Learning-Induced Plasticity in Deep Cerebellar Nucleus

Evidence that cerebellar learning involves more than one site of plasticity comes from, in part, pavlovian eyelid conditioning, where disconnecting the cerebellar cortex abolishes one component of learning, response timing, but spares the expression of abnormally timed short-latency responses (SLRs). Here, we provide evidence that SLRs unmasked by cerebellar cortex lesions are mediated by an associative form of learning-induced plasticity in the anterior interpositus nucleus (AIN) of the cerebellum. We used pharmacological inactivation and/or electrical microstimulation of various sites afferent and efferent to the AIN to systematically eliminate alternative candidate sites of plasticity upstream or downstream from this structure. Collectively, the results suggest that cerebellar learning is mediated in part by plasticity in target nuclei downstream of the cerebellar cortex. These data demonstrate an instance in which an aspect of associative learning, SLRs, can be used as an index of plasticity at a specific site in the brain.

[1]  M. Bitterman PHYLETIC DIFFERENCES IN LEARNING. , 1965, The American psychologist.

[2]  D. Marr A theory of cerebellar cortex , 1969, The Journal of physiology.

[3]  J. Albus A Theory of Cerebellar Function , 1971 .

[4]  F. Kárpáti,et al.  [Mast cell destruction, a new therapeutic possibility in the treatment of interstitial cystitis]. , 1971, Der Urologe.

[5]  F. A. Miles,et al.  Plasticity in the vestibulo-ocular reflex: a new hypothesis. , 1981, Annual review of neuroscience.

[6]  M. Davis,et al.  A primary acoustic startle circuit: lesion and stimulation studies , 1982, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[7]  R. F. Thompson,et al.  Cerebellum: essential involvement in the classically conditioned eyelid response. , 1984, Science.

[8]  R. F. Thompson,et al.  Classical conditioning using stimulation of the inferior olive as the unconditioned stimulus. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[9]  E. Kehoe A layered network model of associative learning: learning to learn and configuration. , 1988, Psychological review.

[10]  R. F. Thompson,et al.  Classical conditioning in rabbits using pontine nucleus stimulation as a conditioned stimulus and inferior olive stimulation as an unconditioned stimulus , 1989, Synapse.

[11]  Richard F. Thompson,et al.  Effects of lidocaine injection in the interpositus nucleus and red nucleus on conditioned behavioral and neuronal responses , 1990, Brain Research.

[12]  C. Yeo Cerebellum and Classical Conditioning of Motor Responses , 1991, Annals of the New York Academy of Sciences.

[13]  M. Mauk,et al.  Cerebellar cortex lesions disrupt learning-dependent timing of conditioned eyelid responses , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[14]  Richard F. Thompson,et al.  Localization of a memory trace in the mammalian brain. , 1993, Science.

[15]  G. Hesslow,et al.  Suppression of cerebellar Purkinje cells during conditioned responses in ferrets. , 1994, Neuroreport.

[16]  S. Lisberger Neural basis for motor learning in the vestibuloocular reflex of primates. III. Computational and behavioral analysis of the sites of learning. , 1994, Journal of neurophysiology.

[17]  M. Mauk,et al.  Extinction of conditioned eyelid responses requires the anterior lobe of cerebellar cortex , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[18]  T. Sejnowski,et al.  Learning and memory in the vestibulo-ocular reflex. , 1995, Annual review of neuroscience.

[19]  S. Lisberger,et al.  The Cerebellum: A Neuronal Learning Machine? , 1996, Science.

[20]  D Jaarsma,et al.  Cholinergic innervation and receptors in the cerebellum. , 1997, Progress in brain research.

[21]  N. Donegan,et al.  A model of Pavlovian eyelid conditioning based on the synaptic organization of the cerebellum. , 1997, Learning & memory.

[22]  C. Anderson,et al.  The Cerebellum and Red Nucleus Are Not Required for In Vitro Classical Conditioning of the Turtle Abducens Nerve Response , 1997, The Journal of Neuroscience.

[23]  M. Mauk Roles of Cerebellar Cortex and Nuclei in Motor Learning: Contradictions or Clues? , 1997, Neuron.

[24]  Jan Voogd,et al.  Chapter 5 Cholinergic innervation and receptors in the cerebellum , 1997 .

[25]  M. Mauk,et al.  Pharmacological analysis of cerebellar contributions to the timing and expression of conditioned eyelid responses , 1998, Neuropharmacology.

[26]  G. Hesslow,et al.  Learned Movements Elicited by Direct Stimulation of Cerebellar Mossy Fiber Afferents , 1999, Neuron.

[27]  M. Mauk,et al.  Cerebellar Cortex Lesions Prevent Acquisition of Conditioned Eyelid Responses , 1999, The Journal of Neuroscience.

[28]  M. Mauk,et al.  Simulations of Cerebellar Motor Learning: Computational Analysis of Plasticity at the Mossy Fiber to Deep Nucleus Synapse , 1999, The Journal of Neuroscience.

[29]  Javier F. Medina,et al.  Timing Mechanisms in the Cerebellum: Testing Predictions of a Large-Scale Computer Simulation , 2000, The Journal of Neuroscience.

[30]  D. Linden,et al.  Rapid, synaptically driven increases in the intrinsic excitability of cerebellar deep nuclear neurons , 2000, Nature Neuroscience.

[31]  M. Ito,et al.  Cerebellar long-term depression: characterization, signal transduction, and functional roles. , 2001, Physiological reviews.

[32]  M. Mauk,et al.  Latent Acquisition of Timed Responses in Cerebellar Cortex , 2001, The Journal of Neuroscience.

[33]  M. Mauk,et al.  A Mechanism for Savings in the Cerebellum , 2001, The Journal of Neuroscience.

[34]  Magnus Ivarsson,et al.  Cerebellar Mechanisms in Eyeblink Conditioning , 2002, Annals of the New York Academy of Sciences.

[35]  John H Freeman,et al.  Synapse formation is associated with memory storage in the cerebellum , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Richard F. Thompson,et al.  Cerebellar cortical inhibition and classical eyeblink conditioning , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[37]  H. C. Hulscher,et al.  Cerebellar LTD and Learning-Dependent Timing of Conditioned Eyelid Responses , 2003, Science.

[38]  June-Seek Choi,et al.  Cerebellar neuronal activity expresses the complex topography of conditioned eyeblink responses. , 2003, Behavioral neuroscience.

[39]  C. Sekirnjak,et al.  Long-Lasting Increases in Intrinsic Excitability Triggered by Inhibition , 2003, Neuron.

[40]  M. Mauk,et al.  Stimulus generalization of conditioned eyelid responses produced without cerebellar cortex: implications for plasticity in the cerebellar nuclei. , 2003, Learning & memory.

[41]  D. Linden,et al.  The other side of the engram: experience-driven changes in neuronal intrinsic excitability , 2003, Nature Reviews Neuroscience.

[42]  V. Bracha,et al.  GABA neurotransmission in the cerebellar interposed nuclei: involvement in classically conditioned eyeblinks and neuronal activity. , 2004, Journal of neurophysiology.

[43]  R. Racine,et al.  Long-term potentiation in the interpositus and vestibular nuclei in the rat , 2004, Experimental Brain Research.

[44]  Wei Zhang,et al.  Persistent changes in the intrinsic excitability of rat deep cerebellar nuclear neurones induced by EPSP or IPSP bursts , 2004, The Journal of physiology.

[45]  D. M. Broussard,et al.  The Site of a Motor Memory Shifts with Consolidation , 2005, The Journal of Neuroscience.

[46]  V Bracha,et al.  Glutamate neurotransmission in the cerebellar interposed nuclei: involvement in classically conditioned eyeblinks and neuronal activity. , 2005, Journal of neurophysiology.

[47]  Aryn H. Gittis,et al.  Decreases in CaMKII Activity Trigger Persistent Potentiation of Intrinsic Excitability in Spontaneously Firing Vestibular Nucleus Neurons , 2005, Neuron.

[48]  E. De Schutter,et al.  Deletion of FMR1 in Purkinje Cells Enhances Parallel Fiber LTD, Enlarges Spines, and Attenuates Cerebellar Eyelid Conditioning in Fragile X Syndrome , 2005, Neuron.

[49]  J. Delgado-García,et al.  Firing activities of identified posterior interpositus nucleus neurons during associative learning in behaving cats , 2005, Brain Research Reviews.

[50]  S. Itohara,et al.  Memory trace of motor learning shifts transsynaptically from cerebellar cortex to nuclei for consolidation , 2006, Neuroscience.

[51]  I. Raman,et al.  Potentiation of Mossy Fiber EPSCs in the Cerebellar Nuclei by NMDA Receptor Activation followed by Postinhibitory Rebound Current , 2006, Neuron.

[52]  Wei Zhang,et al.  Long-Term Depression at the Mossy Fiber–Deep Cerebellar Nucleus Synapse , 2006, The Journal of Neuroscience.

[53]  J. Delgado-García,et al.  Building new motor responses: eyelid conditioning revisited , 2006, Trends in Neurosciences.

[54]  J. Keifer In vitro classical conditioning of the turtle eyeblink reflex: approaching cellular mechanisms of acquisition , 2008, The Cerebellum.