Transgenerational Inheritance of complex learning abilities in the mammalian brain

Whether complex cognitive abilities can be inherited through non-genetic mechanisms in mammals remains unclear. Here, we show that training rodents in a demanding rule-learning task produces an enhancement of learning ability in offspring: naïve offspring across three generations (F1–F3) learned diverse abstract discrimination tasks faster than controls. This effect persisted after cross-fostering and in vitro fertilization, supporting a germline-mediated transmission. Offspring also displayed increased hippocampal pyramidal-neuron excitability caused by reduced M-current–dependent post-burst after-hyperpolarization, resembling trained parents. Pharmacological manipulation confirmed a causal link between reduced M-current activity and accelerated learning. Hippocampal methylome analysis of trained parents identified learning-associated differential methylation enriched for synaptic and M-current/PKC regulatory pathways. Sperm methylome profiling revealed enrichment at regulatory RNA loci predicted to influence the M-current pathway, suggesting a candidate germline mechanism. Together, these findings demonstrate that enhanced learning capacity and associated neuronal excitability in offspring can be driven by transgenerational epigenetic inheritance.