Flexible cellular phenotypes retain a shared type-level organization across response regimes
Abstract
Electrophysiological phenotype is widely used to characterize neuronal identity, but the phenotype measured from a neuron depends on how its intrinsic physiology is probed. Here, we asked which aspects of cellular electrophysiological organization persist across distinct response regimes and how this persistence relates to transcriptomic identity. Using matched Patch-seq measurements from visual cortical GABAergic neurons in male and female mice, we constructed phenotype spaces independently from long-pulse, ramp, and brief-pulse current-clamp responses and compared their organization across the same cells. Cell-level phenotypic relationships were only partially conserved across regimes: cell–cell phenotypic distances were positively correlated across regimes but far from identity, and local neighborhoods reorganized even where global rank structure was partly conserved. Despite this flexibility, transcriptomic type consistently anchored phenotype beyond coarse Cre-driver identity. At the type level, phenotypic relationships were markedly more conserved across regimes, forming a shared relational backbone with a smaller set of regime-selective rewrites. Transcriptomic distance preferentially tracked this shared type-level structure rather than the magnitude of regime-selective reorganization, and predefined excitability-related gene programs showed the same asymmetry. Together, these results reveal a scale-dependent stability of neuronal phenotype: individual cellular relationships are flexible across probes, whereas type-level biological organization is comparatively stable and more strongly reflected in transcriptomic structure.
Significance Statement Electrophysiological properties are often treated as characteristics of neuronal identity, but the phenotype measured from a neuron depends on how that neuron is stimulated. By comparing multiple current-clamp response regimes in the same Patch-seq cells, we show that individual cellular relationships can reorganize substantially while relationships among transcriptomic cell types remain comparatively stable. Transcriptomic similarity preferentially corresponds to this shared type-level structure rather than to regime-dependent changes. These results suggest that cellular phenotype contains both a flexible, probe-dependent expression and a more stable biological organization, clarifying how electrophysiological and transcriptomic descriptions of neuronal identity relate across measurement conditions.
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BibTeX
@article{yang2026flexible,
title = {{Flexible cellular phenotypes retain a shared type-level organization across response regimes}},
author = {Zihan Yang},
journal = {eneuro},
year = {2026},
month = oct,
doi = {10.1523/eneuro.0275-26.2026},
url = {https://www.eneuro.org/lookup/doi/10.1523/ENEURO.0275-26.2026},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Flexible cellular phenotypes retain a shared type-level organization across response regimes
AU - Zihan Yang
PY - 2026
DA - 2026/10/22
JO - eneuro
DO - 10.1523/eneuro.0275-26.2026
UR - https://www.eneuro.org/lookup/doi/10.1523/ENEURO.0275-26.2026
AB - Electrophysiological phenotype is widely used to characterize neuronal identity, but the phenotype measured from a neuron depends on how its intrinsic physiology is probed. Here, we asked which aspects of cellular electrophysiological organization persist across distinct response regimes and how this persistence relates to transcriptomic identity. Using matched Patch-seq measurements from visual cortical GABAergic neurons in male and female mice, we constructed phenotype spaces independently from long-pulse, ramp, and brief-pulse current-clamp responses and compared their organization across the same cells. Cell-level phenotypic relationships were only partially conserved across regimes: cell–cell phenotypic distances were positively correlated across regimes but far from identity, and local neighborhoods reorganized even where global rank structure was partly conserved. Despite this flexibility, transcriptomic type consistently anchored phenotype beyond coarse Cre-driver identity. At the type level, phenotypic relationships were markedly more conserved across regimes, forming a shared relational backbone with a smaller set of regime-selective rewrites. Transcriptomic distance preferentially tracked this shared type-level structure rather than the magnitude of regime-selective reorganization, and predefined excitability-related gene programs showed the same asymmetry. Together, these results reveal a scale-dependent stability of neuronal phenotype: individual cellular relationships are flexible across probes, whereas type-level biological organization is comparatively stable and more strongly reflected in transcriptomic structure. Significance Statement Electrophysiological properties are often treated as characteristics of neuronal identity, but the phenotype measured from a neuron depends on how that neuron is stimulated. By comparing multiple current-clamp response regimes in the same Patch-seq cells, we show that individual cellular relationships can reorganize substantially while relationships among transcriptomic cell types remain comparatively stable. Transcriptomic similarity preferentially corresponds to this shared type-level structure rather than to regime-dependent changes. These results suggest that cellular phenotype contains both a flexible, probe-dependent expression and a more stable biological organization, clarifying how electrophysiological and transcriptomic descriptions of neuronal identity relate across measurement conditions.
SN - 2373-2822
ER -