Molecular and cellular exploration of striatal astrocytes in aging - Abstract As part of the basal ganglia circuitry, the striatum is a large, evolutionarily conserved brain nucleus that serves multiple essential functions throughout the lifespan, including precise information encoding necessary for a range of motor behaviors and skills. Normal aging disrupts striatal function, resulting in degradation of motor learning and susceptibility to age-related neurodegenerative diseases such as Huntington’s disease (HD) and Parkinson’s disease (PD). Glial cells are abundant within the striatum and are known to exhibit age-related decline. For example, human single-nucleus RNA sequencing (snRNAseq) of several brain regions, including the striatum, demonstrated that age degrades the molecular signatures of glia more than those of neurons. Astrocytes are a type of glia and are found throughout the mammalian brain, interacting spatially and functionally with neurons, blood vessels, and other glia. They serve multiple homeostatic and active functions and are involved in neuroinflammation, synapse formation, removal, and regulation. A long standing and open question concerns how astrocytes change during aging. One recent study employing postmortem human tissue found synaptic gene expression changes are coordinated in neurons and astrocytes, and another showed astrocytes lose their complex morphology with aging. In mice, several transcriptomic approaches show that glia display more pronounced changes in gene expression and density than neurons with age. Gene expression analyses of astrocytes across several brain regions of mice also demonstrated marked age-induced shifts in their transcriptomes, with separable patterns of decline that were apparent within individual brain regions. However, the striatum was not included in the evaluations and consequently despite progress how striatal astrocytes change with age in mice remains unknown. Since normal brain aging is a multicellular process, we seek to provide astrocyte-specific proteomic, transcriptomic, and functional data for how astrocytes change with age in the striatum of mice. The availability of these data, along with already available postmortem human gene expression studies, will permit specific mechanistic hypotheses in mouse models to ultimately aid in understanding normal aging and aging-related diseases such as HD and PD that affect the basal ganglia. We will test the hypothesis that striatal astrocytes undergo molecular, cellular, and functional changes with aging that can be assessed rigorously with state-of-the-art methods and understood in molecular terms. Specific Aim 1 will determine striatal astrocyte subproteomes and transcriptome in 18-month-old mice in relation to 2-month-old mice. Specific Aim 2 will evaluate functional and cellular properties of striatal astrocytes in 2- and 18-month-old mice. Our exploratory studies could have widespread applications in striatal and age-related astrocyte research, enabling development of hypothesis driven mechanistic studies in follow up R01 applications.
