? DESCRIPTION (provided by applicant): Alterations in brain structure and function in most individuals with an autism spectrum disorder (ASD) begin early in life, however they continue to change during development and vary throughout lifespan. These age-related differences are region-specific and most evident in higher-order cognitive, social and emotional brain regions. Our longitudinal magnetic resonance imaging (MRI) studies suggest that, of the five lobes, temporal cortical growth in children with ASD deviates most substantially from typical development, beginning at 2 years of life. Although this phenomenon is most evident during childhood, we found that cellular alterations continue and change throughout lifespan. Neuron numbers are reduced in temporal cortical and subcortical regions in ASD adults and a subset of ASD brains has excessive microglial activation, suggesting an aberrant immune response in the brain. Whether these differences exist during childhood or are the result of degenerative cell loss remains a mystery. It is clear though that structural and cellular alterations found in ASD brain vary by region and age, and are cell-specific. The heterogeneity and changing pathology of the ASD brain presents complications for translating biological research to the development of biotheraputics to alter both brain development and function. The development of targeted biological treatments requires an understanding of the molecular signature directly related to the pathogenesis one is attempting to alter. However, molecular transcriptome alterations related to region, age, and cellular pathology in ASD compared to the typically developing brain remains completely unknown and unexplored. In fact, no study to date has focused on cell-specific gene patterns in any brain region at any age in ASD. The study of a large population of live individuals using MRI and molecular studies of blood can provide us with surrogate information on global brain changes. However, postmortem human brain tissue from ASD and unaffected individuals is necessary to uncover the direct link between specific cellular pathology and underlying molecular transcriptomic alterations. To begin to address this critical gap in knowledge, we propose a pilot study to assess the feasibility of this novel avenue of investigation: 1) Characterize cellular alterations with stereological measures of neuronal and microglial cell number and size in superior temporal sulcus (STS), a key social brain region, and contrast findings with adjacent primary auditory cortex (PAC). 2) Identify region- and cell-specific alterations in gene expression in these regions using laser capture microscopy and cell suspension techniques to isolate neurons and microglia for RNA-sequencing. In summary, the overarching goal of this research is to combine markers of cellular and transcriptomic alterations in specific brain regions and cell types to paint a detailed picture of the molecular mechanisms that underlie aberrant brain development in ASD, thus identifying molecular signatures that can be investigated in larger populations and targeted for interventions across lifespan.
|Effective start/end date||9/24/15 → 6/30/17|
- National Institutes of Health: $274,021.00
- National Institutes of Health: $157,000.00