Investigating glial priming by an early-life sensory experience

/ABSTRACT Adverse early-life experiences can have profoundly negative consequences for a person’s behavioral, social, and physical health throughout their lifespan, a problem with great relevance for public health and for the applicant’s career goal of training as a pediatrician-scientist. Nearly three decades after this association was uncovered, the mechanisms by which adverse experiences are biologically embedded in the nervous system during developmental sensitive periods remain largely unknown, due in part to a lack of tractable model systems. This proposal describes a novel model of experience embedding in the Drosophila melanogaster olfactory system, in which the experience of chronic early-life exposure to the common food cue ethyl butyrate (EB) is stored as instructions for glia to activate an innate immune engulfment response and aggressively phagocytose a critical EB-sensing circuit upon (1) stimulation with high levels of EB later in life or (2) injury to EB sensory neurons. The central hypothesis of this proposal is that early-life experiences are embedded in glia as an innate immune memory that primes them to vigorously respond to subsequent experiences or other stimuli, a potentially long-lasting maladaptive state. Previous studies have demonstrated that astrocytes and microglia can store molecular memories of certain stimuli in the form of epigenetic modifications or sustained activation of innate immune pathways. A preliminary screen identified a little-studied yet highly conserved acetyltransferase, histone acetyltransferase 1 (Hat1), which is dispensible for acute pruning but is required in glia for the embedding of early-life EB exposure. This proposal seeks to (1) define the duration, timing, and intensity of the experience required to induce glial priming, and whether a primed response can be evoked by heterologous stimuli, (2) characterize the functional state of primed glia, including their morphology, activity, and activation of innate immune pathways, and (3) interrogate the role of Hat1 in glial priming by engineering the hat1 locus and knocking down expression of Hat1 complex members. These aims take full advantage of the applicant’s training environment, including a research group with deep expertise in Drosophila innate immunity and glial biology, and are well-integrated with the applicant’s training goals and preparation for a career as a physician and independent investigator. Project Number: 1F30AG097357-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Hans Leier | Institution: CASE WESTERN RESERVE UNIVERSITY, CLEVELAND, OH | Award Amount: $54,538 | Activity Code: F30 | Study Section: Special Emphasis Panel[ZRG1 F03A-E (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11241435