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Allopregnanolone is reduced in subsets of individuals with PTSD and has been explored as a novel treatment strategy. Both direct trauma exposure and witnessed trauma are risk factors for PTSD; however, the role of neurosteroids in the behavioral outcomes of these unique experiences has not been explored. Here, we investigate whether observational fear is associated with a reduced capacity for endogenous neurosteroidogenesis and the relationship with behavioral outcomes. We demonstrated that mice directly subjected to a threat (foot shocks) and those witnessing the threat have decreased plasma levels of allopregnanolone. The expression of a key enzyme involved in endogenous neurosteroid synthesis, 5\u03b1\u2010reductase type 2, is decreased in the basolateral amygdala, which is a major emotional processing hub implicated in PTSD. We demonstrated that genetic knockdown or pharmacological inhibition of 5\u03b1\u2010reductase type 2 exaggerates the behavioral expression of fear in response to witnessed trauma, whereas oral treatment with an exogenous, synthetic neuroactive steroid gamma\u2010aminobutyric acid\u2010A receptor positive allosteric modulator with molecular pharmacology similar to allopregnanolone (SGE\u2010516 [tool compound]) decreased the behavioral response to observational fear. These data implicate impaired endogenous neurosteroidogenesis in the pathophysiology of threat exposure, both direct and witnessed. Further, these data suggest that treatment with exogenous 5\u03b1\u2010reduced neurosteroids or targeting endogenous neurosteroidogenesis may be beneficial for the treatment of individuals with PTSD, whether resulting from direct or witnessed trauma.<\/jats:p>","DOI":"10.1111\/jne.13378","type":"journal-article","created":{"date-parts":[[2024,3,14]],"date-time":"2024-03-14T05:34:09Z","timestamp":1710394449000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Witnessed trauma exposure induces fear in mice through a reduction in endogenous neurosteroid synthesis"],"prefix":"10.1111","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6887-1920","authenticated-orcid":false,"given":"Aidan","family":"Evans\u2010Strong","sequence":"first","affiliation":[{"name":"Neuroscience Department Tufts University School of Medicine  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Najah","family":"Walton","sequence":"additional","affiliation":[{"name":"Neuroscience Department Tufts University School of Medicine  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrina","family":"Blandino","sequence":"additional","affiliation":[{"name":"Neuroscience Department Tufts University School of Medicine  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail T. 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