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Interleaving a behaviorally noncontingent neutral cue (CS\u2212) with a threat-predictive, behaviorally contingent cue (CS+) enhanced long-term memory without altering acquisition, demonstrating that differential contingency structure selectively reinforces memory consolidation rather than influencing learning performance. Naive mice of either sex inferred contingencies within a single session, and discrimination achieved during training predicted retrieval precision. However, discrimination operated within defined boundary conditions: Extended training or elevated threat intensity destabilized cue specificity and promoted persistent avoidance generalization. Under high-threat conditions, freezing and shuttling coemerged as complementary defensive responses, indicating a shift from precise cue-based encoding to a generalized defensive state. Remote retrieval recruited oxytocin receptor-expressing cells in the medial prefrontal cortex and activated mTORC1-dependent translational signaling, implicating protein synthesis in maintenance of discriminative avoidance memory. In a tuberous sclerosis complex mouse model with Tsc2 haploinsufficiency in oxytocin-responsive cells, males displayed intact acquisition but generalized avoidance at both recent and remote time points, a deficit not rescued by additional training. These findings identify oxytocin-modulated translational control as a molecular gate stabilizing threat-safety discrimination and show that disruption of this axis\u2014by excessive threat or reduced Tsc2 gene dosage\u2014biases memory toward pathological generalization, providing a mechanistic framework for safety-learning deficits in neurodevelopmental and anxiety-related disorders.<\/jats:p>","DOI":"10.1523\/eneuro.0123-26.2026","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T17:51:01Z","timestamp":1787593861000},"page":"ENEURO.0123-26.2026","update-policy":"https:\/\/doi.org\/10.1523\/eneuro.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Safety Signals Enable Single-Session Active Avoidance Paradigm and Expose Threat Generalization in Tuberous Sclerosis Complex"],"prefix":"10.1523","volume":"13","author":[{"given":"Andrew","family":"Gallagher","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber Victoria","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saheed","family":"Lawal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harshil","family":"Sanghvi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javed","family":"Iqbal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8260-0629","authenticated-orcid":false,"given":"Matthew","family":"Dickinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2989-0408","authenticated-orcid":false,"given":"Brandon","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0933-1837","authenticated-orcid":false,"given":"Daniel Adolfo","family":"Llano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4677-0225","authenticated-orcid":false,"given":"Prerana","family":"Shrestha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2026,8,24]]},"reference":[{"key":"2026090810550993000_13.9.ENEURO.0123-26.2026.1","doi-asserted-by":"crossref","unstructured":"Ali AA , Walker TL , Blackmore DG (2024) The active place avoidance (APA) test, an effective, versatile and repeatable spatial learning task for mice. 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