Transgenerational non-genomic transmission of acquired nervous system Phenotypes: Narrative review and epigenetic insights

Transgenerational epigenetic inheritance (TEI) refers to the transmission of phenotypic traits across multiple generations independent of changes in DNA sequence that are mediated by epigenetic mechanisms, including DNA methylation, histone modifications, chromatin morphology, and non-coding RNAs. This review focuses on manuscripts that report epigenetic mechanisms in the transgenerational inheritance of nervous system phenotypes in both mammalian and non-mammalian experimental models. Non-mammalian organisms such as C. elegans and Drosophila have been instrumental in disclosing TEI pathways comprising small RNA networks, histone-based modifications, and N6-methyladenine modifications that balance limited cytosine methylation. Authenticating TEI in mammals is complex due to extensive elimination of epigenetic factors and pathways essential for mitosis that do not participate in meiosis, germline development, and early embryogenesis, termed epigenetic "erasure" or "reprogramming". Specific epigenetic pathways that guide neural development, including DNA methylation at metastable epialleles and gamete-derived small RNAs, escape erasure, and have been linked to altered neurodevelopment and behavior in offspring. Together, these data indicate a role for epigenetic regulation in tuning neural circuits during neurodevelopment with enduring impacts on brain organization and behavior. This perspective situates neural TEI within a mechanistic framework that links early environmental exposures to long-lived neuronal circuit properties and behavioral outcomes. Accordingly, elucidating neural-specific TEI mechanisms alone and in combination will enhance our understanding of how ancestral environmental exposures shape neurological structures, functions, behaviors, and susceptibilities to disease across generations. The present review synthesizes current evidence, identifies key interpretative challenges, and details directions for future research in neural TEI.