Functional inactivation of orexin 1 receptors in the cerebellum disrupts trace eyeblink conditioning and local theta oscillations in guinea pigs.

The cerebellum plays an essential role in motor learning. Recently, orexins, the newfound lateral hypothalamic neuropeptides, have been found to excite Purkinje cells in the cerebellar cortex and neurons in the deep cerebellar nuclei (DCN). However, little is known about their roles in cerebellum-dependent motor learning. Therefore, the present study was designed to investigate the functional significance of hypothalamic orexinergic system during trace eyeblink conditioning, a tractable behavioral model system of cerebellum-dependent motor learning. It was revealed that the orexin 1 receptors (OXR1) were specifically localized on the soma of Purkinje cells and large DCN neurons. Furthermore, interfering with the endogenous orexins' effects on the cerebellum via the selective OXR1 antagonist SB-334867 disrupted the timing rather than the acquisition of trace conditioned eyeblink responses. In addition to the behavioral effects, the SB-334867 prevented the increase in peak amplitude of cerebellar theta oscillations with learning. These results suggest that the endogenous orexins may modulate motor learning via the activation of cerebellar OXR1.