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Feedback loops of the vestibulocerebellum

前庭小脑的反馈回路

基本信息

批准号：
10305602
负责人：
Jose Ernesto Canton-Josh
金额：
$ 2.47万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10305602
关键词：
3-Dimensional Acute Anatomy Biological Assay Brain Brush Cell Calcium Cell physiology Cells Cerebellar Mossy Fibers Cerebellum Cytoplasmic Granules Data Electrophysiology (science)Enterobacteria phage P1 Cre recombinase Excitatory Synapse Eye Movements Feedback Fiber Fishes Genetic Glutamates Goals Golgi Apparatus Halorhodopsins Image Imaging Techniques Individual Inhibitory Synapse Interneurons Knowledge Label Lead Left Light Lobe Lobule Measures Metabotropic Glutamate Receptors Microscopy Mission Modernization Monitor Mormyridae Mus National Institute of Neurological Disorders and Stroke Neurons Opsin Optics Output Pathologic Pathway interactions Pattern Pharmacology Physiological Population Preparation Property Purkinje Cells Recurrence Research Role Semicircular canal structure Series Slice Stereotyping Stratum Granulosum Structure Synapses System Testing Time Traction Training Transgenic Mice Transgenic Organisms Variant Virus base cell transformation cell type density dorsal cochlear nucleus experimental study granule cell light gated mossy fiber motor control motor learning neuronal circuitry novel optogenetics otoconia postsynaptic promoter protein expression receptor expression response sensor sensory input spatiotemporal theories tool

项目摘要

SUMMARY The cerebellum is characterized by stereotyped cytoarchitecture across all of its lobules. However, recent evidence has revealed new complexity in these circuits, including variation in cells types, connectivity patterns, and receptor expression. Within the vestibulocerebellum, there is an excitatory glutamatergic interneuron cell type known as the unipolar brush cell (UBC). UBCs are heavily enriched within regions of the cerebellum controlling eye movements and vestibular processing. UBCs receive input from mossy fibers entering the cerebellum and form a local recurrent feed- forward excitatory network. This connectivity suggests that UBCs may perform large scale transformations on inputs to the cerebellum. Several distinct functions for these cells within the cerebellum have been proposed, but the resulting hypotheses have been difficult to test without selective genetic tools for targeting UBCs. We have found a transgenic mouse line that selectively labels the most common subtype of UBCs. In addition, our preliminary data show that vestibulocerebellar Purkinje cells make functional inhibitory synapses onto UBCs. The goals of this project are to examine how UBCs modulate information flow to the cerebellum, using a combination of optogenetic, electrophysiology, and imaging techniques and to characterize a novel feedback circuit from Purkinje cells to UBCs. Aim 1 is to characterize the responses of Purkinje cells to optogenetic activation of UBCs. This will be accomplished by using light-gated opsin ChR2 to activate UBCs directly and measuring either the firing responses or synaptic currents in Purkinje cells. We will also use inhibitory opsins to transiently inactivate UBCs and examine how Purkinje cells respond to mossy fiber input in the presence or absence of UBC activity. Aim 2 will examine new synaptic connections between Purkinje cells and UBCs, using promoter-restricted specific optogenetic activation of Purkinje cells with recordings from genetically identified UBCs. Using stimulation of mossy fiber inputs, we will record the spatiotemporal dynamics of UBC activity. This will be done with both cell-attached recordings and rapid 3D light-sheet imaging of calcium dynamics to image activity in dozens of UBCs simultaneously. To measure how circuit level Purkinje cell inhibition of the granular layer neurons alters UBC activity, in interleaved trials, we will combine mossy fiber activation with optogenetically evoked Purkinje cell firing. Carrying out these experiments will build a conceptual framework to explain how UBCs operate within feedback circuits to regulate cerebellar output, relevant to motor control in physiological and pathological conditions.

总结