The impact of the post-complex spike pause in cerebellum-dependent learning

The cerebellum plays a fundamental role in motor movement coordination and motor error correction. By using (and associating) sensory cues present during motor errors, the cerebellum learns to anticipate motor error mistakes and execute correct movements.Damage to the cerebellum, either by trauma or disease, can impair or eliminate this ability, resulting in poor coordination and an inability to adapt or correct motor movements. In order to assist these patients, a detailed understanding of the mechanisms involved during error correction and adaptation learning is needed.Many groups have worked to understand how this learning occurs. One identified area that requires more understanding is at the output of the cerebellum, the synapses made by Purkinje neurons on Deep Cerebellar Nucleus neurons. The climbing fiber input to the cerebellum is believed to serve as a teaching signal during associative, cerebellum-dependent forms of motor learning. In Purkinje neurons the climbing fiber generates a complex spike, and a post-complex spike pause, that interrupts Purkinje neuron pacemaker firing. Because Purkinje neurons forminhibitory (GABAergic) synapses onto DCN neurons, coordinated pauses in Purkinje neuron firing lead to transient periods of dis-inhibition at the DCN, allowing them to be active. We hypothesize that windows of dis-inhibition relay information about the presence of a motor error to the DCN, since the DCN neurons do not actually see the climbing fiber-evoked complex spike that the Purkinje neurons see.In addition to facilitating DCN neurons to activate their downstream targets (including the Red Nucleus and other motor targets), we propose that this relief from inhibition allows for learning-related plasticity mechanisms, like mossy fiber long term potentiation (LTP), to occur at the DCN. It is not entirely understood, however, how theclimbing fiber signal is coordinating changes in cerebellar circuitry during learning.The post-complex spike pause is the final component of the climbing fiber signal transmitted by Purkinje neurons to the DCN following a motor error. The pause itself may therefore play an important role in the motor learning process.In in vitro experiments described in Chapter 3, the post-complex spike pause is reliably prolonged by two different drugs acting by two distinct, and opposing, mechanisms. The same drugs delivered in vivo, during classical eye-blink conditioning experiments described in Chapter 4, facilitated the onset of learning in this paradigm: rats receiving the drugs learned the behavioral association faster than their controlcounterparts. These results elucidate an unappreciated aspect of the climbing fiber teaching signal, the post-complex spike pause, and support a model in which synchrony of postcomplex spike pauses drives learning-related plasticity in the deep cerebellar nucleus