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ORCID

http://orcid.org/0000-0002-9943-7573

Date of Award

Summer 8-15-2021

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

Neurodevelopmental disorders (NDDs) are a heterogeneous family of disorders characterized by the presence of abnormal developmental trajectories. Functional connectivity (FC) neuroimaging provides a minimally-invasive method by which to investigate the progression of these disorders and identify potential biomarkers of disease-related dysfunction for use in therapeutics’ development. My thesis work therefore took several approaches to the question of how the functional connectome reflects developmental change as well as system-wide perturbations from environmental or genetic factors. I explored the use of optical fluorescence and intrinsic signal imaging to characterize FC and stimulation-derived responses in a NDD model of perinatal exposure to selective serotonin reuptake inhibitor, reporting an altered cortical calcium and hemodynamic response to somatosensory stimulation in adulthood (Chapter 2). To provide a template of healthy FC development, I also characterized longitudinal calcium FC between postnatal day 15 (P15) and P60 in the Thy1/GCaMP6f mouse (Chapter 3) using an awake imaging paradigm. I discovered that cortical FC displayed widespread dynamic change during this period, with a region-dependence to the shape of the developmental trajectory across time. Finally, I documented the sex-specific perturbations present in the Mecp2 mouse model of Rett Syndrome, both during development (P35) and at an adult time point proximal to symptom onset and decline for each sex (Chapter 4). I found that Mecp2 males display a strong FC phenotype in both development and adulthood, while Mecp2 females display more subtle variation. These sex-specific differences in FC phenotype reflect the symptomatology present in the Mecp2 animal model and the underlying X-linked genetics of Rett Syndrome. The observed Mecp2 FC phenotypes appeared at P35, consistent with male symptom progression but earlier than females typically display symptom onset, suggesting promise as a presymptomatic biomarker. Altogether, I discovered that FC phenotypes are present and specific to each NDD model, and that there exists a diversity of temporal and spatial changes in FC during development in the healthy mouse cortex. These results suggest that functional connectivity techniques will provide a wealth of opportunities for studies aimed at understanding how the developmental trajectory of various NDDs deviates from typical FC development.

Language

English (en)

Chair and Committee

Joseph D. Dougherty Joseph Culver

Committee Members

Tamara Hershey, Timothy Holy, Jin-Moo Lee, Bradley Schlaggar,

Available for download on Sunday, August 20, 2023

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