Controlling morpho-electrophysiological variability of neurons with detailed biophysical models

Arnaudon, Alexis; Reva, Maria; Zbili, Mickael; Markram, Henry; Van Geit, Werner; Kanari, Lida

doi:10.1016/j.isci.2023.108222

“…These results align with experimental work revealing that highly complex, variable morphologies had no effect on the conservation of physiological waveforms and circuit functions of neurons [36]. Similarly, recent computational work in L5 pyramidal cells has shown morphological variance to be insufficient to reproduce electrical variability [37].…”

Section: Discussionsupporting

confidence: 83%

Morphological variability may limit single-cell specificity to electric field stimulation

Trotter

¹

,

Pariz

²

,

Hutt

³

et al. 2023

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Non-invasive brain stimulation techniques are widely used for manipulating the behaviour of neuronal circuits and the excitability of the neurons therein. While the usage of these techniques is widely studied at the meso- and macroscopic scales, less is known about the specificity of such approaches at the level of individual cells. Here we use models based on the morphologies of real pyramidal and parvalbumin neurons from mouse primary visual cortex created by the Allen Institute for Brain Science to explore the variability and evoked response susceptibility of different morphologies to uniform electric fields. We devised a range of metrics quantifying various aspects of cellular morphology, ranging from whole cell attributes to net compartment length, branching, diameter to orientation. In supporting layer- and cell-type specific responses, none of these physical traits passed statistical significance tests. While electric fields can modulate somatic, dendritic and axonal compartments reliably and subtype-specific responses could be observed, the specificity of such stimuli was blurred by the variability in cellular morphology. These null results suggest that morphology alone may not account for the reported subtype specificity of brain stimulation paradigms, and question the extent to which such techniques may be used to probe and control neural circuitry.

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Ion-channel degeneracy and heterogeneities in the emergence of signature physiological characteristics of dentate gyrus granule cells

Kumari,

Narayanan

2024

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Complex systems are neither fully determined nor completely random. Biological complex systems, including single neurons, manifest intermediate regimes of randomness that recruit integration of specific combinations of functionally segregated subsystems. Such emergence of biological function provides the substrate for the expression of degeneracy, the ability of disparate combinations of subsystems to yield similar function. Here, we present evidence for the expression of degeneracy in morphologically realistic models of dentate gyrus granule cells (GC) through functional integration of disparate ion-channel combinations. We performed a 45-parameter randomized search spanning 16 active and passive ion channels, each biophysically constrained by their gating kinetics and localization profiles, to search for valid GC models. Valid models were those that satisfied 17 sub- and supra-threshold cellular-scale electrophysiological measurements from rat GCs. A vast majority (>99%) of the 15,000 random models were not electrophysiologically valid, demonstrating that arbitrarily random ion-channel combinations wouldn't yield GC functions. The 141 valid models (0.94% of 15,000) manifested heterogeneities in and cross-dependencies across local and propagating electrophysiological measurements, which matched with their respective biological counterparts. Importantly, these valid models were widespread throughout the parametric space and manifested weak cross-dependencies across different parameters. These observations together showed that GC physiology could neither be obtained by entirely random ion-channel combinations nor is there an entirely determined single parametric combination that satisfied all constraints. The complexity, the heterogeneities in measurement and parametric spaces, and degeneracy associated with GC physiology should be rigorously accounted for, while assessing GCs and their robustness under physiological and pathological conditions.

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Ion-channel degeneracy and heterogeneities in the emergence of signature physiological characteristics of dentate gyrus granule cells

Kumari,

Narayanan

2024

Journal of Neurophysiology

0

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Complex systems are neither fully determined nor completely random. Biological complex systems, including single neurons, manifest intermediate regimes of randomness that recruit integration of specific combinations of functionally segregated subsystems. Such emergence of biological function provides the substrate for the expression of degeneracy, the ability of disparate combinations of subsystems to yield similar function. Here, we present evidence for the expression of degeneracy in morphologically realistic models of dentate gyrus granule cells (GC) through functional integration of disparate ion-channel combinations. We performed a 45-parameter randomized search spanning 16 active and passive ion channels, each biophysically constrained by their gating kinetics and localization profiles, to search for valid GC models. Valid models were those that satisfied 17 sub- and supra-threshold cellular-scale electrophysiological measurements from rat GCs. A vast majority (>99%) of the 15,000 random models were not electrophysiologically valid, demonstrating that arbitrarily random ion-channel combinations wouldn't yield GC functions. The 141 valid models (0.94% of 15,000) manifested heterogeneities in and cross-dependencies across local and propagating electrophysiological measurements, which matched with their respective biological counterparts. Importantly, these valid models were widespread throughout the parametric space and manifested weak cross-dependencies across different parameters. These observations together showed that GC physiology could neither be obtained by entirely random ion-channel combinations nor is there an entirely determined single parametric combination that satisfied all constraints. The complexity, the heterogeneities in measurement and parametric spaces, and degeneracy associated with GC physiology should be rigorously accounted for, while assessing GCs and their robustness under physiological and pathological conditions.

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Controlling morpho-electrophysiological variability of neurons with detailed biophysical models

Cited by 3 publications

References 60 publications

Morphological variability may limit single-cell specificity to electric field stimulation

Morphological variability may limit single-cell specificity to electric field stimulation

Ion-channel degeneracy and heterogeneities in the emergence of signature physiological characteristics of dentate gyrus granule cells

Ion-channel degeneracy and heterogeneities in the emergence of signature physiological characteristics of dentate gyrus granule cells

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