NB204 "Circuits of Central Systems" 2006 Week #1 (Feb. 1 & 6), VOR Gain Adaptation, R. Born ([email protected]) Wednesday's lecture will consist of a broad overview on eye movements, a more detailed description of the vestibulo-ocular reflex (VOR) and finally an introduction to a particular form of cerebellum-dependent learning in which the gain of the VOR can be adjusted to adapt to changes in environmental conditions. This will lead us to the development of a general paradigm for thinking about the uses of feedback, both to adjust behavior "on line" as well as to induce synaptic plasticity that leads to longer term adaptive changes in the feedforward circuitry. For a general overview on cerebellar learning, please read: Raymond, J. L., S. G. Lisberger and M. D. Mauk (1996) The Cerebellum: A neuronal learning machine? Science 272:1126-1131. On Monday we will discuss the following paper: De Zeeuw, C. I., C. Hansel, F. Bian, S. K. Koekkoek, A. M. van Alphen, D. J. Linden, and J. Oberdick (1998) Expression of a protein kinase C inhibitor in Purkinje cells blocks cerebellar LTD and adaptation of the vestibulo-ocular reflex. Neuron 20:495-508. Both papers are available as pdf's from the course web site: http://www.hms.harvard.edu/bss/neuro/bornlab/nb204/ The written assignment—due Monday (Feb. 6 before class)—concerns only the De Zeeuw paper. It should consist of a "descriptive" section (max. 750 words) in which you focus on figs. 4, 5, 6 and 8, followed by a critique (max. 500 words) as if you were reviewing the paper for a journal editor. Keep in mind that a "critique" is not necessarily only negative—both weaknesses and particular strengths should be discussed. I chose this paper because it is a particularly heroic example of using molecular techniques to address a specific hypothesis about the mechanism of learning in a simple circuit. It is a real attempt at a "soup-to-nuts" programme in which a particular intracellular signaling pathway is tied to a specific mechanism of synaptic plasticity, which is, in turn, tied to a specific form of learning. It highlights both the promises of such an approach and the pitfalls. In writing your critiques, you might want to consider the following issues/questions (without feeling compelled to address each and every one): 1. Limitations in the temporal and spatial specificity of the molecular manipulation. What have the authors done to improve upon previous efforts? What might be done to improve still more? 2. Relationship between in vitro cellular analysis and in vivo cellular function. How was the defect in LTD documented? What complexities might exist between an early perturbation in a cellular mechanism and its ultimate function in the adult circuit? Whatother experiments would you want to do to convince yourself that the behavioral result is due to a specific defect in LTD? 3. Relationship between the preparation in which the molecular manipulations are performed (mouse) and the preparation in which the circuit has been most studied (monkey). In the current paper, how "normal" does the behavior of the controls look? Might there be interspecies differences in the particular sites and mechanisms of plasticity? (Of course, but are there precedents?) How would you address this potential set of