This comprehensive literature review synthesizes evidence across eight scientific domains supporting the Neonatal Calibration Thesis: that the human Periaqueductal Gray (PAG)—the brainstem structure governing innate defense cascades—is calibrated during the first six months of postnatal life via maternal signaling through breast milk bioactive components, with disruption creating vulnerability for later attachment disorganization and the Limbic Friction profiles described in the ABM Blueprint framework. The eight domains reviewed are: (1) Neonatal PAG ontogeny and the Maximum Plasticity Substrate; (2) Endocannabinoid signaling in breast milk, centering on 2-AG and CB1 receptor activation; (3) Cortisol in breast milk as predictive coding for the infant stress system; (4) Epigenetic programming via NR3C1 methylation and milk exosomal microRNAs; (5) Formula feeding as signal deprivation within the Lactocrine Hypothesis; (6) Cesarean delivery as deprivation of the first calibration event; (7) Fourth trimester recalibration windows including kangaroo care, oxytocin-PAG modulation, and Meaney’s cross-fostering reversal evidence; and (8) The bidirectional feedback loop establishing the lactating dyad as a closed-loop control system. The strongest evidence exists for: milk cortisol programming of infant temperament (human + primate, replicated), the essential role of 2-AG/CB1 in neonatal suckling (mouse, Fride et al.), NR3C1 epigenetic programming by maternal care (rat with human replication via Conradt et al., 2018), and the massive AVP/catecholamine surge difference between vaginal and cesarean delivery (human, 100–200-fold copeptin difference). Critical translational gaps include the near-complete absence of human data on neonatal PAG-specific development, the untested pharmacokinetics of orally ingested milk endocannabinoids, and the lack of direct studies linking formula feeding to altered PAG function. The evidence base is overwhelmingly preclinical for mechanistic claims, while human data is strongest for associational and correlational endpoints. Evidence strength assessments and species annotations are provided for each domain. This review serves as the comprehensive evidential foundation for Paper 7 (The Neonatal Calibration Thesis) and Paper 0 (The Birth Pulse) of the ABM Blueprint Research Series.
Flemming Bust (Sat,) studied this question.