Neurons of the cerebellar nuclei are spontaneously active neurons that integrate excitatory input from mossy fibers and inhibitory input from Purkinje neurons to generate the output of the cerebellum. In real time, cerebellar output corrects errors and facilitates learned, coordinated movements, raising the question of how inhibition, excitation, and intrinsic firing interact to regulate the firing patterns of cerebellar nuclear cells. The present proposal is directed toward testing the idea that nuclear cells'response to Purkinje-mediated inhibition varies according to the correction or regulation produced by the cerebellum at any time. In particular, the degree of inhibitory synchrony may dictate cerebellar output in a task-dependent manner. Experiments will be performed both in vitro and in vivo, in normal and mutant mice and in zebrafish. Voltage-clamp, current-clamp, and extracellular electrophysiological recordings will be used to test the changes in correlation of Purkinje and nuclear cell activity during practiced motor behaviors and during errors, the interaction of excitatory with inhibitory inputs, and the changes in Purkinje synchrony and nuclear cell output during learning.

Public Health Relevance

The cerebellum regulates movements and various aspects of cognitive function, and its dysfunction is associated with ataxia, dystonia, dyslexia, and autism. Information about sensory signals are received by Purkinje neurons in the cerebellum, which then modify the information and send it to neurons in the cerebellar nuclei, which further process the information and then send it to parts of the brain that control the timing and sequencing of behaviors. In the present application, we propose to study how signals are transmitted and transformed as they go from Purkinje neurons to neurons in the cerebellar nuclei, and what changes arise under pathological conditions.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (ZRG1)
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Talley, Edmund M
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Northwestern University at Chicago
Schools of Arts and Sciences
United States
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Mercer, Audrey A; Palarz, Kristin J; Tabatadze, Nino et al. (2016) Sex differences in cerebellar synaptic transmission and sex-specific responses to autism-linked Gabrb3 mutations in mice. Elife 5:
Najac, Marion; Raman, Indira M (2015) Integration of Purkinje cell inhibition by cerebellar nucleo-olivary neurons. J Neurosci 35:544-9
Lewis, Amanda H; Raman, Indira M (2014) Resurgent current of voltage-gated Na(+) channels. J Physiol 592:4825-38
Benton, Mark D; Lewis, Amanda H; Bant, Jason S et al. (2013) Iberiotoxin-sensitive and -insensitive BK currents in Purkinje neuron somata. J Neurophysiol 109:2528-41
Lewis, Amanda H; Raman, Indira M (2013) Interactions among DIV voltage-sensor movement, fast inactivation, and resurgent Na current induced by the NaV?4 open-channel blocking peptide. J Gen Physiol 142:191-206
Bant, Jason S; Aman, Teresa K; Raman, Indira M (2013) Antagonism of lidocaine inhibition by open-channel blockers that generate resurgent Na current. J Neurosci 33:4976-87
Zheng, Nan; Raman, Indira M (2011) Prolonged postinhibitory rebound firing in the cerebellar nuclei mediated by group I metabotropic glutamate receptor potentiation of L-type calcium currents. J Neurosci 31:10283-92
Lewis, Amanda H; Raman, Indira M (2011) Cross-species conservation of open-channel block by Na channel ?4 peptides reveals structural features required for resurgent Na current. J Neurosci 31:11527-36
Aman, Teresa K; Raman, Indira M (2010) Inwardly permeating Na ions generate the voltage dependence of resurgent Na current in cerebellar Purkinje neurons. J Neurosci 30:5629-34
Person, Abigail L; Raman, Indira M (2010) Deactivation of L-type Ca current by inhibition controls LTP at excitatory synapses in the cerebellar nuclei. Neuron 66:550-9

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