RESUMO
Large cortical and hippocampal pyramidal neurons are elements of neuronal circuitry that have been implicated in cross-frequency coupling (CFC) during cognitive tasks. We investigate potential mechanisms for CFC within these neurons by examining the role that the hyperpolarization-activated mixed cation current (Ih) plays in modulating CFC characteristics in multicompartment neuronal models. We quantify CFC along the soma-apical dendrite axis and tuft of three models configured to have different spatial distributions of Ih conductance density: (1) exponential gradient along the soma-apical dendrite axis, (2) uniform distribution, and (3) no Ih conductance. We simulated two current injection scenarios: distal apical 4 Hz modulation and perisomatic 4 Hz modulation, each with perisomatic, mid-apical, and distal apical 40 Hz injections. We used two metrics to quantify CFC strength-modulation index and height ratio-and we analyzed CFC phase properties. For all models, CFC was strongest in distal apical regions when the 40 Hz injection occurred near the soma and the 4 Hz modulation occurred in distal apical dendrite. The strongest CFC values were observed in the model with uniformly distributed Ih conductance density, but when the exponential gradient in Ih conductance density was added, CFC strength decreased by almost 50%. When Ih was in the model, regions with much larger membrane potential fluctuations at 4 Hz than at 40 Hz had stronger CFC. Excluding the Ih conductance from the model resulted in CFC either reduced or comparable in strength relative to the model with the exponential gradient in Ih conductance. The Ih conductance also imposed order on the phase characteristics of CFC such that minimum (maximum) amplitude 40 Hz membrane potential oscillations occurred during Ih conductance deactivation (activation). On the other hand, when there was no Ih conductance, phase relationships between minimum and maximum 40 Hz oscillation often inverted and occurred much closer together. This analysis can help experimentalists discriminate between CFC that originates from different underlying physiological mechanisms and can help illuminate the reasons why there are differences between CFC strength observed in different regions of the brain and between different populations of neurons based on the configuration of the Ih conductance.
RESUMO
Evidence suggests that layer 5 pyramidal neurons can be divided into functional zones with unique afferent connectivity and membrane characteristics that allow for post-synaptic integration of feedforward and feedback inputs. To assess the existence of these zones and their interaction, we characterized the resonance properties of a biophysically-realistic compartmental model of a neocortical layer 5 pyramidal neuron. Consistent with recently published theoretical and empirical findings, our model was configured to have a "hot zone" in distal apical dendrite and apical tuft where both high- and low-threshold Ca2+ ionic conductances had densities 1-2 orders of magnitude higher than anywhere else in the apical dendrite. We simulated injection of broad spectrum sinusoidal currents with linearly increasing frequency to calculate the input impedance of individual compartments, the transfer impedance between the soma and key compartments within the dendritic tree, and a dimensionless term we introduce called resonance quality. We show that input resonance analysis distinguished at least four distinct zones within the model based on properties of their frequency preferences: basal dendrite which displayed little resonance; soma/proximal apical dendrite which displayed resonance at 5-23 Hz, strongest at 5-10 Hz and hyperpolarized/resting membrane potentials; distal apical dendrite which displayed resonance at 8-19 Hz, strongest at 10 Hz and depolarized membrane potentials; and apical tuft which displayed a weak resonance largely between 8 and 10 Hz across a wide range of membrane potentials. Transfer resonance analysis revealed that changes in subthreshold electrical coupling were found to modulate the transfer resonant frequency of signals transmitted from distal apical dendrite and apical tuft to the soma, which would impact the frequencies that individual neurons are expected to respond to and reinforce. Furthermore, eliminating the hot zone was found to reduce amplification of resonance within the model, which contributes to reduced excitability when perisomatic and distal apical regions receive coincident stimulating current injections. These results indicate that the interactions between different functional zones should be considered in a more complete understanding of neuronal integration. Resonance analysis may therefore be a useful tool for assessing the integration of inputs across the entire neuronal membrane.
