Striatal dopamine modulates basal ganglia output and regulates social context-dependent behavioral variability through D1 receptors

Abstract

Cortico-basal ganglia (BG) circuits are thought to promote the acquisition of motor skills through reinforcement learning. In songbirds, a specialized portion of the BG is responsible for song learning and plasticity. This circuit generates song variability that underlies vocal experimentation in young birds and modulates song variability depending on the social context in adult birds. When male birds sing in the presence of a female, a social context associated with decreased BG-induced song variability, the extracellular dopamine (DA) level is increased in the avian BG nucleus Area X. These results suggest that DA could trigger song variability changes through its action in Area X. Consistent with this hypothesis, we report that DA delivered to Area X weakens the output signal of the avian cortico-BG circuit. Acting through D(1) receptors, DA reduced responses in Area X to song playback and to electrical stimulation of its afferent cortical nucleus HVC (used as a proper name). Specifically, DA reduced the response to direct excitatory input and decreased firing variability in Area X pallidal neurons, which provide the output to the thalamus. As a consequence, DA delivery in Area X also decreased responses to song playback in the cortical output nucleus of the BG loop, the lateral magnocellular nucleus of the anterior nidopallium. Further, interfering with D(1) receptor transmission in Area X abolished social context-related changes in song variability. In conclusion, we propose that DA acts on D(1) receptors in Area X to modulate the BG output signal and trigger changes in song variability.

Figure 1.

DA suppresses responses to playback of the BOS in Area X output neurons. A, Schematic parasagittal representation of the song system. In the present study, neuronal activity was recorded in the AFP nuclei Area X and LMAN. Dorsal is up, anterior is to the right. B, Example of a neuron with increased spontaneous activity and decreased song response after DA injection. Top, Oscillogram of song playback. Middle, PSTH around BOS presentation. Bottom, Corresponding raster plot. Black lines, Baseline; red lines, DA; blue lines, washout. C, Example of a neuron in which spontaneous activity was unaffected by DA injection but which also showed decreased song response after DA injection (red trace). PSTH around BOS presentation, with the same conventions as in B. D, Injection of DA (n = 7) or the D₁-type receptor agonist SKF38393 (n = 3) in Area X reduces the response to BOS playback in all neurons. Left, BOS response strength; right, d′. Solid lines indicate DA injections; dotted lines SKF38393 injections. In the left panel, red lines indicate significant changes in BOS response strength. Filled circles indicate BOS response strength and d′ values for the neuron shown in A, and empty circles indicate values for the neuron shown in B. E, Vehicle injection did not change BOS response strength (left) or selectivity index (d′, right).

Figure 2.

Location of neurons recorded in Area X and LMAN in vivo, reconstructed from stereotaxic coordinates and post hoc histological analysis. Each panel represents the medial-lateral coordinate and the depth of all recording locations in one structure. Anteroposterior coordinates of the recording locations are displayed by color. Each recorded neuron is represented with a symbol that denotes the stimulus presented during the recording, the drug treatment applied, and/or the neuron type. A, Location of neurons recorded in Area X. Anteroposterior coordinates: blue, ≤3.5; magenta, 3.5–3.7; red, ≥3.7. Symbols: circles, DA treatment; triangles, SKF38393 treatment; empty symbols, electrical stimulation of HVC; filled symbols, song stimulation and electrical stimulation of HVC. Symbols with a cross denote putative interneurons (<25 sp/s), while others represent pallidal neurons. B, Location of neurons recorded in LMAN. Anteroposterior coordinates: blue, ≤3.9; red, ≥3.9. Empty symbols, Electrical stimulation of HVC; filled symbols, song stimulation.

Figure 3.

DA increases intrinsic activity of Area X output neurons through D₁ receptors. A, Effect of DA injections on the spontaneous activity of pallidal neurons in vivo. B, Effect of DA injections on the spontaneous activity of Area X putative interneurons in vivo. In A and B, red lines denote significant changes in spontaneous activity. C, Effect of D₁-type receptor agonist SKF38393 injection on the spontaneous activity of pallidal neurons in vivo. D, Effect of DA on the spontaneous activity of a putative pallidal neuron in vitro. Left, Time course of the spontaneous activity of the neuron. Horizontal bar indicates when DA (50 μm) was applied. Right, Overlaid spike shapes (black) and average spike shape (red). E, Effect of SKF on the spontaneous activity of a pallidal neuron in vitro. Left, Time course of the spontaneous activity of the neuron. Horizontal bar indicates when the D₁ receptor agonist SKF38393 (10 μm) was applied. Right, Overlaid spike shapes (black) and average spike shape (red). In the right panels in D and E, the horizontal scale bar represents 0.2 ms, and the vertical scale bar 100 μV. F, Effect of dopaminergic drugs on the spontaneous activity of pallidal neurons in vitro. Black, DA only; red, SKF38393; blue, quinpirole; yellow, DA and SCH23390. The changes in intrinsic firing induced by DA in pallidal neurons are mimicked by the D₁ agonist SKF38393 and abolished by the D₁ antagonist SCH23390.

Figure 4.

DA decreases the response of Area X neurons to HVC stimulation. A, B, Changes in the response to HVC stimulation following DA injection in the two Area X neurons displayed in Figure 1, B (A) and C (B). Each panel depicts the PSTH at baseline (black), following DA injection (red), and after washout (blue). C, Average response to HVC stimulation over all Area X pallidal cells at baseline (black), following DA injection in Area X (red) and after washout (blue). D–H, Quantification of responses to HVC stimulation before and after DA injection in Area X in all pallidal neurons. D, Stimulation response strength. E, Excitation relative area (see Materials and Methods). F, Duration of the excitatory component of the response. G, Inhibition relative area (see Materials and Methods). H, Duration of the inhibitory component of the response. Filled circles in D–H indicate values corresponding to the neuron shown in A (same neuron as in Fig. 1A). Empty circles in D–H indicate values for the neuron shown in B (same neuron as in Fig. 1B). Overall, excitatory responses to HVC stimulation are suppressed by DA application, sometimes revealing an inhibitory component in the response. I, Change of the response to HVC stimulation following DA injection in Area X in a putative interneuron. Same conventions as in A and B. J, Quantification of responses to HVC stimulation before and after DA injection in Area X in all Area X putative interneurons. Gray discs in J indicate values for the neuron shown in I. The stimulation response strength is diminished under DA in putative interneurons, although the decrease in response is less pronounced than in pallidal neurons.

Figure 5.

DA reduces the response of pallidal neurons to their excitatory inputs from HVC. A, Example response of a pallidal cell to HVC fiber stimulation in vitro before (black), during CNQX infusion (red), and after washout (blue). B, Strength of the response to HVC fiber stimulation in all pallidal neurons before, during, and after CNQX perfusion. The response to stimulation was abolished by CNQX in all four cells. C, Strength of the response to HVC fiber stimulation in all pallidal neurons before, during, and after mecamylamine and atropine infusion. Cholinergic blockers did not modify the response of pallidal neurons to stimulation. D, Example of a pallidal response to HVC fiber stimulation before (black), during (red), and after (blue) DA infusion. E, Over all pallidal neurons, DA decreased the strength of the response to HVC stimulation. F, Example of a pallidal response to HVC stimulation under the GABA_A receptor blocker picrotoxin before (black), during (red), and after (blue) DA infusion. G, Over all pallidal neurons, DA reduces the strength of the response to HVC fiber stimulation in the presence of picrotoxin.

Figure 6.

DA reduces the response of pallidal neurons to HVC stimulation by acting through D₁ receptors. A, Example of a pallidal response to HVC fiber stimulation before (black), during (red), and after (blue) infusion of DA and SCH23390. SCH23390 was applied first for 2–5 min, followed by 5 min of SCH23390+DA. B, Example response of a pallidal neuron to HVC stimulation before (black), during (red), and after (blue) SKF38393 infusion. C, Strength of the response to HVC stimulation in all pallidal neurons before, during, and after DA and SCH23390 infusion. Over all putative cells, DA did not change the response to stimulation when it was preceded by the infusion of the D₁-type receptor blocker SCH23390. D, Strength of the response to HVC stimulation in all pallidal neurons before, during, and after SKF38393 infusion. Over all pallidal cells, the D₁-type receptor agonist SKF38393 tended to decrease the response of pallidal neurons to stimulation. E, Strength of the response to HVC stimulation in all pallidal neurons before, during, and after quinpirole infusion. The D₂ receptor agonist quinpirole did not change the response of pallidal neurons to HVC stimulation.

Figure 7.

DA reduces the variability in the spontaneous and evoked firing of pallidal neurons. A, B, ISI distributions (top, in spontaneous activity; middle, in response to BOS playback; bottom, in response to HVC stimulation) for the two neurons shown in Figure 1, B (A) and C (B), at baseline (black), following DA injection in Area X (red), and after washout (blue). C, Average spontaneous ISI distribution over all pallidal neurons at baseline (black) and following DA injection in Area X (red). D, DA injection in Area X decreased the CV of the spontaneous ISI distribution in all pallidal neurons. E, Average ISI distribution in response to BOS playback over all pallidal neurons at baseline (black) and following DA injection in Area X (red). F, DA injection in Area X decreased the CV of the ISI distribution in response to BOS playback in all but one pallidal neuron. G, Average ISI distribution in response to HVC stimulation over all pallidal neurons at baseline (black) and following DA injection in Area X (red). H, Over all pallidal neurons, DA injection in Area X decreased the CV of the ISI distribution in response to HVC stimulation. Filled circles in D, F, and H indicate CV values for the neuron shown in A (same neuron as in 1A and 3A). Empty circles in D, F, and H indicate CV values for the neuron shown in B (same neuron as in 1B and 3B).

Figure 8.

DA reduces response to BOS playback in LMAN neurons. A, Example response to BOS playback in a LMAN neuron before (black), during (red), and after (blue) two consecutive injections of DA in Area X. Left, PSTH (top) and raster (bottom). Black lines, Baseline: red lines, DA; blue lines, washout. Bottom right inset, BOS response strength as a function of time, aligned to the raster plot. B, BOS response strength over all recorded LMAN neurons before and after DA injection in Area X. Red lines denote significant decreases in the BOS response strength. Over all LMAN neurons, DA application in Area X strongly decreased the song BOS response strength. C, Selectivity in the response to song in LMAN was also strongly decreased by DA injection in Area X. Filled circles in B and C indicate values corresponding to the neuron shown in A. D, E, Saline injections did not change the BOS response strength (D) or selectivity index [E, d′, (dprime)].

Figure 9.

DA injection into Area X decreases the response to HVC stimulation in most LMAN neurons. A, Example of a neuron with decreased response to HVC stimulation following DA injection in Area X. Black, Baseline; red, DA; blue, washout. B, C, Stimulation response strength (B) and response peak (C) show that all but one LMAN neuron had a decreased response to HVC stimulation following DA injection in Area X. In B, red lines denote a significant change from baseline. D, The duration of LMAN responses was significantly decreased after DA injection in Area X. Black dots in B–D indicate values corresponding to the neuron shown in A.

Figure 10.

Infusion of the D₁ receptor antagonist SCH23390 in Area X abolishes differences in song variability due to social context. A, Example of a song spectrogram of bird 1. This bird displayed five subsyllabic elements with a clear harmonic structure. The dashed ellipse indicates the subsyllabic element considered in C. B, cresyl violet staining of a 50 μm parasagittal brain section showing the track of the cannula used to infuse drugs in the behaving bird. Solid gray lines denote the position of the cannula. Area X contours are outlined with white arrows, while LMAN is outlined with black arrows. The dashed white line outlines the pallial–subpallial lamina, which separates the BG from pallial structures. C, Distribution of the frequency of the lowest harmonic of the subsyllabic element highlighted in A in four different conditions: in the absence of female before surgery (dotted dashed black line), in the presence of a female before surgery (solid black line), in the presence of a female during SCH23390 infusion in Area X (solid red line), and in the presence of a female during saline infusion in Area X (blue line, following the SCH23390 infusion). D, Context-dependent changes in song variability in three different conditions. In each paired graph, the left column refers to singing in the absence of female, while the right column refers to singing in the presence of a female. Left, Before surgery; middle, during the infusion of SCH23390; right, during saline infusion. Saline infusion followed SCH infusion in three of four birds. The two social contexts are associated with different song variability before surgery and during saline infusion, while SCH infusion abolishes differences in variability related to social context. E, Relative song variability in the three behavioral conditions for the 12 subsyllabic elements displayed context-related changes in variability. The relative song variability is calculated as the SD of the lower harmonic frequency when the bird was singing to a female in each condition divided by the SD of the lowest harmonic frequency when singing alone before surgery. Left, Before surgery; middle, during the infusion of SCH23390; right, during saline infusion. In D and E, the red discs indicate values corresponding to the subsyllabic element shown in A and C.