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Cited by 26Neural dynamics and brain functionNeuroscience and Neuropharmacology ResearchIon channel regulation and function

Gating of homeostatic regulation of intrinsic excitability produces cryptic long-term storage of prior perturbations

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Alonso, Leandro M., Rue, Mara C. P., Marder, Eve·2023·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2222016120PMC PMC10293857
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Abstract

Neurons and neuronal circuits must maintain their function throughout the life of the organism despite changing environments. Previous theoretical and experimental work suggests that neurons monitor their activity using intracellular calcium concentrations to regulate their intrinsic excitability. Models with multiple sensors can distinguish among different patterns of activity, but previous work using models with multiple sensors produced instabilities that lead the models’ conductances to oscillate and then to grow without bound and diverge. We now introduce a nonlinear degradation term that explicitly prevents the maximal conductances to grow beyond a bound. We combine the sensors’ signals into a master feedback signal that can be used to modulate the timescale of conductance evolution. Effectively, this means that the negative feedback can be gated on and off according to how far the neuron is from its target. The modified model recovers from multiple perturbations. Interestingly, depolarizing the models to the same membrane potential with current injection or with simulated high extracellular K + produces different changes in conductances, arguing that caution must be used in interpreting manipulations that serve as a proxy for increased neuronal activity. Finally, these models accrue traces of prior perturbations that are not visible in their control activity after perturbation but that shape their responses to subsequent perturbations. These cryptic or hidden changes may provide insight into disorders such as posttraumatic stress disorder that only become visible in response to specific perturbations.

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  • In computational models it is feasible to examine the structures of the parameter spaces that contribute to an output or a physiological state.

    “In computational models it is feasible to examine the structures of the parameter spaces that contribute to an output or a physiological state [31,42,46,47].”

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Authors
Alonso, L. M., Rue, M. C. P., & Marder, E.
Affiliations
Brandeis University (US)
Corresponding author
  • Alonso, Leandro M.
  • Marder, Eve
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2023-06-20
Volume
120
Issue
26
Pages
e2222016120-e2222016120
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2222016120
PMC
PMC10293857
OpenAlex
W4381432380
Cited by
26
References
0
Citations by year
2026: 10 · 2025: 9 · 2024: 5 · 2023: 2
FWCI
3.63
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • HHS | NIH | National Institute of Neurological Disorders and Stroke (NS097343, F31-NS113383)
  • HHS | NIH | National Institute of Mental Health (MH046742)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
Keywords
intrinsic excitability, homeostatic regulation, intracellular calcium, conductance modulation, nonlinear degradation, negative feedback, perturbation recovery, neuronal activity monitoring, post-traumatic stress disorder, extracellular potassium, current injection
MeSH terms
Action Potentials, Homeostasis, Membrane Potentials, Neurons

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