M-current modulation of cortical slow oscillations: Network dynamics and computational modeling

Abstract

The slow oscillation is a synchronized network activity expressed by the cortical network in slow wave sleep and under anesthesia. Waking up requires a transition from this synchronized brain state to a desynchronized one. Cholinergic innervation is critical for the transition from slow-wave-sleep to wakefulness, and muscarinic action is largely exerted through the muscarinic-sensitive potassium current (M-current) block. We investigated the dynamical impact of blocking the M-current on slow oscillations, both in cortical slices and in a cortical network computational model. Blocking M-current resulted in an elongation of Up states (by four times) and in a significant firing rate increase, reflecting an increased network excitability, albeit no epileptiform discharges occurred. These effects were replicated in a biophysical cortical model, where a parametric reduction of the M-current resulted in a progressive elongation of Up states and firing rate. All neurons, and not only those modeled with M-current, increased their firing rates due to network recurrency. Further increases in excitability induced even longer Up states, approaching the microarousals described in the transition towards wakefulness. Our results bridge an ionic current with network modulation, providing a mechanistic insight into network dynamics of awakening.

H-current modulation of cortical Up and Down states

“…In other words, Down states have an activity-dependent component which can be mediated to a large extent by hyperpolarizing currents, probably potassium currents. This dynamical link has been demonstrated both experimentally 24,26,28 and computationally 8,50 . This relationship is also observed here, not only in the scatter plot but also in the raster plots (Fig.…”

“…To investigate the underlying mechanisms through which the h-current modulates cortical slow oscillations, we implemented a biophysically detailed computational model of the cortical network 8,28 . The model comprises pyramidal ( n =1024) and inhibitory ( n =256) conductance-based neurons evenly spaced along a line, connected with a probability that decays with the distance between neurons (Fig.…”

“…The model consists of 1024 pyramidal neurons and 256 inhibitory neurons interconnected through biologically plausible synaptic dynamics. The neurons are equidistantly distributed on a line and sparsely connected to each other, as in the control network described in 8,28 . Each neuron makes a 20±5 (SD) connection to its postsynaptic targets (autapses are not allowed).…”

“…The maximal conductances are: g L = 0.1025 ± 0.0025 mS/ cm 2 , g ka = 35 mS/cm 2 , and g K = 9 mS/cm 2 . All the details of the implementation of these currents are described in 8 except for I ℎ and I L , which are described in 28 . Briefly, the M-current was implemented as described in 72 : I L = g L m ( V − V K ).…”

“…Although considerable progress has been made towards a detailed understanding of the mechanisms controlling slow oscillations, most of these studies focus on synaptic properties and network connectivity [19][20][21][22][23][24][25][26] . Nonetheless, ion channels also play a fundamental role in shaping brain dynamics, often being targeted by neuromodulators 1,12,27,28 . One important target of neuromodulators is the hyperpolarization-activated cation current (h-current or Ih) (for a review, see 29,30 ).…”