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Adjunctive therapy is most typically used with medications that influence serotonin balance, such as selective serotonin reuptake inhibitors (SSRIs). Contrary to expectations, SSRIs show an anxiety-increasing effect during the initial treatment phase. Among the 14 different serotonin receptor subtypes, pharmacological studies have demonstrated that 5-HT2C receptors (5-HT2CRs) in the bed nucleus of the stria terminalis (BNST) play a significant role in the anxiogenic effect of acute SSRI treatment. Although numerous studies have confirmed the role of the 5-HT2CR in anxiety behavior, little is known about its involvement in learned fear and fear extinction. In particular, fear extinction is considered a central neural mechanism in the treatment of PTSD patients. Recent results from 5-HT2CR knockout mice (2CKO) revealed that global loss of 5-HT2CRs enhances fear extinction, without affecting fear acquisition. Here, we implemented a chemogenetic approach to examine the neuronal substrate which underlies this extinction-enhancing effect in 2CKO mice. DREADD-activation of BNST\n                    <jats:sup>CRF<\/jats:sup>\n                    neurons promotes fear extinction in 5-HT2CR WT mice, whereas DREADD-inactivation of BNST\n                    <jats:sup>CRF<\/jats:sup>\n                    neurons impairs fear extinction in 2CKO mice. Thus, using activating and inactivating DREADDs, we were able to bidirectionally modulate fear extinction. These findings provide a possible explanation for the fear extinction-enhancing effect in 2CKO mice with relevance for the treatment of PTSD patients.\n                  <\/jats:p>","DOI":"10.1038\/s41398-025-03799-1","type":"journal-article","created":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T18:43:42Z","timestamp":1768070622000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Chemogenetic modulation of CRF neurons in the BNST compensates for phenotypic behavioral differences in fear extinction learning of 5-HT2C receptor mutant mice"],"prefix":"10.1038","volume":"16","author":[{"given":"Hannah","family":"Schulte","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2839-3630","authenticated-orcid":false,"given":"Hanna","family":"B\u00f6ke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"L\u00f6ssl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Worm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida","family":"Siveke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Herlitze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4132-0655","authenticated-orcid":false,"given":"Katharina","family":"Spoida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,10]]},"reference":[{"key":"3799_CR1","doi-asserted-by":"publisher","first-page":"231","DOI":"10.31887\/DCNS.2002.4.3\/tsteimer","volume":"4","author":"T Steimer","year":"2002","unstructured":"Steimer T. 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