{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T20:55:45Z","timestamp":1792270545024,"version":"4.4.0"},"reference-count":108,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:00:00Z","timestamp":1784332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004702","name":"University of Genova","doi-asserted-by":"publisher","award":["FRA 2024"],"award-info":[{"award-number":["FRA 2024"]}],"id":[{"id":"10.13039\/501100004702","id-type":"DOI","asserted-by":"publisher"}]},{"award":["FRA 2024"],"award-info":[{"award-number":["FRA 2024"]}],"id":[{"id":"https:\/\/ror.org\/0107c5v14","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Post-traumatic stress disorder (PTSD) is a severe condition triggered by traumatic exposure, characterized by symptoms like trauma re-experiencing, avoidance, mood alterations, hypervigilance, and sleep disturbances. While its exact mechanisms remain uncertain, PTSD involves dysregulation across neurobiological systems underlying fear conditioning, threat appraisal, executive control, and stress response. Although research highlights the sympathetic\u2013adreno\u2013medullary (SAM) system and the hypothalamic\u2013pituitary\u2013adrenal (HPA) axis, findings on stress-related mediators remain inconsistent regarding their precise contributions over time. To address this, we propose a hypothetical model viewing PTSD as a multistable system shifting from physiological to pathological steady states. We assume that intense, repeated emotional stress triggers spike activation in the amygdala, driving an amygdala\u2013locus coeruleus loop into a high-activation state via reciprocal excitation, mediated by corticotropin-releasing hormone (CRH) and noradrenaline. This sequentially alters amygdala\u2013hippocampus and prefrontal cortex loops, reinforcing fear expression and impairing extinction. This model is consistent with key features of PTSD, including its higher prevalence among females, increased glucocorticoid receptor sensitivity, the frequently observed hypocortisolism, and the partial efficacy of serotonin and norepinephrine reuptake inhibitor (SNRI) and CRH receptor antagonists. While requiring experimental validation, this framework connects molecular, circuit, and behavioral data to help identify novel interventions for restoring adaptive stress-response dynamics.<\/jats:p>","DOI":"10.3390\/ijms27146384","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T09:32:54Z","timestamp":1784539974000},"page":"6384","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hypothesis on PTSD Pathophysiology: Role of CRH, Noradrenaline, and Glucocorticoid Receptors in an Amygdala-Centered Closed-Loop System"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6894-8223","authenticated-orcid":false,"given":"Ilaria","family":"Demori","sequence":"first","affiliation":[{"name":"Department of Pharmacy, DIFAR, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7545-0311","authenticated-orcid":false,"given":"Bruno","family":"Burlando","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, DIFAR, University of Genova, Viale Benedetto XV, 3, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.amjmed.2005.09.027","article-title":"Posttraumatic stress disorder: Clinical features, pathophysiology, and treatment","volume":"119","author":"Vieweg","year":"2006","journal-title":"Am. 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