Activity of neurons embedded in networks is an inseparable composition of intrinsic
and evoked processes. Prevalence of either component depends on the neuron's function
(e.g., signal pacemaker vs. transmitter) and state (e.g., low vs. high depolarization
states). Complex firing patterns of a neuron are conventionally attributed to complex
spatial-temporal organization of inputs received from the network-mates via synapses,
in vast majority dendritic. However, these views require revisiting with account of
active properties of the dendrites. Structural features of the arborization inevitably
impact on electrical states of its constituting parts at different levels of organization,
from branches and sub-trees to ion channels. This Research Topic aimed at bringing
together contributions of researches from different domains and gaining deeper insight
into the nature of neuronal intrinsic firing patterns. Being cross-listed in Frontiers
in Cellular Neuroscience and Frontiers in Computational Neuroscience, it contains
22 articles (14 and 8 in the respective journal specialties, respectively) including
14 original research articles, 4 reviews; 1 mini review, 1 methods, and 2 hypothesis
and theory articles.
Historical perspectives of studies of structure-related intrinsic neuronal activity
Llinás who pioneered in discovery of active membrane properties of neuronal dendrites
and putting forward the notion the intrinsic activity of neurons, provides a historical
perspective of studies, which flagged beginning of modification of the reflex viewpoint
of brain function, as the global neuroscience paradigm, toward one, in which sensory
input modulates rather than dictates brain function. The author explains how unique
firing signatures of different type neurons are related to their specific sets of
voltage-gated ion channels, dendritic in particular, and notes that complex intrinsic
properties allow neurons to function either as relay systems, or as oscillators and/or
resonators.
Bower describes his view of the history, achievements and merits of the first “community
model,” a Purkinje neuron model with detailed morphology and appropriate active conductances
of the dendrites. The author emphasizes on importance of using such models for testing,
interpreting, and predicting experimental data rather than for demonstrating the plausibility
of a particular idea and illustrates implementations of this approach in their “community
model” of Purkinje cell.
Dendritic origins of firing patterns in neurons
Alford and Alpert review dendritic mechanisms of synaptic integration in neurons forming
the spinal central pattern generator in lamprey. These mechanisms transform an unpatterned
glutamatergic input into a patterned, rhythmic output that is a feature of the spinal
network. Dendritic origin of the intrinsic oscillatory activity is defined by the
interplay of Ca2+ entry through NMDA-type glutamatergic channels with contribution
from voltage-gated Ca2+ channels and outward current through Ca2+-sensitive K+ channels
producing in-phase oscillations of intracellular Ca2+ and the membrane potential in
the dendrites.
Magnani et al. address specific oscillatory and firing properties of stellate cells
in layer II of the medial entorhinal cortex. Using the quadratic sinusoidal analysis
the authors compare characteristics of subthreshold membrane potential oscillations
and supra-threshold firing of action potentials (APs) generated in response to multi-sinusoidal
current stimulation. The quadratic responses were likely dominated by the dendrites
and contained frequencies that were not present in the input signal and the characteristics
of the subthreshold oscillations at resonance frequencies near the threshold were
similar to those of the supra-threshold spike trains.
Based on the analysis of somatic and dendritic plateau properties observed in spiny
neurons of amygdala, striatum, and cortex Oikonomou et al. describe their hypothesis
stating that the somatic voltage upstates are determined by dendritic plateau potentials.
This view is supported in experiments using voltage-sensitive dye imaging, which reported
rising of the somatic plateau after the onset of the dendritic voltage transient and
collapsing with the breakdown of the dendritic plateau depolarization. It is hypothesized
that dendritic plateau potentials underlay detection and transformation of coherent
network activity into a ubiquitous neuronal upstate.
Psarrou et al. investigated the effects of the basal dendrites morphology on the firing
behavior on models of reconstructed pyramidal neurons in layer V of rat prefrontal
cortex. Earlier studies revealed in these cells characteristic firing patterns: regular
spiking (RS), intrinsic bursting (IB), and repetitive oscillatory bursting. Variation
of dendritic geometry and distribution of ion conductances allowed the authors to
derive pattern-predictive structural characteristics. The RS- or IB-generating cells
were best discriminated by the total length, volume, and branch number, regardless
of the distribution of conductances in basal trees.
Tran-Van-Minh et al. review the biophysical determinants of linear, sublinear, and
supralinear effects of multiple co-activated synapses contacting active neuronal dendrites.
The authors highlight the interplay of dendritic morphology and channels, spiking
threshold and distribution of synaptic inputs. Sublinear relations are favored by
the combination of thin dendritic diameter and low expression of voltage-gated channels,
whereas thick dendrites expressing voltage-gated channels of inward current favor
supralinear relations, from boosting synaptic depolarization to regenerative dendritic
spikes.
Firing patterns in normally developing and degenerating neurons
The geometry, expression and properties of membrane ion channel of neuronal dendrites
are subject to changes during normal development and neurodegenerative disease. Some
of these aspects are addressed in the following contributions.
Durand et al. explored mouse lumbar motoneurons in isolated spinal cord at a postnatal
age of P3-P9 just before mice weigh-bear and walk. The authors characterized the reconstructed
dendritic geometry and firing patterns evoked by somatically applied depolarizing
currents, particularly of triangular ascending-descending time course (ramps). A transient
type pattern was firing during the ascending phase of the current. It was observed
in about 40% of cells between P3 and P5 and tended to disappear with age. Linear and
clockwise hysteresis firing patterns dominated at P6–P7 age. Prolonged sustained and
counterclockwise hysteresis (mature) firing patterns emerged at P8–P9 age and likely
were related to maturation of dendritic L-type Ca2+ channels. Hence, it is P8–P9 age,
when the electrical properties of mouse motoneurons rapidly change to provide the
mature motor behaviors.
Dhupia et al. on a model of reconstructed CA1 pyramidal neuron studied the role of
geometry of atrophied dendrites in electrical responsiveness of the dendritic tree
with distributed hyperpolarization-activated h-channels. The atrophy was mimicked
by pruning outer branches. Based on analysis of responses evoked by sinusoidal currents
of constant amplitude and linearly increasing frequency, the authors conclude that,
in the presence of an h-channel gradient, atrophied neurons respond to incoming inputs
and transfer signals across the dendritic tree more efficiently, have significantly
diminished spatial gradients of input resistance and local/transfer impedance than
those in unpruned cell.
Functional compartmentalization of dendrites and somato-dendritic coupling
Firing patterns of spinal motoneurons containing channels of persistent inward current
(PIC) in the dendritic membrane were explored by Kim and Heckman on a two-compartment
model. The authors analyzed model responses to application of triangular current depending
on the somato-dendritic electrical coupling, dendritic location and activation of
PIC conductances. A variation of PIC activation parameters mimicking neuromodulatory
effects of brain stem systems led to narrowing the structure-dependent coupling resistance
range, in which the model generated nonlinear (hysteretic) firing patterns. Outside
the range, the firing mode became linear irrespectively of PIC location. It is concluded
that neuromodulation by the brainstem systems may play a role in switching the motoneurons
between linear and non-linear firing modes.
Manuel et al. investigated a two-compartment model of lumbar motoneuron expressing
L-type Ca2+ conductance and Ca2+ -sensitive K+ conductance responsible for afterhyperpolarization
(AHP) and having a strong electrical coupling of the somatic and dendritic compartments.
The cells with different somato-denritic distribution of those conductances were stimulated
by triangular ramp currents to determine conditions for a counterclockwise hysteresis
of firing frequency-to-current relation associated with the motoneuron bistability.
This occurred when L-type conductance in proximal dendrite or soma was co-expressed
with and counterbalanced by the AHP conductance. The authors conclude that for the
motoneuron firing pattern the dynamical interaction between the L-type and AHP currents
is as fundamental as the segregation of the L-type current in dendrites.
Simões-de-Souza et al. developed computational models of three classes of the olfactory
bulb granule cells with distinct distributions of spines along their active reconstructed
dendrites and investigated how each class integrate synaptic inputs. The classes were
defined by the regions, to which their dendrites were confined: the whole external
plexiform layer for class I, and lower or upper 1/2 to 1/3 of this layer for class
II or III, respectively. Independently of the location of the stimuli and the dendritic
tree morphology, the AP always originated in the terminal dendrites and required different
quantities of spines to be activated in each dendritic region. The authors conclude
that these model predictions might have important computational implications in the
context of functioning of olfactory bulb circuits.
Yang et al. studied response properties of CA1 pyramidal neurons in acute brain slices
employing the 3D digital holographic photolysis to uncage glutamate at multiple dendritic
sites. The somatic responses were integrated supra-linearly or sub-linearly if the
stimulation sites were, respectively, clustered on a single dendrite or distributed
across multiple dendrites. Such difference was observed for oblique and basal dendrites,
but not for the tuft dendrites responding linearly to both types of stimulation. Multi-branch
integration occurring at oblique and basal dendrites allows somatic AP firing to follow
the driving stimuli over a significantly wider frequency range than in case of single
branch integration. However, multi-branch integration requires greater input strength
to drive the somatic APs. These data show that integration of such driving signals
in a single dendrite is fundamentally different from that in multiple dendrites.
In a study on models of reconstructed CA1 pyramidal cells, Ferrante and Ascoli analyzed
how synaptically evoked spiking in these neurons exhibiting higher or lower excitability
is regulated by different feedforward inhibition (FFI) GABAergic pathways. The pathways
mediated by fast-spiking, perisomatic-targeting basket cells and regular-spiking,
dendritic-targeting bistratified cells were stimulated separately or jointly at different
strengths. Bistratified interneurons affected low-, but not high-excitable pyramidal
cells; whereas basket cells affected both pyramidal cell types similarly. Selective
FFI produced by bistratified and basket cells alone modulated respectively, threshold
and gain of pyramidal cell firing. Simultaneous FFI via both pathways acting synergistically
enlarged the dynamic range of response. The authors conclude that their results provide
experimentally testable hypotheses of the differential function of those interneurons.
Iannella and Launey used a biophysically detailed model of a reconstructed neocortical
layer 2/3 pyramidal cell to investigate the effect of changes in parameters of the
spike timing-dependent plasticity (STDP) of dendritic synapses on the formation of
the so-called “dendritic mosaic” composed of clusters of synapses with similar efficacies.
The mosaic formation depended on the balance between potentiation and depression,
mean presynaptic firing rate and, crucially, the dendritic morphology. Any imbalance
led to degradation of such cluster organization. The authors suggest that, synaptic
plasticity favors the formation of clustered efficacy engrams.
Tools for studies of dendritic and axonal processes
Du et al. describe an approach to the reduction of models of neurons possessing weakly
excitable large dendritic trees and the strongly excitable small spike initiation
zone. It is illustrated on an example of the lobula giant movement detector neuron
of the locust. An initial 879-compartment model was transformed by decoupling its
branches, reducing separately active and quasi-active branches, re-coupling these
two reduced components into a resulting model. The latter being faster retained the
full integrative qualities of the original two-order larger model as follows from
close similarity of these two models responses to similar stimuli.
Slice preparations are common in electrophysiological studies of neurons and identification
of their processes as axon or dendrites in the ongoing experiment is not trivial.
Petersen et al. describe a new method allowing reliable identification of axon initial
segment (IS) and dendrites by timing of averaged somatic spike and local field potential
(LFP) recorded near a targeted neurite. Informative is the timing of the negative
LFP event relative to the spike threshold calculated as the first positive peak on
the third derivative of the LFP: the event starting before or after reaching the somatic
spike threshold indicated location of the LFP electrode near axon IS or dendrite origin,
respectively.
Biophysical properties of synaptic receptor channels are important for determining
of both efficacy of synaptic transmission and activation of dendritic voltage-gated
channels underlying active properties of dendrites. Stepanyuk et al. describe a new
method using a maximum likelihood approach to non-stationary fluctuation analysis
that allows to estimate a number of synaptic transmission parameters from a small
set of postsynaptic current recordings. The method is illustrated on examples of processing
of simulated macroscopic synaptic currents, from which the pre-defined parameters
of synaptic receptor channels were accurately retrieved.
Singh and Zald describe a new form of dendrite-to-soma transfer function employing
separation of slow and fast components of the dendritic electrical events. On an example
of analysis of postsynaptic signal transfer along dendrites possessing non-linear
NMDA-type conductance, the authors show that their linear “hook” function, being a
computational cost-efficient alternative to sigmoid transfer functions, correctly
reproduces saturation and linear behaviors for large and small inputs, respectively.
Fine temporal structure of firing patterns
Mrówczyński et al. in their mini-review discuss occurrence and functional significance
of the doublets of the APs frequently observed at the onset of contractions of mammalian
motor units during recruitment to strong or fast movements. The authors draw attention
to the duration of the AHP, which follows the APs, results from activation of corresponding
potassium conductance and significantly influences firing rate in both slow and fast
motoneurons.
Mlinar et al. examined spiking activity in a large number of genetically identified
serotonergic neurons of the dorsal raphe nucleus (DRN) in slices. They found wide
homogeneous distribution of firing rates suggesting that, in terms of intrinsic firing
properties, the DRN serotonergic neurons represent a single cellular population. The
majority of neurons exhibited regular, pacemaker-like activity with the spiking regularity
proportional to the firing rate. In a small subset of neurons, the firing rate exhibited
low frequency oscillations. The observed transitions between regular and oscillatory
firing suggested that the oscillatory firing mode is an alternative to regular firing
in serotonergic neurons.
Cho et al. explored fine temporal structure of firing APs evoked in nociceptive cutaneous
C-fibers by application of noxious chemical stimuli and related the firing patterns
with pain behavior. They extracted groups of three consecutive spikes (spikelets)
and analyzed their duration and within-group inter-spike intervals. The analysis revealed
substance-specific patterns: continuous firing for KCl, single or multiple bursts
for capsaicin, and repeated short bursts (chattering) for GABA. The authors suggested
that information about the agonist chemicals may be encoded by C-afferents in specific
temporal patterns, which, via different temporal summation of postsynaptic responses,
may influence the pain sensation.
Author contributions
The author confirms being the sole contributor of this work and approved it for publication.
Conflict of interest statement
The author declares that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.