Normal and diseased circuitry in the cerebellar and cerebral cortex
Neurosurgeon, Hennepin Healthcare
Neurological Surgery Resident, University of Minnesota
Undergraduate Institution and Major/Degree:
- B.S., Molecular Biology, 2008
University of Wisconsin
- Tim Ebner, MD, Ph.D.
The first aim of my thesis research is to investigate the functional role of parallel fibers in cerebellar physiology. A major controversy in the field centers on the geometry of the response produced by parallel fiber activity in the cerebellar cortex. One side argues in favor of the “radial” hypothesis and the other for the “beam” hypothesis. The radial hypothesis states that the ascending branch of the granule cell provides the most important granule cell input to Purkinje cells. The beam hypothesis argues that the parallel fibers are central inputs to Purkinje cells. Using calcium imaging in the cerebellar cortex in vivo, coupled with pharmacological and electrical stimulation of inputs, I have demonstrated that direct and selective activation of granule cells results in beams of parallel fiber activity, strong support for the beam hypothesis. I have also shown that more natural, peripheral sensory input is capable of evoking parallel fiber-like beams. A critical controlling factor in whether inputs evoke beam-like or patch-like responses appears to be the spatial distribution of excitatory amino acid transporters on Purkinje cells.
The majority of my thesis examines the mechanisms of episodic cerebellar dysfunction. The global hypothesis is that in the tottering mouse, a model of episodic ataxia type 2, the reduction in P/Q-type Ca2+ channel function results in unstable Purkinje cell dynamics. These unstable dynamics in Purkinje cells produce low frequency oscillation in the cerebellar cortex that disrupts cerebellar function and generates the episodic movement disorder. Initial studies aim to investigate hypothesized disruptions in the intrinsic cerebellar circuitry that develop during the low frequency oscillations as well as investigate the effects of low frequency oscillations on the firing patterns of the deep cerebellar nuclear neurons, the output neurons of the cerebellar cortex. To test the overall hypothesis that Purkinje cells initiate episodes of dystonia in the tottering mouse, I have been working to implement the technique of optogenetics.
- Tim Ebner
- Kelvin Lim
- Laura Ranum
Courses Taken Beyond the Core Courses:
Graduate Level Minor:
Conferences Attended and Presentations:
- Society for Neuroscience Annual Meeting - Fall 2010, 2012
- Society for the Neural Control of Movement annual meeting - Spring 2012
- Paul Mermelstain - Chair
- Harry Orr
- Paulo Kofuji
- Tim Ebner - Advisor
- Cramer SW, Popa LS, Carter RE, Chen G, Ebner TJ. Abnormal excitability and episodic low-frequency oscillations in the cerebral cortex of the tottering mouse. J Neurosci. 2015;35:5664-79.
- Armbrust KR, Wang X, Hathorn TJ, Cramer SW, Chen G, Zu T, Kangas T, Zink AN, Öz G, Ebner TJ, Ranum LP. Mutant β-III spectrin causes mGluR1α mislocalization and functional deficits in a mouse model of spinocerebellar ataxia type 5. J Neurosci. 2014;34(30):9891-904.
- Cramer SW, Gao W, Chen G, Ebner TJ. Reevaluation of the beam and radial hypotheses of parallel fiber action in the cerebellar cortex. J Neurosci. 2013;33(28):11412-24.
- Ebner TJ, Wang X, Gao W, Cramer SW, Chen G. Parasagittal zones in the cerebellar cortex differ in excitability, information processing, and synaptic plasticity. Cerebellum. 2012;11:418-9.
- Luo J, Wang Y, Chen H, Kintner DB, Cramer SW, Gerdts JK, Chen X, Shull GE, Philipson KD, Sun D. A concerted role of Na+ -K+ -Cl- cotransporter and Na+/Ca2+ exchanger in ischemic damage. J Cereb Blood Flow Metab. 2008;28(4):737-46.
- Cramer SW, Baggott C, Cain J, Tilghman J, Allcock B, Miranpuri G, Rajpal S, Sun D, Resnick D. The role of cation-dependent chloride transporters in neuropathic pain following spinal cord injury. Mol Pain. 2008 Sep 17;4:36.
- Wang Y, Luo J, Chen X, Chen H, Cramer SW, Sun D. Gene inactivation of Na+/H+ exchanger isoform 1 attenuates apoptosis and mitochondrial damage following transient focal cerebral ischemia. Eur J Neurosci. 2008 Jul;28(1):51-61.
Awards and Honors:
- Morris Smithberg Memorial Prize, 2011
- Milne-Brandenburg Award, 2012
- Poppele Prize, 2012
- NINDS F31 NRSA “Optogenetic modulation of episodic dystonia in the tottering mouse”
- Frederick M. Stark Travel Award - 2014
- Sping & Ying-Ngoh T. Lin Graduate Fellowship - 2014