Early-life experience can modulate risk versus resilience to emotional and cognitive disorders in adulthood. This suggests that there is a particularly sensitive period early in life, during which beneficial or adverse events can cause a later propensity toward stress resilience or vulnerability, respectively. Most early-life experiences are generated from signals received from the primary caregiver, and perturbations in these signals can program stress-related behaviors throughout life. These maternal signals cause lasting changes in brain circuitry and function, including networks associated with learning and memory, and with emotional and stress responses. Underlying these changes in brain circuits are transcriptional and epigenetic mechanisms. These molecular changes are instigated by early-life experiences and set in motion a signaling cascade that can determine resilience or vulnerabilities in adulthood.

Resilience to stress-related emotional disorders is governed in part by early-life experiences. Here we demonstrate experience-dependent re-programming of stress-sensitive hypothalamic neurons, which takes place through modification of neuronal gene expression via epigenetic mechanisms. Specifically, we found that augmented maternal care reduced glutamatergic synapses onto stress-sensitive hypothalamic neurons and repressed expression of the stress-responsive gene, Crh. In hypothalamus in vitro, reduced glutamatergic neurotransmission recapitulated the repressive effects of augmented maternal care on Crh, and this required recruitment of the transcriptional repressor repressor element-1 silencing transcription factor/neuron restrictive silencing factor (NRSF). Increased NRSF binding to chromatin was accompanied by sequential repressive epigenetic changes which outlasted NRSF binding. chromatin immunoprecipitation-seq analyses of NRSF targets identified gene networks that, in addition to Crh, likely contributed to the augmented care-induced phenotype, including diminished depression-like and anxiety-like behaviors. Together, we believe these findings provide the first causal link between enriched neonatal experience, synaptic refinement and induction of epigenetic processes within specific neurons. They uncover a novel mechanistic pathway from neonatal environment to emotional resilience.