Vascular Learning as a Substrate for PTSD Chronicity: A Cerebrovascular Receptor-Site Hypothesis

Version 106a-p (preprint track), April 17, 2026. This is the updated Zenodo preprint incorporating the Pardridge integration, the NVU integration, and two earlier-recommendation additions prepared in April 2026. The full theoretical monograph is retained. A companion submission-version branch (v106a-iii) with §8 triage and Prediction 1b Amendment applied is being prepared separately for peer review at Neuroscience & Biobehavioral Reviews. The hypothesis. This paper proposes that experience-dependent remodeling of the cerebrovascular receptor landscape constitutes a previously unconsidered substrate for the chronicity of posttraumatic stress disorder — what we term vascular learning. The mechanism operates through a broad vasoactive milieu acting on receptors expressed on the blood-facing surfaces of cerebral vessel endothelium and smooth muscle without requiring those molecules to enter the neural parenchyma. The hypothesis rests on a gatekeeper assumption — the Differential Vascular Architecture (DVA) — that amygdala-serving and mPFC-serving cerebrovascular beds differ in baseline receptor composition in ways that produce regionally differentiated responses to the same circulating stress hormones. Given the DVA, three components follow: repeated stress-hormone activation upregulates adrenergic receptor density in amygdala-serving beds while impairing de-escalation responsiveness in mPFC-serving vessels; this remodeling displaces the resting vascular baseline, producing asymmetric hysteresis; and the chronically mPFC-reduced vascular state impairs prefrontal processing during trauma retrieval. Nine testable predictions across three empirical phases specify the framework. A novel therapeutic target class — targeted vasoceptive density modulation (TVDM) — is proposed, and arterial spin labelling perfusion MRI with pharmacological challenge is identified as an immediately feasible biomarker for chronification severity. Nightmares are reframed as a principal engine of chronicity rather than merely a symptom. Changes from v105. Pardridge integration — BBB reframed as a dynamic pharmacological interface (Pardridge 2005, 2012; Banks 2016); new §5.7 subsection on transporter-mediated pharmacokinetics (P-glycoprotein, BCRP, MRPs) and the luminal-concentration problem; new BBB-transporter column added to Table 1 across all 18 vasoactive actors; upgraded Prediction 1 pre-registration (laser-capture microdissection, subtype-selective radioligands, capillary-depletion controls, parallel RNA-seq); upgraded Prediction 1a pre-registration (DCE-MRI / Evans-blue extravasation); new §8.18 opening framing tone and permeability as coupled outputs of the same receptor landscape. NVU integration — new §2.1 astrocyte end-feet paragraph; capillary-pericyte / arteriolar-VSMC terminology clarification; §8.18 TJ-signalling citation extended to ROCK/PKC/MLCK; NVU-structural readouts added to Predictions 1 and 1a (PDGFRβ/CD13, basement membrane, aquaporin-4 end-foot coverage, claudin-5/occludin/ZO-1 immunogold); CSF soluble PDGFRβ added to Prediction 6. Earlier recommendations — new "Consumer chemistry as therapeutic confound" paragraph in §8.33; new "Computational modeling as a fourth empirical pillar" paragraph in §6 preamble; TVDM iatrogenic overshoot risk added to §5.7. Nine new references added: Pardridge (2005, 2012); Karssen et al. (2001); Hardebo & Owman (1980); Abbott et al. (2010); Armulik, Genové, & Betsholtz (2011); Hawkins & Davis (2005); Wolburg et al. (2009); Nation et al. (2019). Keywords: PTSD, chronicity, cerebrovascular, adrenergic receptors, vascular learning, receptor density flexibility, reconsolidation, asymmetric hysteresis, arterial spin labelling, TVDM, therapeutic alliance, MDMA, differential vascular architecture, blood-brain barrier, neurovascular unit, pericytes, tight junctions. About 560 words. Zenodo's description field accepts HTML, so the bold and italic markers should render if you paste with formatting preserved; if Zenodo's editor strips them, you can reapply bold/italic in-editor with minimal fuss. Other metadata fields Zenodo's "New version" flow will auto-populate from v105 — just verify them: Title — keep unchanged; the record title represents the work, not the version. Creators — Keim, Tabaac, Keim (A.). Same as v105. Publication date — April 17, 2026. Resource type — Preprint. Keywords — expand with the additional terms in the description (blood-brain barrier, neurovascular unit, pericytes, tight junctions) if v105's keyword list didn't include them. Related identifiers — Zenodo handles this automatically via the Concept DOI linkage; no manual entry needed.