Neurons in the deep cerebellar nuclei (DCN) form the sole output of the cerebellum and provide the sole readout for Purkinje cells (PC) in the cerebellar cortex that form the basis of many studies in cerebellar physiology. However, the mechanism by which the DCN produces this output remains an open question, particularly during behavior. The output of cells in these areas is influenced by a massive, convergent, inhibitory input from PC axons complemented by excitatory inputs from climbing fibers and mossy fiber collaterals that provide two inputs to the cerebellum. However, the degree to which these inputs shape the firing rate, the degree to which the firing rate is an appropriate assay about cerebellar information processing, and the degree to which firing activity varies within cells receive similar inputs remains unknown. It has been hypothesized that, given strong enough synaptic activation, DCN cells would respond to bipartite input to the cerebellum by a sequence of excitation, inhibition, and rebound bursting following disinhibition. This hypothesis is derived from the observation that slow calcium conductances play a role in deep cerebellar activity in vitro and the observation that short-term plasticity of the PC axon-DCN inhibitory synapse favors synchronized activity in the cerebellar cortex. However, this hypothesis remains to be fleshed out in vivo. This study aims to establish the nature of deep cerebellar readout and the role of cortical synchrony in the awake, behaving animal using delay eyeblink conditioning, a well-established cerebellar behavioral paradigm. Previous work in the Wang and Medina laboratories has established the freely behaving, head-restrained mouse as an animal model of delay eyeblink conditioning on par with the animal model typically used in these experiments, the rabbit. These labs have used this preparation in concert with two-photon calcium imaging to evaluate the presence of cerebellar-cortical synchrony before and after eyeblink training. This preparation is easily adapted to extracellular recording, both singularly to characterize firing an in concert with two-photon calcium imaging to provide correlations between these two stages of cerebellar processing in the behaving animal. Understanding the mechanisms by which the cerebellum performs its computations is critical to selecting the appropriate level of detail for studying afflictions of the cerebellum. The afflictions have classically involved motor disorders, such as cerebellar ataxia and cerebellar dystonia, but may also involve cognitive disorders that have well-known cerebellar anatomical deficits, such as dyslexia, attentive-deficit/hyperactivity disorder, and autism. Mouse models of cerebellum have previously allowed the investigation of development and synaptic transmission deficits in vitro;development of behavioral paradigms to accompany these mouse models would allow the integration of systems-level studies. This integrative understanding of cerebellar function would then facilitate a better understanding of functional imaging result in a clinical setting, and would facilitate the development of genetic and/or therapeutic interventions.

Public Health Relevance

The cerebellum is thought to play a role of honing and controlling motor and cognitive processes in the brain, and has been implicated in disorders from ataxia and dystonia-parkinsonism to autism and dyslexia. However, the mechanism by which the cerebellum provides this control remains a subject of hot scientific debate. This project aims to address the neurophysiology of the deep cerebellar nuclei, the area that processes and relays the output of the cerebellum to the rest of the brain, in the behaving mouse.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F02B-M (20))
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Rosemond, Erica K
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Princeton University
Schools of Arts and Sciences
United States
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Kloth, Alexander D; Badura, Aleksandra; Li, Amy et al. (2015) Cerebellar associative sensory learning defects in five mouse autism models. Elife 4:e06085
Wang, Samuel S-H; Kloth, Alexander D; Badura, Aleksandra (2014) The cerebellum, sensitive periods, and autism. Neuron 83:518-32
Schoenfeld, Timothy J; Kloth, Alexander D; Hsueh, Brian et al. (2014) Gap junctions in the ventral hippocampal-medial prefrontal pathway are involved in anxiety regulation. J Neurosci 34:15679-88
Piochon, Claire; Kloth, Alexander D; Grasselli, Giorgio et al. (2014) Cerebellar plasticity and motor learning deficits in a copy-number variation mouse model of autism. Nat Commun 5:5586