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Imprinted effects in the brain: from the X chromosome to single autosomal loci

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dc.contributor.advisor Osten, Pavel en_US
dc.contributor.advisor Huang, Josh Z en_US
dc.contributor.author Szelenyi, Eric en_US
dc.contributor.other Department of Neuroscience en_US
dc.date.accessioned 2017-09-20T16:50:40Z
dc.date.available 2017-09-20T16:50:40Z
dc.date.issued 2017-05-01 en_US
dc.identifier.uri http://hdl.handle.net/11401/76569 en_US
dc.description 182 pgs en_US
dc.description.abstract Proper brain functioning relies on imprintsepigenetic marks controlling gene expression in a parent-of-origin (PO)-specific manner. Early in development imprinting occurs upon the X-chromosome in females, and also in both sexes amongst ~100 known imprinted genes, such as Growth factor receptor-binding protein 10 (Grb10). Uniquely, the control over gene dosage endowed by both forms of imprinting (X-chromosome inactivation, XCI, and genomic imprinting, respectively) outweighs the benefits of diploidy. Thus, their existence highlights a functional significance. Spatial arrangements of imprinted brain cells have implicated systems and circuit-level functions over behavior. However, until now we have lacked the means for adequate spatial analysis required to link imprinted brain patterns to specific behavioral functions. My dissertation targets this problem using advanced whole-brain microscopy and computational methods in combination with novel mouse genetics and behavior. Through these approaches, my dissertation provides results that 1) define XCI brain pattern dynamics in female mice, 2) determine its behavioral influence in an X-linked brain disease model, and 3) identify novel behavioral brain circuitry affiliated with the cellular imprint status of Grb10. To determine whole-brain XCI dynamics, I quantified active X-chromosome (XCa) cell density on maternal (Xm) or paternal (Xp) XCa-GFP reporting mice. Whole-brain quantifications revealed a modest but statistically significant ~10% maternal XCa bias amongst all brain areas. The overall individual variability observed in whole-brain XCI ratios, ranging as wide as 25%/75%, was found to strongly predict skewing across brain areas, suggesting brain XC imprinting occurs prior to differentiation of the neural germ layer. Together, these results suggested an Xm favoring of inherited X-linked behavioral traits and disease penetrance. To test this hypothesis, I examined behaviors of heterozygous fragile X syndrome (FXS) model mice. Disease penetrance was observed only in maternal FXS mice, which phenocopied the human female FXS symptoms of exploratory alterations, spatial memory deficits, and social avoidance accompanied with hyperarousal. To identify putative neural circuit correlates of the disrupted behaviors I used correlational analyses amongst healthy XCa cell density and behavioral scores across 740 brain regions. First, time of center exploration in an open field positively correlated with an integrated sensorimotor and arousal network of connected regions. Second, altered social exploration in a 3-chamber test negatively correlated to interconnected regions outlining a socio-spatial encoding network. Collectively, these results described the dynamics of brain XCI and its relationship to behavioral function in an X-linked disease state. In the second part of my dissertation I examined the brain-wide distribution of Grb10's imprint status with respect to systems of behavior. I generated non-gene disruptive allelic-reporter/Cre mouse lines that allowed me to map, trace, and manipulate the activity of neurons expressing Grb10 maternal or paternal alleles. Dual color-assisted, PO-specific expression mapping in double transgenic mice revealed predominant and diffuse monoallelic paternal expression in subcortical stress centers and monoallelic maternal expression within non-neuronal cells of the vasculature. Novel biallelic neuronal populations were found in defensive subcortical nodes, including the ventrolateral PAG (vlPAG). The vlPAG biallelic population contained a mix of novel ovBNST-projecting VIP+ and midline thalamus and amygdala-projecting GAD2+ neurons. Acute (inhibitory DREADD) or chronic (Cre-dependent ablation) loss-of-function manipulations of these cells suggested a suppressive role in fear memory-specific freezing behavior. These results demonstrated brain system-specific roles of each Grb10 allele in behavioral function. In summary, my dissertation broadens the behavioral relevance of XC and gene-specific imprinting in providing novel systems-level regulation over behavior. en_US
dc.description.sponsorship This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. en_US
dc.format Monograph en_US
dc.format.medium Electronic Resource en_US
dc.language.iso en_US en_US
dc.publisher The Graduate School, Stony Brook University: Stony Brook, NY. en_US
dc.subject.lcsh Neurosciences -- Genetics -- Behavioral sciences en_US
dc.subject.other behavior, genomic imprinting, microscopy, neural circuits, x chromosome, XCI en_US
dc.title Imprinted effects in the brain: from the X chromosome to single autosomal loci en_US
dc.type Dissertation en_US
dc.mimetype Application/PDF en_US
dc.contributor.committeemember Li, Bo en_US
dc.contributor.committeemember Talmage, David en_US
dc.contributor.committeemember Alberini, Cristina en_US

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