This item is under embargo and not available online per the author's request. For access information, please visit http://libanswers.wustl.edu/faq/5640.

ORCID

http://orcid.org/0000-0002-6879-4228

Date of Award

Spring 5-15-2020

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Neural circuits endow the brain with capacities for perception, motor control, language, emotion, and cognition, but it remains unclear how information is encoded by circuits to support these functions and how proper coding is established during development. In the present work, I have used the mouse cerebellum, a hindbrain structure with stereotyped circuitry and significant development during the postnatal period, as a model system to probe two principles of neural circuit formation and function in vivo. The first set of investigations, spanning from the molecular to the circuit level, evaluate the mechanisms and consequences of chromatin remodeling on neural circuit development. Focusing on the nucleosome remodeling and deacetylating (NuRD) chromatin remodeling complex in developing cerebellar granule neurons, these studies reveal a novel mechanism by which the NuRD complex alters histone structure to inactivate activity-dependent transcription and elucidate its key role in the regulation of dendrite morphology and establishment of a sparse sensorimotor code in vivo. In a second major line of studies, I investigate the properties and developmental organization of information encoded by granule neurons of the vermal cerebellum, a region critical for postural control and locomotion. In vivo calcium imaging studies of cerebellar granule neuron responses to sensorimotor stimuli reveal novel functional populations of granule neurons, including populations of neurons that respond differentially to voluntary and enforced locomotion. In addition, I study the impact of the birth order of granule neurons on their morphologic and functional properties, revealing that early and late born granule neurons convey a diverse sensorimotor code to distinct efferent targets in the cerebellar circuit. Collectively, these studies leverage state-of-the-art tools to address longstanding questions in the fields of epigenetics, developmental neurobiology, and cerebellar physiology. This work advances our understanding of how neural circuit assembly is controlled during normal development and how circuit development facilitates the proper encoding of information.

Language

English (en)

Chair and Committee

Azad Bonni

Committee Members

Martha Bagnall, Pablo Blazquez, Bradley Schlaggar,

Available for download on Wednesday, May 15, 2120

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