Inhibitory control of up states and their propagation in the cortical network

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Spontaneous high-frequency (10-80 Hz) oscillations during up states in the cerebral cortex in vitro

High-frequency oscillations in cortical networks have been linked to a variety of cognitive and perceptual processes. They have also been recorded in small cortical slices in vitro, indicating that neuronal synchronization at these frequencies is generated in the local cortical circuit. However, in vitro experiments have hitherto necessitated exogenous pharmacological or electrical stimulation to generate robust synchronized activity in the β/γ range. Here, we demonstrate that the isolated cortical microcircuitry generates β and γ oscillations spontaneously in the absence of externally applied neuromodulators or synaptic agonists. We show this in a spontaneously active slice preparation that engages in slow oscillatory activity similar to activity during slow-wave sleep. β and γ synchronization appeared during the up states of the slow oscillation. Simultaneous intracellular and extracellular recordings revealed synchronization between the timing of incoming synaptic events and population activity. This rhythm was mechanistically similar to pharmacologically induced γ rhythms, as it also included sparse, irregular firing of neurons within the population oscillation, predominant involvement of inhibitory neurons, and a decrease of oscillation frequency after barbiturate application. Finally, we show in a computer model how a synaptic loop between excitatory and inhibitory neurons can explain the emergence of both the slow (<1 Hz) and the β-range oscillations in the neocortical network. We therefore conclude that oscillations in the β/γ range that share mechanisms with activity reported in vivo or in pharmacologically activated in vitro preparations can be generated during slow oscillatory activity in the local cortical circuit, even without exogenous pharmacological or electrical stimulation. Copyright © 2008 Society for Neuroscience.This work was supported by the Spanish Ministry of Science and Innovation and the European Regional Development Fund. A.C. was supported by a Ramón y Cajal Research Fellowship of the Spanish Ministry of Science and is currently supported by the Researcher Stabilization Program of the Health Department of the Generalitat de Catalunya.Peer Reviewe

Adaptation in the Visual Cortex: Influence of Membrane Trajectory and Neuronal Firing Pattern on Slow Afterpotentials

<div><p>The input/output relationship in primary visual cortex neurons is influenced by the history of the preceding activity. To understand the impact that membrane potential trajectory and firing pattern has on the activation of slow conductances in cortical neurons we compared the afterpotentials that followed responses to different stimuli evoking similar numbers of action potentials. In particular, we compared afterpotentials following the intracellular injection of either square or sinusoidal currents lasting 20 seconds. Both stimuli were intracellular surrogates of different neuronal responses to prolonged visual stimulation. Recordings from 99 neurons in slices of visual cortex revealed that for stimuli evoking an equivalent number of spikes, sinusoidal current injection activated a slow afterhyperpolarization of significantly larger amplitude (8.5±3.3 mV) and duration (33±17 s) than that evoked by a square pulse (6.4±3.7 mV, 28±17 s; p<0.05). Spike frequency adaptation had a faster time course and was larger during plateau (square pulse) than during intermittent (sinusoidal) depolarizations. Similar results were obtained in 17 neurons intracellularly recorded from the visual cortex <i>in vivo</i>. The differences in the afterpotentials evoked with both protocols were abolished by removing calcium from the extracellular medium or by application of the L-type calcium channel blocker nifedipine, suggesting that the activation of a calcium-dependent current is at the base of this afterpotential difference. These findings suggest that not only the spikes, but the membrane potential values and firing patterns evoked by a particular stimulation protocol determine the responses to any subsequent incoming input in a time window that spans for tens of seconds to even minutes.</p></div

Data for 99 neurons in the visual cortex

<p>Table of parameters measured in intracellular recorded primary visual cortical neurons following different current injection protocols as in Descalzo et al 2014, Plos One.</p

Slow postpotential induced by two different patterns of stimulation in visual cortex neurons <i>in vitro</i>.

<p><b>A</b>. The postpotential evoked by the injection of a depolarizing square pulse of 20 sec of duration is compared against the one induced by injection sinusoidal current for 20 sec (right) in the same neuron recorded <i>in vitro</i>. The intensity (nA) of both stimuli was adjusted to evoke similar number of action potentials (245 spikes with the square pulse and 282 spikes with the sinusoid). In both cases, a slow afterhyperpolarization following the current injection was observed. A larger AHP (11 mV, 41 s duration) followed the injection of sinusoidal current than the square pulse (8 mV, 39 s duration). <b>B</b>. Expanded traces from A. <b>a, b, c, d</b>: Comparison of spike-frequency adaptation generated in response to intracellular injection of square pulse (<b>a, b</b>) and sinusoidal current (<b>c, d</b>). Notice that action potential discharge had adapted strongly at the end of the square pulse. <b>C</b>. Plot of the difference in the number of action potential evoked with both protocols for each of the neurons against the difference in afterpotential amplitude. Black point show the neurons with the difference of AP was ≤50.</p

Comparison of firing adaptation and afterpotential measured <i>in vivo</i> or <i>in vitro</i>.

<p><b>A.</b> AHPs recorded from a visual neuron <i>in vivo</i>: the square pulse evoked a smaller postpotential than sinusoidal current injection (4 mV and 49 s vs 6 mV and 54 s). <b>B</b>. Comparison between <i>in vivo</i> and <i>in vitro</i> conditions. Data are reported as mean ± SE. For sinusoidal current injection the values of adaptation index and postpotential was very similar in both conditions. <i>In vitro</i> conditions we observed a similar adaptation index from the same protocol but the postpotential was larger than <i>in vivo</i> condition.</p

The difference in afterpotentials generated by pulses and sinusoids is calcium dependent.

<p><b>A</b>. Intracellular injection of square pulse results in the generation of an ADP (<b>A</b>) and of sinusoidal current in a slow AHP (<b>B</b>). In low calcium (0.1 mM; B) the ADP disappeared and both protocols evoked similar AHPs (<b>A, B</b>). Left panels show the substraction of the afterpotentials. <b>C–D</b>. In a different neuron, local application of 500µM Nifedipine also abolished the differences in afterpotentials.</p

Slow adaptation during action potential discharge.

<p>The time course and strength of the firing rate adaptation varies with the type of intracellular injection current (square pulse or sinusoidal current). <b>A</b>. Example of the plot of the rate of the decay (fit by a single exponential) during square pulse intracellular injection current. The firing rate has been normalized such that 100% corresponds to the firing rate at the beginning of each stimulus. <b>B</b>. Comparison of the time courses and amplitudes of adaptation during the injection of each stimulus in 10 cortical neurons. Note a larger adaptation evoked by square pulse than sinusoidal injection current. <b>C, D</b>. Distributions of adaptation index values calculated for 99 cortical neurons recorded <i>in vitro</i> for square pulses (40±20%, C) and for sinusoidal current (67±18%, D). Adaptation index is the percentage of spikes during the last 500 ms of the protocol with respect to the number of spikes during the first 500 ms.</p

Rhythmic spontaneous activity in the piriform cortex

Slow spontaneous rhythmic activity is generated and propagates in neocortical slices when bathed in an artificial cerebrospinal fluid with ionic concentrations similar to the ones in vivo. This activity is extraordinarily similar to the activation of the cortex in physiological conditions (e.g., slow-wave sleep), thus representing a unique in vitro model to understand how cortical networks maintain and control ongoing activity. Here we have characterized the activity generated in the olfactory or piriform cortex and endopiriform nucleus (piriform network). Because these structures are prone to generate epileptic discharges, it seems critical to understand how they generate and regulate their physiological rhythmic activity. The piriform network gave rise to rhythmic spontaneous activity consisting of a succession of up and down states at an average frequency of 1.8 Hz, qualitatively similar to the corresponding neocortical activity. This activity originated in the deep layers of the piriform network, which displayed higher excitability and denser connectivity. A remarkable difference with neocortical activity was the speed of horizontal propagation (114 mm/s), one order of magnitude faster in the piriform network. Properties of the piriform cortex subserving fast horizontal propagation may underlie the higher vulnerability of this area to epileptic seizures.Ministerio de Educación y Ciencia (M.V.S.V.); Ministerio de Educación y Ciencia (A.C.); Formación de Personal Investigador fellowship (Ministerio de Educación y Ciencia) (V.F.D.); and CSIC-Bancaja fellowship (R.R.).Peer Reviewe

Inhibitory modulation of cortical up states

The balance between excitation and inhibition is critical in the physiology of the cerebral cortex. To understand the influence of inhibitory control on the emergent activity of the cortical network, inhibition was progressively blocked in a slice preparation that generates spontaneous rhythmic up states at a similar frequency to those occurring in vivo during slow-wave sleep or anesthesia. Progressive removal of inhibition induced a parametric shortening of up state duration and elongation of the down states, the frequency of oscillations decaying. Concurrently, a gradual increase in the network firing rate during up states occurred. The slope of transitions between up and down states was quantified for different levels of inhibition. The slope of upward transitions reflects the recruitment of the local network and was progressively increased when inhibition was decreased, whereas the speed of activity propagation became faster. Removal of inhibition eventually resulted in epileptiform activity. Whereas gradual reduction of inhibition induced linear changes in up/down states and their propagation, epileptiform activity was the result of a nonlinear transformation. A computational network model showed that strong recurrence plus activity-dependent hyperpolarizing currents were sufficient to account for the observed up state modulations and predicted an increase in activity-dependent hyperpolarization following up states when inhibition was decreased, which was confirmed experimentally. Copyright © 2010 The American Physiological Society.This work was supported by a Ministerio de Ciencia e Innovación (MICINN) grant to M. V. Sanchez-Vives and A. Compte and a PhD Fellowship MICINN-FPI to M. Winograd.Peer Reviewe