Selective effects of dopamine depletion and L-DOPA therapy on learning-related firing dynamics of striatal neurons

Abstract

Despite evidence that dopamine neurotransmission in the striatum is critical for learning as well as for movement control, little is yet known about how the learning-related dynamics of striatal activity are affected by dopamine depletion, a condition faced in Parkinson's disease. We made localized intrastriatal 6-hydroxydopamine lesions in rats and recorded within the dopamine-depleted sensorimotor striatal zone and its contralateral correspondent as the animals learned a conditional maze task. Rather than producing global, nonspecific elevations in firing rate across the task, the dopamine depletion altered striatal projection neuron activity and fast-spiking interneuron activity selectively, with sharply task-specific and cell type-specific effects, and often, with learning-stage selective effects as well. Striatal projection neurons with strong responses during the maze runs had especially elevated responsiveness during the maze runs. Projection neurons that, instead, fired most strongly before maze running showed elevated pre-start firing rates, but not during maze running, as learning progressed. The intrastriatal dopamine depletion severely affected the learning-related patterning of fast-spiking interneuron ensembles, especially during maze running and after extended training. Remarkably, L-DOPA treatment almost entirely reversed the depletion-induced elevations in pre-run firing of the projection neurons, and elevated their responses around start and end of maze runs. By contrast, L-DOPA failed to normalize fast-spiking interneuron activity. Thus the effects of striatal dopamine depletion and restoration on striatal activity are highly dependent not only on cell type, as previously shown, but also on the behavioral activity called for and the state of behavioral learning achieved.

Figure 1.

Experimental design and behavioral results. A, The T-maze task. B, Recording sites in the dopamine-depleted region (light gray) and in contralateral intact region in the dorsolateral striatum. Colors indicate different rats. C, Experimental timeline. D–F, Percentage of correct response (D), response reaction time (gate opening to start, E), and running times (start to goal reaching, F) averaged across all rats. Training stages are as follows: 1 = first day of training; 2 = second day of training; 3 and 4 = first session with percent-correct ≥ 60 and 70%, respectively; 5–10 = 2 consecutive sessions with performance above a learning criterion (percent-correct ≥ 72.5%) combined for each stage. Error bars indicate SEM.

Figure 2.

Dopamine depletion measured with fast-scan cyclic voltammetry. A, Examples of dopamine release measured in the dorsolateral striatum on the control (left) and 6-OHDA lesion (right) sides. Top, Redox currents as a function of potential during consecutive voltammetric scans around the time of MFB electrical stimulation (time 0). Note the increase in current around the peak dopamine oxidation potential (0.6 V; white dashed line). Bottom, Currents generated by dopamine oxidation showing release on the control side (left) and its absence on the 6-OHDA lesion side (right). Insets show background subtracted cyclic voltammograms after MFB stimulation. B, Concentration of dopamine following MFB stimulation measured by probes placed in the control (n = 7) and dopamine-depleted (n = 12) striatum of four rats. C, Phasic dopamine release at a representative site in the dopamine-depleted region in the dorsolateral striatum (left) and a site ventral to the depleted zone in the same hemisphere (right) in response to MFB stimulation, shown as in A.

Figure 3.

Classification of recorded units. A, Proportions of task-activated MSNs (left), FSIs (middle), and TANs (right) during acquisition and overtraining, Learning stages are as in Figure 1D. B–E, Peri-event histograms and raster plots illustrating activity of putatively identified single units categorized as task-activated MSN (B), tonically suppressed MSN (C), task-activated FSI (D), and task-activated/suppressed TAN (E). For each unit, an autocorrelogram and interspike interval plot are shown at left. Peri-event histograms and raster plots for three task events at right illustrate task-related responses of these units. Red and blue horizontal lines in histograms represent the mean firing rates and ±2 SDs calculated for their pre-trial baseline activity, respectively. Red dots in raster plots indicate other task events.

Figure 4.

Selective disruption of activity of striatal projection neurons by dopamine depletion. A, C, Ensemble activity of putative task-activated (A) and task-suppressed (C) MSNs recorded in the control (left) and dopamine-depleted (right) dorsolateral striatum. Firing rate of each unit during ±200 ms around each of seven task events (as labeled on x-axis) were normalized to its minimum-to-maximum scale (0–1) and activity of individual units were averaged for each training stage (stages 1–10 on y-axis). Color scale is shown at right. Numbers of units for the stage are indicated to the right of each row. B, D, Mean raw firing rates of task-activated (B) and task-suppressed (D) MSNs on the control (blue) and dopamine-depleted (red) sides during acquisition (stages 1–4), early overtraining (5–7), and late overtraining (8–10), plotted across task time. Shading represents SEM. Task-suppressed units were further classified to tonically suppressed (TS) and dynamically suppressed (DS) subpopulations. Arrow indicates increased pre-run firing rate in the dopamine-depleted side for TS units. Task events are as follows: baseline (BL; 1.9–1.4 s before warning click); warning click (WC), gate opening (GO), start (ST), tone onset (TO), turn start (TS), turn end (TE), and goal-reaching (GR). E, Average pre-task (from 2 s before warning click to gate opening) and in-task (from start to goal reaching) firing rates of task-activated (left); tonically suppressed (middle); and dynamically suppressed (right) MSNs during acquisition, early overtraining, and late overtraining phases. Asterisks indicate significant differences in overall firing rates (black) and in period-specific firing rates (orange) between two sides (*p < 0.05; **p < 0.01; ***p < 0.0001). Error bars indicate SEM.

Figure 5.

Learning- and time-dependent effects of dopamine depletion on tonically suppressed MSNs. A, Raw firing rates of tonically suppressed MSNs recorded in the control (blue) and dopamine-depleted (red) striatum of rats with short (top) and long (bottom) delays between 6-OHDA lesions and the onset of T-maze training. Plots are made as in Figure 4B for the entire task period after warning click. B, Activity of tonically suppressed MSNs, plotted as in A for the pre- and in-task periods, including pre-trial baseline period. Orange line indicates warning click signaling task start. BL, baseline; WC, warning click; GO, gate opening; ST, start; TO, tone onset; TS, turn start; TE, turn end; and GR, goal-reaching.

Figure 6.

Effects of dopamine depletion on activity of striatal interneurons. A, C, Population activity of putative task-activated FSIs (A) and all TANs (C) recorded in the control (left) and dopamine-depleted (right) striatum, plotted as in Figure 4. For TANs, activity of the entire recorded population is shown because of small numbers of task-activated and task-suppressed units per training stage. B, D, Mean raw firing rates of task-activated FSIs (B) and all recorded TANs (D) on the control (blue) and dopamine-depleted side (red). E, Pre- and in-task activity of task-activated FSIs (left) and all recorded TANs (right) during acquisition and overtraining. Asterisks indicate significant differences as in Figure 4E. BL, baseline; WC, warning click; GO, gate opening; ST, start; TO, tone onset; TS, turn start; TE, turn end; and GR, goal-reaching.

Figure 7.

L-DOPA administration modifies activity of striatal projection neurons. A, Response accuracy (left), reaction times (middle), and running times (right) during last five overtraining (OT; light blue), saline (S; gray), and first five L-DOPA (light brown) sessions. Error bars indicate SEM. B, E, Ensemble activity of task-activated (B) and tonically task-suppressed (E) MSNs during the last five overtraining, saline, and first five L-DOPA sessions. Conventions are as in Figure 4. C, F, Raw firing rates of task-activated (C) and task-suppressed (F) MSNs in the control (blue) and dopamine-depleted (red) striatum, averaged across last five overtraining sessions (left) and first five L-DOPA sessions (right). L-DOPA treatment reduced the enhanced pre-task activity of tonically suppressed MSNs (TS; arrow) but did not affect the dynamically suppressed (DS) MSN population. D, G, Pre-task and in-task firing rates of task-activated (D), tonically suppressed (G, top), and dynamically suppressed (G, bottom) MSNs, averaged over last five overtraining sessions and first five L-DOPA sessions. Asterisks indicate significant differences as in Figure 4E. BL, baseline; WC, warning click; GO, gate opening; ST, start; TO, tone onset; TS, turn start; TE, turn end; and GR, goal-reaching.

Figure 8.

Differential effects of L-DOPA treatment on the activity of striatal interneuron populations. A, C, Raw firing rates of task-activated FSIs (A) and all recorded TANs (C) averaged over the last five overtraining sessions (left) and first five L-DOPA sessions (right). B, D, Mean pre- and in-task firing rates of task-activated FSI ensembles (B) and all recorded TAN ensembles (D). Asterisks indicate significant differences as in Figure 4E. BL, baseline; WC, warning click; GO, gate opening; ST, start; TO, tone onset; TS, turn start; TE, turn end; and GR, goal-reaching.