The long-term objective of the proposed work is to characterize the plasticity at cerebellar synapses that is involved in the adaptation or learning of movements. This information will provide i) a more detailed understanding of the cerebellum and its role in the control of movements, ii) a more detailed understanding of how the mechanisms of synaptic plasticity are engaged by the behavioral events of learning, and iii) a deeper understanding of the neural building blocks of learning which may generalize to other forms of learning and other regions of the brain. Thus, this information will contribute to a better understanding of the normal, healthy mechanisms of learning, and a better understanding of pathologies of memory. Moreover, since evidence indicates that the human cerebellum also mediates certain cognitive functions, such information may be useful in identifying the neural basis of cognition and its malfunction in mental illness. Many factors combine to facilitate analysis of the cerebellum and its contribution to motor learning; these include the extensive characterization of cerebellar synaptic organization and the specific and fortuitous ways in which it is engaged by several well characterized forms of motor learning. These advantages will be exploited in the proposed studies to undertake a detailed analysis of the sites of cerebellar plasticity that mediate motor learning and the rules that govern plasticity at these sites. This analysis will also emphasize the functional significance of the interactions between these sites/rules for plasticity and the network dynamics of the cerebellum. The primary method employed will be the induction of reversible lesions through micro-infusion of various substances through cannulae implanted in critical regions. These substances will include local anesthetics that prevent all activity in the region, as well as specific agonists and antagonists of critical neurotransmitters.
The specific aims will test a series of detailed hypotheses regarding the sites and rules for synaptic plasticity.
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| Khilkevich, Andrei; Zambrano, Juan; Richards, Molly-Marie et al. (2018) Cerebellar implementation of movement sequences through feedback. Elife 7: |
| Khilkevich, Andrei; Canton-Josh, Jose; DeLord, Evan et al. (2018) A cerebellar adaptation to uncertain inputs. Sci Adv 4:eaap9660 |
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| Halverson, Hunter E; Hoffmann, Loren C; Kim, Yujin et al. (2016) Systematic variation of acquisition rate in delay eyelid conditioning. Behav Neurosci 130:553-62 |
| Halverson, Hunter E; Khilkevich, Andrei; Mauk, Michael D (2015) Relating cerebellar purkinje cell activity to the timing and amplitude of conditioned eyelid responses. J Neurosci 35:7813-32 |
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