Biology subjects

Crodelle, J.

Publications and source records attributed to Crodelle, J..

3 recordsLinked to original sources

bioRxiv2024

Biophysical Modeling and Experimental Analysis of the Dynamics of C. elegans Body-Wall Muscle Cells

This study combines experimental techniques and mathematical modeling to investigate the dynamics of C. elegans body-wall muscle cells. Specifically, by conducting voltage clamp and mutant experiments, we identify key ion channels, particularly the L-type voltage-gated calcium channel (EGL-19) and potassium channels (SHK-1, SLO-2), which are crucial for generating action potentials. We develop Hodgkin-Huxley-based models for these channels and integrate them to capture the cells electrical activity. To ensure the model accurately reflects cellular responses under depolarizing currents, we develop a parallel simulation-based inference method for determining the models free parameters. This method performs rapid parallel sampling across high-dimensional parameter spaces, fitting the model to the responses of muscle cells to specific stimuli and yielding accurate parameter estimates. We validate our model by comparing its predictions against cellular responses to various current stimuli in experiments and show that our approach effectively determines suitable parameters for accurately modeling the dynamics in mutant cases. Additionally, we discover an optimal response frequency in body-wall muscle cells, which corresponds to a burst firing mode rather than regular firing mode. Our work provides the first experimentally constrained and biophysically detailed muscle cell model of C. elegans, and our analytical framework combined with robust and efficient parametric estimation method can be extended to model construction in other species. Author summaryDespite the availability of many biophysical neuron models of C. elegans, a biologically detailed model of its muscle cell remains lacking, which hampers an integrated understanding of the motion control process. We conduct voltage clamp and mutant experiments to identify ion channels that influence the dynamics of body-wall muscle cells. Using these data, we establish Hodgkin-Huxley-based models for these ion channels and integrate them to simulate the electrical activity of the muscle cells. To determine the free parameters of the model, we develop a simulation-based inference method with parallel sampling that aligns the model with the muscle cells responses to specific stimuli. Our method allows for swift parallel sampling of parameters in high dimensions, facilitating efficient and accurate parameter estimation. To validate the effectiveness of the determined parameters, we verify the cells responses under different current stimuli in wild type and mutant cases. Furthermore, we investigate the optimal response frequency of body-wall muscle cells and find that it exhibits a frequency consistent with burst firing mode rather than regular firing mode. Our research introduces the first experimentally validated and biophysically detailed model of muscle cells in C. elegans. Additionally, our modeling and simulation framework for efficient parametric estimation in high-dimensional dynamical systems can be extended to model constructions in other scenarios.

neuroscience↗

bioRxiv2024

Mechanisms for dysregulation of excitatory-inhibitory balance underlying allodynia in dorsal horn neural subcircuits

Chronic pain is a wide-spread condition that is debilitating and expensive to manage, costing the United States alone around $600 billion in 2010. In a common type of chronic pain called allodynia, non-painful stimuli produce painful responses with highly variable presentations across individuals. While the specific mechanisms remain unclear, allodynia is hypothesized to be caused by the dysregulation of excitatory-inhibitory (E-I) balance in pain-processing neural circuitry in the dorsal horn of the spinal cord. In this work, we analyze biophysically-motivated subcircuit structures that represent common motifs in neural circuits in layers I-II of the dorsal horn. These circuits are hypothesized to be part of the neural pathways that mediate two different types of allodynia: static and dynamic. We use neural firing rate models to describe the activity of populations of excitatory and inhibitory interneurons within each subcircuit. By accounting for experimentally-observed responses under healthy conditions, we specify model parameters defining populations of subcircuits that yield typical behavior under normal conditions. Then, we implement a sensitivity analysis approach to identify the mechanisms most likely to cause allodynia-producing dysregulation of the subcircuits E-I signaling. We find that disruption of E-I balance generally occurs either due to downregulation of inhibitory signaling so that excitatory neurons are "released" from inhibitory control, or due to upregulation of excitatory neuron responses so that excitatory neurons "escape" their inhibitory control. Which of these mechanisms is most likely to occur, the subcircuit components involved in the mechanism, and the proportion of subcircuits exhibiting the mechanism can vary depending on the subcircuit structure. These results suggest specific hypotheses about diverse mechanisms that may be most likely responsible for allodynia, thus offering predictions for the high interindividual variability observed in allodynia and identifying targets for further experimental studies on the underlying mechanisms of this chronic pain condition. Author summaryWhile chronic pain affects roughly 20% of the US adult population [1], symptoms and presentations of the condition are highly variable across individuals and its causes remain largely unknown. A prevailing hypothesis for the cause of a type of chronic pain called allodynia is that the balance between excitatory and inhibitory signaling pathways between neuron populations in the spinal cord dorsal horn may be disrupted. To help better understand neural mechanisms underlying allodynia, we analyze biologically-motivated mathematical models of subcircuits of neuron populations that are part of the pain processing signaling pathway in the dorsal horn of the spinal cord. We use a novel sensitivity analysis approach to identify mechanisms of subcircuit dysregulation that may contribute to two different types of allodynia. The model results identify specific subcircuit components that are most likely to contribute to each type of allodynia. These mechanisms suggest targets for further experimental study, as well as for pharmacological intervention for better pain treatments.

neuroscience↗

bioRxiv2020

Idealized model of the developing visual cortex

Recent experiments in the developing mammalian visual cortex have revealed that gap junctions couple excitatory cells and potentially influence the formation of chemical synapses. Though gap junctions between inhibitory cells are ubiquitous in the adult cortex, and their presence has been shown to promote synchronous network firing, their function among excitatory, pyramidal cells remains poorly understood. During development, pyramidal cells that were derived from the same progenitor cell, called sister cells, are preferentially connected by a gap junction during the first postnatal week, while chemical synapses are still being formed. Additionally, these sister cells tend to share an orientation preference and a chemical synapse in the adult cortex, a property that is diminished when gap junctions are blocked. In this work, we construct an idealized model of the mouse visual cortex during the first two postnatal weeks of development to analyze the response properties of gap-junction-coupled cells and their effect on synaptic plasticity. Further, as an application of this model, we investigate the interplay of gap-junction coupling and synaptic plasticity on the order, or organization, of the resulting cortical map of orientation preference. Author summaryGap junctions, or sites of direct electrical connections between neurons, have a significant presence in the cortex, both during development and in adulthood. Their primary function during either of these periods, however, is still poorly understood. In the adult cortex, gap junctions between local, inhibitory neurons have been shown to promote synchronous firing, a network characteristic thought to be important for learning, attention, and memory. During development, gap junctions between excitatory, pyramidal cells, have been conjectured to play a role in synaptic plasticity and the formation of cortical circuits. In the visual cortex, where neurons exhibit tuned responses to properties of visual input such as orientation and direction, recent experiments show that excitatory cells are coupled by gap junctions during the first postnatal week and are replaced by chemical synapses during the second week. In this work, we explore the possible contribution of gap-junction coupling during development to the formation of chemical synapses both into the visual cortex from the thalamus and within the visual cortex between cortical cells. Specifically, within a mathematical model of the visual cortex during development, we identify the response properties of gap-junction-coupled cells and their influence on the formation of the cortical map of orientation preference.

neuroscience↗