Hyperpolarization-activated cation channels shape the spiking frequency preference of human cortical layer 5 pyramidal neurons
Bibliographic record
Abstract
Abstract Discerning the contribution of specific ionic currents to complex neuronal dynamics is a difficult, but important, task. This challenge is exacerbated in the human setting, although the widely-characterized uniqueness of the human brain as compared to preclinical models necessitates the direct study of human neurons. Neuronal spiking frequency preference is of particular interest given its role in rhythm generation and signal transmission in cortical circuits. Here, we combine the frequency-dependent gain (FDG), a measure of spiking frequency preference, and novel in silico analyses to dissect the contributions of individual ionic currents to key FDG features of human L5 neurons. We confirm that a contemporary model of such a neuron, primarily constrained to capture subthreshold activity driven by the hyperpolarization-activated cyclic nucleotide gated (h-) current, replicates key features of the in vitro FDG both with and without h-current activity. With the model confirmed as a viable approximation of the biophysical features of interest, we applied new analysis techniques to quantify the activity of each modeled ionic current in the moments prior to spiking, revealing unique dynamics of the h-current. These findings motivated patch-clamp recordings in analogous rodent neurons to characterize their FDG, which confirmed that a biophysically-detailed model of these neurons captures key inter-species differences in the FDG. These differences are correlated with distinct contributions of the h-current to neuronal activity. Together, this interdisciplinary and multi-species study provides new insights directly relating the dynamics of the h-current to neuronal spiking frequency preference in human L5 neurons. Significance Statement Understanding the contributions of individual ionic currents to neuronal activity is vital, considering the established role of ion channel modifications in neuropsychiatric conditions. We combine in vitro characterization of the spiking frequency preference of human L5 cortical pyramidal neurons via the frequency-dependent gain (FDG) with new analyses of a biophysically-detailed computational model of such a neuron to delineate the connection between the dynamics of the hyperpolarization-activated cyclic nucleotide gated (h-) current prior to spiking and key properties of the FDG. By further determining that both these FDG properties and h-current dynamics are distinct in analogous rodent neurons, we provide convincing evidence for the key role of the h-current in the frequency preference of human L5 cortical neurons.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".