Systemic harmaline blocks associative and motor learning by the actions of the inferior olive.

Is there a role for the inferior olive in learning? Novel paradigms of conditioning involving tongue protrusion were developed using the rat to test whether: (a) the indole alkaloid harmaline blocks associative learning via actions within the inferior olive, and (b) the inferior olive is required for associative and motor learning. Harmaline blocked associative learning as measured by the absence of conditioned responses to a tone over six daily sessions of conditioning and the absence of retention without harmaline. Harmaline's effect on associative learning was completely blocked by prior removal of the inferior olive with 3-acetylpyridine. Rats whose inferior olives were chronically lesioned showed normal associative learning, normal associative memory, and could learn to modify tongue protrusion via a motor learning paradigm involving response shaping. Removal of the inferior olive degraded the performance of the licking motor system by increasing the latency of conditioned tongue protrusions and by increasing the temporal variability of rhythmic licking elicited by intraoral water. The experiments raise doubt as to whether the inferior olive encodes memory in the cerebellum but demonstrate that the inferior olive is essential for the temporal precision of movement. The results indicate that harmaline's antilearning action is produced by its ability to exaggerate the normal propensity of olivary neurons to fire rhythmically, a process that must be constrained under physiological conditions for normal learning to occur. It is concluded that there may be an important role for the rhythmic activity of inferior olivary neurons in the temporal processes that underlie both motor control and learning.