Cortico-striatal spike-timing dependent plasticity after activation of subcortical pathways

Abstract

Cortico-striatal spike-timing dependent plasticity (STDP) is modulated by dopamine in vitro. The present study investigated STDP in vivo using alternative procedures for modulating dopaminergic inputs. Postsynaptic potentials (PSP) were evoked in intracellularly recorded spiny neurons by electrical stimulation of the contralateral motor cortex. PSPs often consisted of up to three distinct components, likely representing distinct cortico-striatal pathways. After baseline recording, bicuculline (BIC) was ejected into the superior colliculus (SC) to disinhibit visual pathways to the dopamine cells and striatum. Repetitive cortical stimulation (∼60; 0.2 Hz) was then paired with postsynaptic spike discharge induced by an intracellular current pulse, with each pairing followed 250 ms later by a light flash to the contralateral eye (n = 13). Changes in PSPs, measured as the maximal slope normalized to 5-min pre, ranged from potentiation (∼120%) to depression (∼80%). The determining factor was the relative timing between PSP components and spike: PSP components coinciding or closely following the spike tended towards potentiation, whereas PSP components preceding the spike were depressed. Importantly, STDP was only seen in experiments with successful BIC-mediated disinhibition (n = 10). Cortico-striatal high-frequency stimulation (50 pulses at 100 Hz) followed 100 ms later by a light flash did not induce more robust synaptic plasticity (n = 9). However, an elevated post-light spike rate correlated with depression across plasticity protocols (R(2) = 0.55, p = 0.009, n = 11 active neurons). These results confirm that the direction of cortico-striatal plasticity is determined by the timing of pre- and postsynaptic activity and that synaptic modification is dependent on the activation of additional subcortical inputs.

Keywords: HFS; STDP; dopamine; in vivo; intracellular; spiny projection neuron; striatum; superior colliculus.

Figure 1

Properties of SPNs and cortico-striatal PSPs. (A) Membrane potential response to linear current steps. The inset shows the current–voltage relationship; the input resistance was derived from the slope of the regression line. (B) Biocytin-filled SPN. The dendrites are densely studded with spines. (C) Dependence of PSP (mean of 5–63 trials) on membrane potential. All PSPs recorded over 15 min were sorted according to initial membrane potential and then averaged. Note the decreased amplitude when cortical stimulation was applied at depolarized membrane potentials. (D) PSPs consisted of several components. Distribution of latencies to maximum slope shows that latencies scattered around three distinct values representing PSP components as indicated in the mean PSP (inset).

Figure 2

Example traces from all four pairing protocols used. Intracellular recording (top trace), intracellular current injection (middle) and LFP recorded in the SC (bottom) are shown. The start of the light flash is indicated by the red dashed line. Note the negative deflection in the LFP recording indicating the VEP enabled by BIC. (A) HFS + spikes then light. (B) HFS then light + spikes. Note the absence of spikes during the HFS in this recording. (C) Single stimulus then light. In this trial, the SPN elicited a spike following cortical stimulation and rebound activation after the stimulus-induced cortical disfacilitation. (D) Pre-post pairing then light, with a single spike elicited using a short current pulse.

Figure 3

Effects of visual-evoked inputs in combination with cortico-striatal HFS. Panels a, time-resolved membrane potential distribution. Gray-scale indicates the probability for the neuron to be at respective membrane potential (y-axis); black depicts a high probability, white a low probability. Time on the x-axis is given in relation to BIC ejection (dotted line at 0). Maximum amplitude of PSPs are indicated. Panels b, maximal slopes of PSP. Dashed line indicates mean PSP slopes at baseline. Running average of 9 consecutive values is indicated (red trace). PSP traces (top right inset in a) are mean PSPs recorded in the time indicated by the gray and black bars, respectively. (A) Representative example of cortico-striatal HFS with current-evoked spike discharge followed by light. No significant changes were induced. (B) HFS followed by light with current-evoked spike discharge induced depression (p = 0.002; Wilcoxon rank sum test).

Figure 4

Effects of post-light spike rate on cortico-striatal plasticity in experiments involving pre-post pairing. Format for panels a and b is the same as in Figure 3. Panels c, raster plot and peri-stimulus time histogram of spikes during the pairing protocol. Cortical stimulus was applied at 0, the intracellular current pulse at approximately 10 ms, and light at 250 ms (red dashed line). (A) Example recording showing depression (p < 0.001; Wilcoxon rank sum test). Note the high spike rate post light. (B) Example recording showing selective increases in a PSP component (red arrow head; p < 0.05; Wilcoxon rank sum test) without a significant change of the overall PSP slope.

Figure 5

Spike-timing-dependent increases and decreases in cortico-striatal synaptic efficacy. Format for panels a and b is the same as in Figure 3. Panels c, latencies of maximal slope measurements (blue dots) and spike times during the plasticity protocol (red dots). (A) Example recording showing potentiation (p < 0.001; Wilcoxon rank sum test) after pairing PSPs with a postsynaptic spike elicited by somatic current injection. Note spike latencies were relatively early compared to maximal slope latencies. (B) Example recording showing depression (p = 0.038; Wilcoxon rank sum test) after pairing with current-evoked spikes following the maximal PSP slope. Note the relative higher frequency of later latency components after the protocol.

Figure 6

Summary of cortico-striatal plasticity after visual activation of subcortical pathways. In all panels, significant changes from baseline are indicated by filled circles. (A) Effects of HFS on normalized PSP slope. Current-evoked spike discharge during visual inputs (red, n = 4) resulted in depression (asterisks; p < 0.05, t-test) when compared to current-evoked spike discharge during HFS (blue, n = 5). (B) Panel a, pre-post pairing resulted in variable outcomes across experiments (gray traces). One SPN (purple; same as Figure 4A) was excluded because of a high post-light spike rate. Panels b–d, analysis of individual PSP components. Means (black) of binned data (3-ms bins; number of included points in brackets) indicate that changes did not depend on latency (B, panel b) but on relative timing to evoked spike (B, panel d). Although the true relationship between spike-timing and synaptic change was complex (approximated by a 5th order polynomial fit in B, panel c), there was a significant linear correlation for spike-timing values between −4.5 and 4.5 ms (p < 0.05, n = 16; B, panel d). (C) PSP components remained largely unchanged in experiments without BIC-mediated disinhihibition of the SC (n = 3). (D) Significant effect of post-light spike rate on normalized PSP slope 10–20 min post across experimental groups (p = 0.009). Color-code is the same as in (A–C); green represents pairing of visual and single cortical stimuli without a postsynaptic current step.