Impact of persistent cortical activity (up States) on intracortical and thalamocortical synaptic inputs

Abstract

The neocortex generates short epochs of persistent activity called up states, which are associated with changes in cellular and network excitability. Using somatosensory thalamocortical slices, we studied the impact of persistent cortical activity during spontaneous up states on intrinsic cellular excitability (input resistance) and on excitatory synaptic inputs of cortical cells. At the intrinsic excitability level, we found that the expected decrease in input resistance (high conductance) resulting from synaptic barrages during up states is counteracted by an increase in input resistance due to depolarization per se. The result is a variable but on average relatively small reduction in input resistance during up states. At the synaptic level, up states enhanced a late synaptic component of short-latency thalamocortical field potential responses but suppressed intracortical field potential responses. The thalamocortical enhancement did not reflect an increase in synaptic strength, as determined by measuring the evoked postsynaptic current, but instead an increase in evoked action potential (spike) probability due to depolarization during up states. In contrast, the intracortical suppression was associated with a reduction in synaptic strength, apparently driven by increased presynaptic intracortical activity during up states. In addition, intracortical suppression also reflected a reduction in evoked spike latency caused by depolarization and the abolishment of longer-latency spikes caused by stronger inhibitory drive during up states. In conclusion, depolarization during up states increases the success of excitatory synaptic inputs to reach firing. However, activity-dependent synaptic depression caused by increased presynaptic firing during up states and the enhancement of evoked inhibitory drive caused by depolarization suppress excitatory intracortical synaptic inputs.

FIG. 1.

Effect of up states on input resistance. A: typical intracellular and field potential (FP) recording and classification of spontaneous activity as up and down states based solely on FP network activity. Note, however, that to classify an event as up or down, both the V_m of the cell and the FP are considered (see methods for details). B: examples of 50-ms current pulses (−0.2 nA) delivered every 300 ms to the cell to measure input resistance during spontaneous activity. C: averaged traces from the cell in B corresponding to pulses delivered during the down or up state classified based on FP alone. D: input resistance values from 1 cell obtained during minutes of recordings plotted against the membrane potential of the cell before each current pulse. Each value is color coded according to the state of the network as up (red) or down (black) defined based on FP recordings. Moreover, these measurements were made when the cell was held at rest (no current injected; middle) and when the cell was either depolarized (right) or hyperpolarized (left) with current injection. E: same data as in D separated according to state. Left: plot of the down state values shown in the 3 panels in D (black filled circles) and color coded according to whether the cell was at rest (gray), depolarized (green), or hyperpolarized (blue) with current injection. Right: plot of Up state values shown in the 3 panels in D (red filled circles).

FIG. 2.

Population data showing the effect of up states on input resistance. A: up states significantly suppress the mean but increase the coefficient of variation of input resistance (R_in) per cell. Top: data for each cell; bottom: averages (means ± SE; * P < 0.01). B: effect of depolarization and hyperpolarization during the down and up states on input resistance. Depolarization increases input resistance during the down and up states. (means ± SE; * P < 0.05 vs. down state at rest).

FIG. 3.

Effect of up states on FP responses. A: typical FP traces corresponding to average thalamocortical (TC) and intracortical (IC) responses evoked during down and up states. The baselines of the traces during both states are superimposed for comparison. B: population data showing the effect of up states on the peak amplitude of short-latency responses measured between 2 and 10 ms (TC) and 3 and 10 (IC) ms poststimulus. (means ± SE; *P < 0.01).

FIG. 4.

Effect of up states on PSPs. A: overlaid individual traces of short-latency thalamo- and intracortical evoked responses during down and up states. Note that up states enhanced firing probability of thalamocortical responses and shifted the spike onset of intracortical responses. B: peristimulus time histograms (PSTH) of spikes evoked by thalamo- and intracortical responses during down and up states. C: average PSPs obtained by averaging traces after spikes were eliminated using a median filter. Also shown are the simultaneously recorded FP responses. Average traces and PSTHs were computed from 30 stimulus trials per state.

FIG. 5.

Population data showing the effect of up states on evoked spikes. A: PSTHs showing the effect of up states on thalamocortical (n = 8) and intracortical (n = 18) short-latency evoked spikes. B: effect of up states on spike probability measured during a short-latency response time window poststimulus (2–10 ms). Shown is the effect of up states on spontaneous firing (Spont), on evoked responses (Evoked) and on evoked responses in which the spontaneous firing has been subtracted (Evoked-Spont). (means ± SE; *P < 0.01).

FIG. 6.

Effect of depolarization during down states on evoked spikes. Overlaid individual traces of short-latency thalamocortical (A) and intracortical (B) evoked responses during down states and during depolarization produced by current injection equivalent to a spontaneous up state in the recorded cells. Bottom: a PSTH of evoked spikes and FP responses.

FIG. 7.

Effect of up states and depolarization on subthreshold excitatory and inhibitory postsynaptic potentials (EPSPs and IPSPs). A: average intracellular and FP traces evoked during down states (black), up states (red), and depolarization (green) for thalamo- and intracortical responses. The baselines are overlaid for comparison. B: effect of up states and depolarization on the peak amplitude of subthreshold EPSPs measured between 2 and 10 ms poststimulus. The EPSP amplitude is plotted as a percentage of the down state response (means ± SE; *P < 0.01). C: effect of up states and depolarization on the peak amplitude of IPSPs measured between the peak of the EPSPs and 50 ms poststimulus (means ± SE; *P < 0.01).

FIG. 8.

Effect of up states on synaptic currents. A: typical example of the effect of up states on evoked synaptic currents recorded in voltage clamp. Average postsynaptic current (PSC) and FP traces evoked during the down and up states are overlaid for comparison. B: population data showing the peak amplitude of the EPSC measured 2–10 ms poststimulus during down and up states (means ± SE; *P < 0.01).

FIG. 9.

Up states increase paired-pulse ratios of intracortical responses. A, top trace: overlaid FP responses evoked by intracortical stimulation consisting of a pair of pulses with a 100-ms interstimulus interval during down and up states. Bottom: population data of paired-pulse ratios calculated from the 2nd or the 4th stimulus in a 10-Hz train (means ± SE; *P < 0.01). B: example of retrogradely labeled thalamic cells after iontophoretic application of neurobiotin in the cortex of a thalamocortical slice. Four closely spaced injections were done in layer 4 around the area that produced the largest FP responses evoked by electrical stimulation of the thalamus. In all cases, cortical neurobiotin either labeled no cells or only a small cluster of cells in ventrobasal thalamus (see arrow). This example was the largest thalamic labeling observed.