{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:41:08Z","timestamp":1785436868253,"version":"3.56.0"},"posted":{"date-parts":[[2026,3,3]]},"group-title":"Animal Behavior and Cognition","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"award":["R01MH132795"],"award-info":[{"award-number":["R01MH132795"]}],"id":[{"id":"https:\/\/ror.org\/04xeg9z08","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01DC013073"],"award-info":[{"award-number":["R01DC013073"]}],"id":[{"id":"https:\/\/ror.org\/04mhx6838","id-type":"ROR","asserted-by":"publisher"}]},{"award":["FG-2022-94485"],"award-info":[{"award-number":["FG-2022-94485"]}],"id":[{"id":"https:\/\/ror.org\/052csg198","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Animals must flexibly discriminate between threat and non-threat to deploy adaptive defensive strategies. We introduce a single-episode differential signaled active avoidance (DSAA) paradigm that temporally dissociates acquisition, consolidation, and retrieval of instrumental avoidance memory. Interleaving a behaviorally noncontingent neutral cue (CS-) 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. Na\u00efve animals inferred contingencies within a single episode, and discrimination achieved during training predicted retrieval precision. However, discrimination operated within defined boundary conditions: overtraining or elevated threat intensity destabilized cue specificity and promoted persistent avoidance generalization. Under high-threat conditions, freezing and shuttling co-emerged 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 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 - by excessive threat or reduced Tsc2 gene dosage - biases memory toward pathological generalization, providing a mechanistic framework for safety-learning deficits in neurodevelopmental and anxiety-related disorders.<\/jats:p>","DOI":"10.64898\/2026.02.28.708704","type":"posted-content","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T17:10:12Z","timestamp":1772557812000},"source":"Crossref","is-referenced-by-count":0,"title":["Safety Signals Enable Single-Episode Active Avoidance paradigm and Expose Threat Generalization in Tuberous Sclerosis Complex"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-1006-0352","authenticated-orcid":false,"given":"Andrew Vincent","family":"Gallagher","sequence":"first","affiliation":[{"name":"Graduate Program in Neuroscience, Stony Brook University, Stony 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