The parafascicular thalamic nucleus concomitantly influences behavioral flexibility and dorsomedial striatal acetylcholine output in rats

Abstract

Recent evidence suggests that a circuit involving the centromedian-parafascicular (Pf) thalamus and basal ganglia is critical for a shift away from biased actions. In particular, excitatory input from the Pf onto striatal cholinergic neurons may facilitate behavioral flexibility. Accumulating evidence indicates that an endogenous increase in dorsomedial striatal acetylcholine (ACh) output enhances behavioral flexibility. The present experiments investigated whether the rat (Rattus norvegicus) Pf supports flexibility during reversal learning, in part, by modifying dorsomedial striatal ACh output. This was determined first by examining the effects of Pf inactivation, through infusion of the GABA agonists baclofen and muscimol, on place acquisition and reversal learning. Additional experiments examined Pf inactivation on dorsomedial striatal ACh output during reversal learning and a resting condition. Behavioral testing was performed in a cross-maze. In vivo microdialysis combined with HPLC/electrochemical detection was used to sample ACh from the dorsomedial striatum. Pf inactivation selectively impaired reversal learning in a dose-dependent manner. A subsequent study showed that an increase in dorsomedial striatal ACh efflux (∼30% above basal levels) during reversal learning was blocked by Pf inactivation, which concomitantly impaired reversal learning. In the resting condition, a dose of baclofen and muscimol that blocked a behaviorally induced increase in dorsomedial striatal ACh output did not reduce basal ACh efflux. Together, the present findings indicate that the Pf is an intralaminar thalamic nucleus critical for behavioral flexibility, in part, by directly affecting striatal ACh output under conditions that require a shift in choice patterns.

Figure 1.

Representative cannula placements in the parafascicular thalamic nucleus and dorsomedial striatum. A, Photomicrograph of a typical cannula placement into the parafascicular thalamic nucleus. B, Photomicrograph of a typical microdialysis cannula placement into the dorsomedial striatum.

Figure 2.

Behavioral performance on the place discrimination in experiment 1. Each rat received bilateral infusions of saline (Sal) or one of three different doses of Bac–Mus into the Pf 5 min before each test session. The treatments on the x-axis represent the treatment received before acquisition (top) and before reversal learning (bottom). A, Mean ± SEM trials to criterion on place acquisition. Infusion of Bac–Mus had no effect on acquisition. B, Mean ± SEM trials to criterion on place reversal learning. The middle and high dose of Bac–Mus significantly impaired reversal learning. *p < 0.05 versus saline/saline, Bac–Mus/saline, and saline/Bac–Mus low dose. **p < 0.01 versus saline/saline, Bac–Mus/saline, and saline/ Bac–Mus low dose. C, Mean ± SEM perseverative errors committed during reversal learning. Bac–Mus treatment did not affect the number of perseverative errors. D, Mean ± SEM regressive errors committed during reversal learning. The middle and high dose of Bac–Mus significantly increased regressive errors. ⁺p < 0.05 versus saline/saline, Bac–Mus/saline, and saline/Bac–Mus low dose. ⁺⁺p < 0.01 versus saline/saline, Bac–Mus/saline, saline/Bac–Mus low dose, and saline/Bac–Mus high dose.

Figure 3.

Dorsomedial striatal ACh output and behavioral performance during place reversal learning. Each rat received bilateral infusions of saline (Sal) or one of two different doses of Bac–Mus into the Pf 6 min before reversal learning. Rats were tested for 30 min across five 6-min test blocks (T1–T5). A, ACh output in the dorsomedial striatum during reversal learning. Dorsomedial striatal ACh output significantly increased above basal levels in the saline and the Bac–Mus low-dose groups. The middle dose of Bac–Mus infused into the Pf significantly attenuated the performance-induced increase in dorsomedial striatal ACh efflux throughout reversal learning. ⁺p < 0.05 versus saline and p < 0.01 versus Bac–Mus low dose. **p < 0.01 versus saline and Bac–Mus low dose. B, Mean percentage correct during place reversal learning. Infusion of the low dose of Bac–Mus into the Pf significantly reduced performance during T1 compared with that of other treatment groups. Infusion of the middle dose of Bac–Mus into the Pf significantly reduced reversal learning performance compared with that of the other treatment groups during T4 and T5 and also compared with saline in T3. ^xp < 0.05 saline and Bac–Mus middle dose versus Bac–Mus low dose. ⁺p < 0.05 saline versus Bac–Mus middle dose. *p < 0.05 Bac–Mus middle dose versus saline and Bac–Mus low dose. **p < 0.01 Bac–Mus middle dose versus saline and Bac–Mus low dose.

Figure 4.

The effect of parafascicular inactivation on ACh output in the dorsomedial striatum during a resting condition. Samples were collected at 6 min intervals. Infusion of either saline or the middle dose of Bac–Mus had no effect on basal ACh efflux.