Project Summary The gut microbiota, a community of symbiotic bacteria, fungi, and archaea residing in the mammalian gastrointestinal tract, plays an integral role in the neurodevelopment and neurophysiology of the host. Its disruption has been associated with neurodevelopmental and neurodegenerative diseases. Microglia are the resident immune cells in the central nervous system; they are continually influenced by gut microbiota, raising the possibility that microglia dysfunction may be the link between dysbiosis and altered brain functions. This proposal investigates how early-life exposure to penicillin, the most-used antibiotics in perinatal medicine, affects the interplay between gut microbiota, the immune system, cortical development, and sensory processing in mice, and explores the potential of probiotics as a preventative measure. Aim 1 studies how perinatal penicillin exposure (PPE)-induced gut dysbiosis affects cortical microglia and sensory processing in adolescent and adult mice. It also explores whether early postnatal normalization of gut microbiota prevents microglia activation and behavioral defects later in life. Aim 2 studies how PPE alters microglia motility, their synaptic contact, synapse pruning, and cortical neuronal activities associated with the defective sensory processing. This study will advance our understanding of the gut-immune-brain axis in neural development, circuit function, and behavior, with significant relevance to clinical medicine and public health.