Brain Aging in Adults with Autism Spectrum Disorder

The goal of my F31 Predoctoral Fellowship application is to receive integrated multidisciplinary training in cellular and molecular neurobiology and immunology toward establishing my future independent research career at the critical intersection of neurodevelopmental disorders and aging. Neurodevelopmental disorders are most commonly studied in childhood and adolescence, however the challenges associated with aging for the nearly 6 million adults in the United States currently living with autism spectrum disorder (ASD) remain largely unexplored. Decades of research reveal that the brains of children with ASD undergo an altered growth trajectory characterized by excess brain volume, neuron density, and connectivity. Although comparatively little is known about the course of brain development throughout adulthood in ASD, alterations are characterized by cell, spine, and myelin loss –signaling an increased risk of developing age-related cognitive impairments. Chronic neuroimmune activation in ASD throughout development provides a plausible mechanism for increased vulnerability to age-related processes. My dissertation explores part of an overarching framework that early excess brain growth, local hyper-connectivity, and imbalanced neuronal signaling triggers a cycle of neuroinflammatory responses and cell damage contributing to neuropathogenic processes into adulthood. With my outstanding mentorship team, I propose to characterize age-related changes in neuroimmune profiles (Aim 1), immune cell phenotypes (Aim 2), and neuronal inflammation (Aim 3) throughout adulthood. I will use postmortem human brain tissue from individuals with ASD and unaffected controls 20-70 years of age and target regions related to core socioemotional deficits, the amygdala and superior temporal gyrus (STG), and the hippocampal formation, a region principally implicated in aging. I have unique access to an extensive collection of clinically and genetically well characterized postmortem human brains through our tissue collection program. Through my dissertation research, I will receive training in novel, cutting edge methods on human tissue including single molecule fluorescence in situ hybridization (smFISH) HiPlex RNAscope to spatially map within-cell transcriptomic profiles. With these findings, we can begin to identify cellular and molecular phenotypes most vulnerable to pathological aging and windows for intervention to promote healthy aging in the rapidly growing population of autistic adults.