The cerebellum is involved in behaviors ranging from motor learning to social behaviors. It is therefore important to understand the cerebellar circuit and how it's dysfunction can lead to neurological disorders, such as ataxia and autism. To accomplish this it is necessary to clarify the function and connectivity of Purkinje cells (PCs), te sole output cells of the cerebellar cortex. Much is known about the intrinsic firing properties, synaptic integration and plasticity of PC inputs. However, it is unclear how PC collaterals allow PCs to influence cells within the cerebellar cortex. Our primary goal is to elucidate the propertie and functional roles of PC collaterals in juveniles and adults by answering several fundamental questions. First, what are the properties of PC collaterals in juveniles and adults and what are their targets? It is known that in newborn mice PC collaterals are prominent. They provide the primary source of inhibition to PCs, and they can mediate widespread travelling waves of activity. This is not the case in older animals where it is not clear if PC collaterals are extensie and what their targets are. Our initial studies indicate that all PCs have extensive collaterals confined to a parasagittal plane. A variety of light and electron microscopy techniques will be used in combination with electrophysiological investigations to identify cellular targets. Second, do PC collaterals allow PCs to regulate the excitability of the input layer of the cerebellum? Optogenetic approaches will be combined with slice and in vivo electrophysiology to determine the targets of PC collaterals within the granular layer and to test the hypothesis that a primary function of the collateral is to allow the output of the cerebellar cortex to feedback and regulate the input layer. Third, do PC collaterals promote synchronous PC firing and do synchronously firing PCs converge on cells in the deep cerebellar nuclei (DCN) to control their spiking? It has been proposed that synchrony allows PCs to control the spiking of cells in the DCN: If PCs fire asynchronously they suppress DCN neuron firing, and if they fire synchronously they promote phase-locked DCN firing. Our initial slice studies suggest that PC collaterals inhibit neighboring PCs and can promote synchronous activity. We will test the hypothesis that the spatial extent of PC collaterals determines the range of synchronous firing in vivo. We will also test the hypothesis that synaptically-connected PCs converge onto the same DCN neuron and regulate its firing. These studies will extend our understanding of cerebellar processing and will provide important insights into neurological disorders that arise from cerebellar dysfunction.

Public Health Relevance

Cerebellar dysfunction can result in motor disorders such as ataxia and cognitive impairments such as autism spectrum disorders. Purkinje cells are the sole output cells of the cerebellar cortex, but very little is known about the properties of Purkinje cel collaterals. This study will clarify the anatomy, synaptic targets and function of Purkinje cell collaterals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS092707-02
Application #
9146428
Study Section
Sensorimotor Integration Study Section (SMI)
Program Officer
Chen, Daofen
Project Start
2015-09-22
Project End
2017-11-30
Budget Start
2016-07-01
Budget End
2017-11-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
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