Intellectual and developmental disabilities (IDDs) are a collection of disorders that are characterized by abnormalities in individuals' developmental trajectory, but the underlying biological correlates are not always well-understood. Functional connectivity (FC) as measured by magnetic resonance imaging (fcMRI) provides a powerful and noninvasive tool to probe the systems-level features of IDDs and resample an individual at multiple developmental timepoints. However, for all of the human functional neuroimaging studies of development, they have not yet established a functional connectome across age nor its links to behavior. How FC changes across development from infancy to adulthood, and whether FC mirrors abnormal developmental behavior trajectories in IDDs, remain questions. Rett Syndrome (RTT) is an IDD with a known genetic cause and manifests motor and respiratory deficits as well as certain behaviors seen in IDDs such as autism spectrum disorder. However, RTT's complete effect on neural circuits and processes is still not well-understood, in part because the brain architecture and connectivity have not been comprehensively evaluated at the systems level. Tracing the FC and behavioral phenotype of RTT across development could establish a presence or lack of coupling between FC and behavior. Use of an animal model better controls for the potentially confounding genetic and environmental heterogeneity present in human studies. This proposal will therefore track FC across development in mice, using optical intrinsic signal imaging measures of functional connectivity (fcOIS) to circumvent fcMRI's signal-to-noise challenges in mice. FC networks in human infants have been previously shown to vary in their development, with somatomotor areas showing more connectivity than association cortex in infancy. Because of this difference between developmental extremes but the lack of data regarding the developmental progression between them, I will longitudinally image mice at 5 developmental timepoints from P15 to early adulthood and establish a baseline pattern of FC in neurologically typical mice using calcium imaging. To establish sensitivity to IDD-related traits, I will characterize FC patterns in the Rett Syndrome model Mecp2lox-stop and explore inter-individual differences in the population. Finally, to probe beyond these correlative questions, I will examine how the rescue of the Mecp2 model's gene expression in GABAergic neurons affects its FC phenotype, and I will evaluate the relationship between the model's behavioral phenotypes after rescue and its FC measures. Ultimately, the results of this study will shed light on the nuances of longitudinal network architecture development and the interactions between genotype, FC, and behavior that are incompletely characterized in RTT and other IDDs.
Human functional neuroimaging studies have shown that infants display a distinct pattern of functional connectivity in the brain, suggesting that development proceeds at different rates or in bursts in different cortical regions. This study aims to use optical fluorescence imaging to track neural activity and ask what functional connectivity changes occur from adolescence to adulthood in the mouse cortex, in a manner which could relate these results back to the development of brain function across childhood and into adulthood in humans. Results from this research study can pinpoint where and when neurodevelopmental disorders like Rett Syndrome begin to display brain connectivity dysfunction, and whether functional deficits are reversible if the baseline, cellular- level protein deficits are recovered in a model like the Mecp2 mouse model of Rett Syndrome.
