We introduce the Rosa-Margin Hypothesis (RMH): when the excitability buffer in ventral CA1 (ΔVmargin) narrows below ≈ 5 mV, ordinary network transients begin to trigger involuntary replay of emotional engrams. A meta-analysis of chronic-restraint-stress recordings shows that four convergent processes— KCC2 down-regulation, NKCC1 up-regulation, loss of GIRK/TASK leak currents and reduced Na⁺/K⁺-ATPase α1—depolarise vCA1 by 11.3 ± 1.4 mV. Risk alleles such as CACNA1C rs1006737 A and common psychoactive agents further prolong EPSPs or lower rheobase, while four forced recalls add a transient +3.2 mV to ≈ 5 % of CREB-high neurons. In a realistic CRS + hot-spot + CACNA1C rs1006737 A scenario the safety margin shrinks to 5.7 mV; a gain-of-function SCN2A variant leaves only 2.7 mV, so theta and ripple events routinely cross threshold. Once this critical buffer is breached, the content (valence) of the spontaneously re-activated hot-spot steers the ensuing neuromodulatory cascade: fear-laden engrams drive a dopaminecortisol loop that reproduces the circuit signature of schizophrenia, sadness-laden engrams recruit a CRF-dominated loop converging on major depression, whereas trauma-laden engrams engage a noradrenaline burst that evolves towards the PTSD phenotype. We further hypothesise that 7–30 Hz extremely-low-frequency magnetic fields, transduced by brain magnetite, phase-lock the theta generator and double co-activation probability in urban settings (relative risk ≈ 2.4). A prospective environment-to-clinical beta loop (β-loop) study will test this ELF–magnetite coupling. RMH predicts that long-term remission requires widening ΔVmargin to ≥ 7 mV. We therefore outline Four-Axis Reset (FAR): concurrent hyperpolarisation of Vrest, chloride reset, restoration of PV/KCC2 with ROS reduction, and narrowing of the γ/θ integration window. A pilot randomised trial (n = 30) will examine whether FAR raises PET-KCC2 binding ≥ 15 %, suppresses γ-band bursts ≥ 35 % and increases HRV rMSSD ≥ 5 ms. Meeting ≥ 2 of these criteria would constitute the first in-vivo validation of RMH.
Pedro G. P. Rosa (Fri,) studied this question.