Thalamic inputs to dorsomedial striatum are involved in inhibitory control: evidence from the five-choice serial reaction time task in rats

Abstract

Rationale: Corticostriatal circuits are widely implicated in the top-down control of attention including inhibitory control and behavioural flexibility. However, recent neurophysiological evidence also suggests a role for thalamic inputs to striatum in behaviours related to salient, reward-paired cues.

Objectives: Here, we used designer receptors exclusively activated by designer drugs (DREADDs) to investigate the role of parafascicular (Pf) thalamic inputs to the dorsomedial striatum (DMS) using the five-choice serial reaction time task (5CSRTT) in rats.

Methods: The 5CSRTT requires sustained attention in order to detect spatially and temporally distributed visual cues and provides measures of inhibitory control related to impulsivity (premature responses) and compulsivity (perseverative responses). Rats underwent bilateral Pf injections of the DREADD vector, AAV2-CaMKIIa-HA-hM4D(Gi)-IRES-mCitrine. The DREADD agonist, clozapine N-oxide (CNO; 1 μl bilateral; 3 μM) or vehicle, was injected into DMS 1 h before behavioural testing. Task parameters were manipulated to increase attention load or reduce stimulus predictability respectively.

Results: We found that inhibition of the Pf-DMS projection significantly increased perseverative responses when stimulus predictability was reduced but had no effect on premature responses or response accuracy, even under increased attentional load. Control experiments showed no effects on locomotor activity in an open field.

Conclusions: These results complement previous lesion work in which the DMS and orbitofrontal cortex were similarly implicated in perseverative responses and suggest a specific role for thalamostriatal inputs in inhibitory control.

Keywords: 5-choice serial reaction time task; Dorsomedial striatum; Parafascicular thalamic nucleus; Thalamostriatal pathway.

Fig. 1

Surgical preparation and immunohistochemical verification of anatomical targets. a Sagittal view of the rat brain indicating sites of virus injection (AAV2-CaMKIIa-HA-hM4D(Gi)-IRES-mCitrine) in the Pf and CNO in the DMS. b Left panel shows diagram of coronal view of the intralaminar thalamic nuclei with green eclipses indicating individual virus diffusion areas. Right panel shows confocal image of a thalamic slice indicating midline and intralaminar thalamic nuclei with GFP indicating expression of the DREADD (arrow). Inset shows Pf in higher magnification. c Left panel shows a coronal view of striatum indicating individual cannula tracks. Right panel shows a confocal image of striatum with injection tracks indicated. Inset shows DMS in higher magnification to show presence of GFP indicating DREADD expression in Pf-DMS axonal processes (marked with arrows)

Fig. 2

Inhibiting Pf-DMS projections with CNO injections in dorsomedial striatum produce a specific perseverance deficit when stimulus predictability is degraded by varying ITI duration. No significant effects of CNO are seen in response accuracy (a), percentage omissions (b) or premature responses (c). In contrast, CNO injection increases perseverative errors (d). Response latency (e) or latency to collect reward (f) is not affected. *Significant difference from vehicle, p < .05 (within-subject ANOVA). Error bars indicate SEM. Data is averaged across ITIs and the two repetitions

Fig. 3

Local administration of CNO into dorsomedial striatum produces no deficits in locomotor activity. Locomotion was measured as distance travelled (mean ± SEM) in an open field after vehicle (artificial CSF) or CNO administration recorded in 5-min bins. The inset shows distance travelled (mean ± SEM) averaged for the whole 40-min session