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Tigerholm, J.

Publications and source records attributed to Tigerholm, J..

2 recordsLinked to original sources

Modeling the Memory of Unmyelinated Axons: Integration of a Data-Driven Approach with Physiological Memory Concept

In this study, we present a simplified and resource-efficient computational model to predict activity-dependent conduction velocity changes of action in unmyelinated axons. This model serves as a complementary tool to Hodgkin-Huxley models. Our approach is based on the concept of "memory," where the speed of subsequent action potentials is modulated by prior activity. We utilized microneurography data from 95 mechano-insensitive C-fibers of healthy human participants, including both sexes, across various stimulation protocols to optimize model parameters. The model incorporates linear long-term and non-linear short-term memory components. By convolving the history of recorded action potentials with the memory function, the model can effectively predict the propagation speed of subsequent action potentials with low mean squared errors for the proposed one-dimensional and two-dimensional memory functions. This computational framework provides insights into the dynamics of unmyelinated axons under varying conditions and thus in signal processing along the axon and the short-term memory of axons. The models rapid computation times make it suitable for real-time applications in electrophysiological experiments. Significance StatementThis study introduces a novel model for simulating activity-dependent conduction velocity changes in unmyelinated axons, which crucially shape signal processing during conduction. While traditional Hodgkin-Huxley (HH) models offer valuable physiological insights, they are computationally intensive and challenging to adapt due to numerous parameters. Our approach leverages the concept of fiber "memory," capturing how prior activity shapes conduction. It requires fewer parameters and therefore makes it easier to fit to diverse datasets, including patient data. Importantly, our model is highly efficient and suitable for real-time applications, enabling rapid simulation and analysis that are not feasible with HH models.

neuroscience↗

Biophysics of sodium channels during subthreshold depolarization in vitro and in silico

Voltage-gated sodium channels (VGSC) in the peripheral nervous system shape action potentials (AP) and thereby support the detection of sensory stimuli. Most of the nine mammalian VGSC subtypes are expressed in nociceptors, but predominantly, three are linked to several human pain syndromes: while Nav1.7 is suggested to be a (sub-)threshold channel, Nav1.8 is thought to support the fast AP upstroke. Nav1.9, as it produces large persistent currents, is attributed a role in determining the resting membrane potential. We characterized gating of Nav1.1-Nav1.3 and Nav1.5-Nav1.9 in manual patch clamp with focus on the AP subthreshold depolarization phase. Nav1.9 exhibited the most hyperpolarized activation while its fast inactivation resembled the depolarized inactivation of Nav1.8. For some VGSCs (e.g., Nav1.1 and Nav1.2), a positive correlation between ramp current and window current was detected. Using a modified Hodgkin-Huxley model which accounts for the time needed for inactivation to occur, we used the acquired data to simulate two nociceptive nerve fiber types (an A{delta}-and a mechano-insensitive C-nociceptor) containing VGSC conductances according to published human RNAseq data. Our simulations suggest that Nav1.9 is supporting both the AP upstroke and its shoulder. A reduced threshold for AP generation was induced by enhancing Nav1.7 conductivity or shifting its activation to more hyperpolarized potentials, as observed in Nav1.7-related pain disorders. Here, we provide a comprehensive, comparative functional characterization of VGSCs relevant in nociception and describe their gating with Hodgkin-Huxley-like models, which can serve as a tool to study their specific contributions to AP shape and sodium channel-related diseases. DisclaimerParts of this study were published as a preprint on bioRxiv: Koster, P.A., T. Stiehl, J. Tigerholm, A. Maxion, B. Namer, and A. Lampert. 2023. Biophysics of sodium channels during subthreshold depolarization in vitro and in silico. bioRxiv. doi.org/10.1101/2023.09.03.556095 (Preprint posted September 6, 2023) SummarySubthreshold gating of seven sodium channels (Nav1.1-3, Nav1.5-8) is determined by manual patch clamp and, together with Nav1.9, integrated into a computer model of an A{delta}-and a mechano-insensitive nociceptor (CMi). Simulations reveal contribution of Nav1.9 to the action potential upstroke and shoulder and prove useful for Nav1.7-related disease modelling.

physiology↗