reach their detectability level faster than those associated with the low avidity clones, independent of what T-cell killing efficacies are. Such outcomes are consistent with experimental observations in humans and they provide a rationale for observing rapid and slow progressors of T1D in high risk subjects. Our analysis of the models also reveals that it is possible to improve disease outcomes by unexpectedly increasing the avidity of certain subclones of T-cells. The decline in the number of β-cells in these cases still occurs, but it terminates early, leaving sufficient number of functioning β-cells in operation and the affected individual asymptomatic. These results indicate that the models presented here are of clinical relevance because of their potential use in developing predictive algorithms of rapid and slow progression to clinical T1D.

The P2X4 receptor (P2X4R) is a member of a family of purinergic channels activated by extracellular ATP through three orthosteric binding sites and allosterically regulated by ivermectin (IVM), a broad-spectrum antiparasitic agent. Treatment with IVM increases the efficacy of ATP to activate P2X4R, slows both receptor desensitization during sustained ATP application and receptor deactivation after ATP washout, and makes the receptor pore permeable to NMDG+, a large organic cation. Previously, we developed a Markov model based on the presence of one IVM binding site, which described some effects of IVM on rat P2X4R. Here we present two novel models, both with three IVM binding sites. The simpler one-layer model can reproduce many of the observed time series of evoked currents, but does not capture well the short time scales of activation, desensitization, and deactivation. A more complex two-layer model can reproduce the transient changes in desensitization observed upon IVM application, the significant increase in ATP-induced current amplitudes at low IVM concentrations, and the modest increase in the unitary conductance. In addition, the two-layer model suggests that this receptor can exist in a deeply inactivated state, not responsive to ATP, and that its desensitization rate can be altered by each of the three IVM binding sites. In summary, this study provides a detailed analysis of P2X4R kinetics and elucidates the orthosteric and allosteric mechanisms regulating its channel gating.