Indirect pathway from caudate tail mediates rejection of bad objects in periphery

Abstract

The essential everyday task of making appropriate choices is a process controlled mainly by the basal ganglia. To this end, subjects need not only to find "good" objects in their environment but also to reject "bad" objects. To reveal this rejection mechanism, we created a sequential saccade choice task for monkeys and studied the role of the indirect pathway from the CDt (tail of the caudate nucleus) mediated by cvGPe (caudal-ventral globus pallidus externus). Neurons in cvGPe were typically inhibited by the appearance of bad objects; however, this inhibition was reduced on trials when the monkeys made undesired saccades to the bad objects. Moreover, disrupting the inhibitory influence of CDt on cvGPe by local injection of bicuculline (GABA_A receptor antagonist) impaired the monkeys' ability to suppress saccades to bad objects. Thus, the indirect pathway mediates the rejection of bad choices, a crucial component of goal-directed behavior.

Fig. 1. Value-coding circuits in the basal ganglia.

(A) Object-reward association learning task. (B) Passive viewing task. (C) Representative cvGPe neuron inhibited by bad objects during passive viewing task (n = 33 trials; t₃₂ = 5.17; ***P < 0.001, paired t test). Its activity, which is shown by raster plots (above) and spike density functions (below), is aligned on object onset and offset. Responses are shown separately for all eight objects (above) and as the averaged responses to good and bad objects (below). (D) Representative cdlSNr neuron excited by bad objects (n = 34 trials; t₃₃ = −8.38; ***P < 0.001, paired t test). (E) Neuronal circuit model for value-based saccades. Value signals for bad objects (blue) are sent through the indirect pathway (CDt-cvGPe-cdlSNr), while value signals for good objects (red) are sent through the direct pathway (CDt-cdlSNr), both within the basal ganglia (gray region). Upward and downward arrows indicate excitation and inhibition, respectively.

Fig. 2. Neuronal activity for rejecting bad object.

(A) Sequential saccade choice task. (B) Learning of saccade choice for each object set, averaged across four sets (32 objects) in each monkey (ZB and SP). Red and blue symbols indicate averaged saccade rate (%) to good and bad objects, respectively, across learning sessions. Error bars indicate SEM. The same task was also tested long after the last learning was completed (retention, >1 month) (ZB: t₃ = −3.87; *P = 0.030, paired t test; SP: t₃ = −19.4; ***P < 0.001, paired t test). (C) Averaged activity of cvGPe neurons (n = 55 neurons) in response to good (red) and bad objects (cyan and blue). The inhibition by bad objects (t₅₄ = 3.77; ***P < 0.001, paired t test) was stronger when no saccade occurred (blue) than when saccades occurred (cyan) (gray period; t₅₄ = −2.94; **P = 0.0047, paired t test). (D) Averaged activity of cdlSNr neurons (n = 52 neurons), shown in the same format. The excitation by bad objects (t₅₁ = −7.12; ***P < 0.001, paired t test) was stronger when no saccade occurred (blue) than when saccade occurred (cyan) (gray period; t₅₁ = 4.65; ***P < 0.001, paired t test). (E) Hypothetical role of cvGPe-cdlSNr pathway to control responses to bad objects. Blue and cyan indicate no saccade and saccade conditions, respectively. Black dashed line indicates a threshold level for suppressing a saccade.

Fig. 3. Blocking of the indirect pathway impairs rejection of bad object during sequential saccade choice task.

(A) Local injection of GABA blocker (bicuculline) in cvGPe, while neuronal activity in cdlSNr was recorded. (B) Magnetic resonance images showing five injection sites (orange) in cvGPe of monkey ZB that were located in three coronal sections (9, 10, and 11 mm posterior to the anterior commissure). (C) Comparison of saccade rates between before and after the bicuculline injection in response to contralateral good objects (red; n = 9 sessions; P = 1.00, Wilcoxon signed-rank test) and bad objects (blue; n = 9 sessions; **P = 0.0039, Wilcoxon signed-rank test). Each bar indicates median of saccade rate to contralateral objects. Each pair of connected dots depicts a single injection session. N.S., not significant. (D) Comparison of one cdlSNr neuron’s activity between before and after the bicuculline injection in response to good objects (red; n = 64 trials; P = 0.99, Mann-Whitney U test) and bad objects (blue; n = 64 trials; ***P < 0.001, Mann-Whitney U test). (E) Schematic model for explaining the neuronal and behavioral effects (orange arrows) of GABA blocker in cvGPe. Blue solid and dotted lines indicate responses to bad objects before and after the bicuculline injection.

Fig. 4. Blocking of the indirect pathway impairs choice of good objects.

(A) Simultaneous saccade choice task. (B) Comparison of bad object choice before versus after the bicuculline injection in cvGPe (n = 9 sessions; *P = 0.027, Wilcoxon signed-rank test). Each bar indicates median of choice rate. Each pair of connected dots depicts a single injection session.