Early-life musical intervention programs neuroimmune activity and synaptic plasticity to enhance adult learning and memory.

Early-life sensory environments can shape lifelong brain function, yet the neuroimmune and neuroplastic mechanisms through which musical stimulation influences cognitive development remain poorly understood. Here, we examined how graded musical brain intervention (MBI) during embryonic and early postnatal periods affects adult cognition and its underlying immune and neural substrates. Pregnant C57BL/6J mice were exposed to a standardized music paradigm starting on embryonic day 13, with groups differing in how long exposure continued into the early postnatal period to test how the developmental extent of auditory stimulation influences adult outcomes. MBI produced robust, exposure-dependent improvements in spatial learning, recognition memory, working memory, and long-term fear memory. Under auditory-control conditions, white noise did not recapitulate the learning and memory benefits observed after MBI, whereas E13-initiated exposure produced stronger effects than D15-onset exposure. Maternal pup retrieval, maternal heart rate, and maternal-offspring HPA-axis indices also varied across exposure conditions. Transcriptomic profiling of the hippocampus (Hip) and nucleus accumbens (NAC) revealed coordinated shifts in endocrine, G protein-coupled receptor (GPCR), serotonin, and autonomic regulatory pathways, indicating broad transcriptional reprogramming. Golgi-Cox analyses demonstrated enhanced dendritic complexity and spine density in a region- and exposure-dependent manner, accompanied by increased expression of DCX and MAP2, suggesting strengthened synaptic remodeling and neuronal maturation. MBI also attenuated astrocytic and microglial reactivity, together with reduced pro-inflammatory cytokine expression, indicating modulation of the neuroimmune state. Together, these findings suggest that early-life structured music exposure is associated with coordinated developmental modulation of neuroimmune activity, synaptic architecture, and gene regulatory networks. These convergent findings provide experimental support for further investigation of music-based interventions in neurodevelopmental and cognitive disorders.