Multiple forms of activity dependent, synaptic plasticity have been described in the cerebellar cortex. Hypothesized to play a central role in motor learning, the overall goal of this proposal is to address key questions concerning cerebellar synaptic plasticity in the intact animal. The experimental approach is based on optical imaging of activity in the mouse cerebellar cortex to evaluate the spatial and temporal aspects of the long-term changes. Theoretical models and behavioral data require that parallel fiber (PF) activity precede climbing fiber (CF) input for PF-Purkinje cell (PC) long-term depression (LTD) to support learning. Therefore, Specific Aim 1 investigates the optimal timing and stimulation parameters for evoking PF-PC LTD in vivo.
Specific Aim 1 also characterizes the signaling requirements, examines whether granular layer and mossy fiber stimulation generates PF-PC LTD, and tests the hypothesis that PF-PC LTD should modify the responses evoked in the cerebellar cortex by peripheral inputs. Long-term potentiation (LTP) has been described at the PF-PC synapse in vitro.
Specific Aim 2 tests in vivo whether LTP occurs at the PF-PC synapse, characterizing the stimulation parameters, stimulation at different stages in the circuitry, signaling requirements and spatial characteristics.
Specific Aim 2 also examines how PF-PC LTP modifies the responses evoked by peripheral inputs. Central to theories of the cerebellum's role in motor learning is the reversibility of both LTD and LTP. Reversibility has only been demonstrated in vitro with little information on reversibility in vivo.
Specific Aim 3 tests whether induction of LTP can reverse PF-PC LTD and conversely whether induction of LTD can reverse PF-PC LTP. Recent evidence suggests that the synaptic connections between the PFs and the molecular layer inhibitory interneurons are modifiable. Using an optical imaging methodology that allows monitoring the off-beam inhibition evoked by PF stimulation, Specific Aim 4 investigates the induction properties, spatial characteristics, and signaling mechanisms of these long-term changes in the molecular layer inhibitory network. Understanding the role of cerebellar synaptic plasticity will require studying LTD and LTP in the awake, behaving animal. Therefore, Specific Aim 5 first characterizes LTD and LTP in the awake animal.
Then Specific Aim 5 also tests the hypothesis that LTD and LTP contribute to the changes in cerebellar cortical activity that occur with adaptation to a mechanical perturbation of a forelimb reaching movement. The goal is to directly link the changes in the cerebellar cortex occurring during motor learning to synaptic plasticity at the PF-PC synapses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS048944-05S1
Application #
7848607
Study Section
Sensorimotor Integration Study Section (SMI)
Program Officer
Chen, Daofen
Project Start
2005-04-01
Project End
2011-08-31
Budget Start
2009-07-21
Budget End
2011-08-31
Support Year
5
Fiscal Year
2009
Total Cost
$26,437
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Neurosciences
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Willoughby, Christy L; Fleuriet, Jérome; Walton, Mark M et al. (2015) Adaptability of the Immature Ocular Motor Control System: Unilateral IGF-1 Medial Rectus Treatment. Invest Ophthalmol Vis Sci 56:3484-96
Chabot-Doré, A-J; Schuster, D J; Stone, L S et al. (2015) Analgesic synergy between opioid and ?2 -adrenoceptors. Br J Pharmacol 172:388-402
Willoughby, Christy L; Fleuriet, Jérome; Walton, Mark M et al. (2015) Adaptation of slow myofibers: the effect of sustained BDNF treatment of extraocular muscles in infant nonhuman primates. Invest Ophthalmol Vis Sci 56:3467-83
Schuster, D J; Metcalf, M D; Kitto, K F et al. (2015) Ligand requirements for involvement of PKC? in synergistic analgesic interactions between spinal ? and ? opioid receptors. Br J Pharmacol 172:642-53
Moser, Hannah R; Giesler Jr, Glenn J (2014) Characterization of pruriceptive trigeminothalamic tract neurons in rats. J Neurophysiol 111:1574-89
Caldwell, Michael S; Lee, Norman; Schrode, Katrina M et al. (2014) Spatial hearing in Cope's gray treefrog: II. Frequency-dependent directionality in the amplitude and phase of tympanum vibrations. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 200:285-304
Armbrust, Karen R; Wang, Xinming; Hathorn, Tyisha J et al. (2014) Mutant ?-III spectrin causes mGluR1? mislocalization and functional deficits in a mouse model of spinocerebellar ataxia type 5. J Neurosci 34:9891-904
Steiner, Adam P; Redish, A David (2014) Behavioral and neurophysiological correlates of regret in rat decision-making on a neuroeconomic task. Nat Neurosci 17:995-1002
Wiggin, Timothy D; Peck, Jack H; Masino, Mark A (2014) Coordination of fictive motor activity in the larval zebrafish is generated by non-segmental mechanisms. PLoS One 9:e109117
Schrode, Katrina M; Buerkle, Nathan P; Brittan-Powell, Elizabeth F et al. (2014) Auditory brainstem responses in Cope's gray treefrog (Hyla chrysoscelis): effects of frequency, level, sex and size. J Comp Physiol A Neuroethol Sens Neural Behav Physiol 200:221-38

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