Degeneracy in the emergence of spike-triggered average of hippocampal pyramidal neurons

Abstract

Hippocampal pyramidal neurons are endowed with signature excitability characteristics, exhibit theta-frequency selectivity-manifesting as impedance resonance and as a band-pass structure in the spike-triggered average (StA)-and coincidence detection tuned for gamma-frequency inputs. Are there specific constraints on molecular-scale (ion channel) properties in the concomitant emergence of cellular-scale encoding (feature detection and selectivity) and excitability characteristics? Here, we employed a biophysically-constrained unbiased stochastic search strategy involving thousands of conductance-based models, spanning 11 active ion channels, to assess the concomitant emergence of 14 different electrophysiological measurements. Despite the strong biophysical and physiological constraints, we found models that were similar in terms of their spectral selectivity, operating mode along the integrator-coincidence detection continuum and intrinsic excitability characteristics. the parametric combinations that resulted in these functionally similar models were non-unique with weak pair-wise correlations. employing virtual knockout of individual ion channels in these functionally similar models, we found a many-to-many relationship between channels and physiological characteristics to mediate this degeneracy, and predicted a dominant role for HCN and transient potassium channels in regulating hippocampal neuronal StA. our analyses reveals the expression of degeneracy, that results from synergistic interactions among disparate channel components, in the concomitant emergence of neuronal excitability and encoding characteristics. Degeneracy, the ability of distinct structural components to elicit similar physiology, is ubiquitous in biology, across organisms and across scales 1-8. Several studies have shown that models with disparate combinations of ion channel conductances can have physiological measurements with values within their experimentally determined ranges 4,6,8-19. Most of these studies, however, have focused largely on measures of excitability, with the focus primarily on homeostasis. However, neurons are also endowed with specific physiological properties that define the features that they encode, their operating mode (i.e., their position along the integrator-coincidence detector (I-CD) continuum), and coincidence detection capabilities 20-26. Could degeneracy be a substrate for neurons to encode specific characteristics, to be endowed with specific operational characteristics and still maintain their excitability properties within experimental bounds? Could the feature detection/extraction goals of a neuron coexist with its ability to maintain specific levels of excitability? Could disparate combinations of ion channels mediate such co-existence? Is there a dominance hierarchy among different channels in determining a neuron's operating mode? To address these questions, we carried out computational analyses that employed hippocampal CA1 pyramidal neuron models as substrates. We used this particular category of...

Effects of Ih and TASK-like shunting current on dendritic impedance in layer 5 pyramidal-tract neurons

“…For example, there is evidence for upregulation of HCN channel expression following epileptic seizure [42, 63, 69]. And while HCN channels are necessary for resonance in PTs, the dendritic impedance profile can be significantly altered upon modulation of other local conductances or morphological changes to the dendritic tree [15, 17, 28, 30, 32, 60, 62, 83]. A number of studies have explored the possibility of modulating the dendritic impedance profile by manipulating other channels like A- and M-type K + channels or Ca 2 + channel “hot-zones” [14, 17, 60]; however, the possibility of modulating dendritic impedance via TASK-like shunting current has not previously been investigated.…”

Minimal requirements for a neuron to co-regulate many properties and the implications for ion channel correlations and robustness

“…Ion channel correlations have been studied using both simulations 8,30,33,37,63,[67][68][69] and experiments 47,[70][71][72][73][74] . These correlations have been ascribed to the co-regulation of ion channels.…”

“…The ability of distinct elements to produce the same outcome is referred to as degeneracy 19 and has attracted increasing attention in neuroscience 18,[20][21][22][23][24][25][26][27] . Many aspects of neural function at the genetic 28,29 , synaptic 30,31 , cellular [32][33][34][35][36][37][38][39] , and network [40][41][42][43][44] levels are now recognized as being degenerate. Ion channel degeneracy facilitates robust homeostatic regulation of neuronal excitability by enabling a disruptive change in one ion channel to be offset by compensatory changes in other ion channels 22,34,35,[45][46][47][48][49][50] .…”

Spatial information transfer in hippocampal place cells depends on trial-to-trial variability, symmetry of place-field firing and biophysical heterogeneities

“…We took advantage of our conductance-based modeling framework, and employed the virtual knockout approach (Basak & Narayanan, 2018Jain & Narayanan, 2020;Mittal & Narayanan, 2018;Mukunda & Narayanan, 2017;Rathour & Narayanan, 2014;Seenivasan & Narayanan, 2020) to assess the contribution of individual ion channels to spatial information transfer. Specifically, we systematically assessed information transfer profiles in each of the valid models after virtually knocking out individual ion channels by setting their conductance value to zero (Fig.…”

“…Ion-channel degeneracy in the hippocampal formation is ubiquitous, and expresses across different scales of analyses (Mishra & Narayanan, 2019;Mittal & Narayanan, 2018;Rathour & Narayanan, 2019). In hippocampal CA1 pyramidal neurons, the expression of degeneracy has been demonstrated with reference to the concomitant emergence of several somato-dendritic intrinsic properties (R. Migliore, et al, 2018;Rathour, Malik, & Narayanan, 2016;Rathour & Narayanan, 2012Srikanth & Narayanan, 2015), spike-triggered average (Das & Narayanan, 2014Das, Rathour, & Narayanan, 2017;Jain & Narayanan, 2020), short- (Mukunda & Narayanan, 2017) as well as long-term (Anirudhan & Narayanan, 2015) plasticity profiles. More specifically, with reference to the firing properties of CA1 pyramidal neurons as place cells, degeneracy has been shown to express in the sharpness of place-field firing properties with reference to biophysical as well as morphological parameters (Basak & Narayanan, 2018, which has been confirmed in this study with a larger set of ion channels incorporated into the model.…”