{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T20:15:13Z","timestamp":1785788113409,"version":"3.56.0"},"reference-count":29,"publisher":"Cold Spring Harbor Laboratory","issue":"6-7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Learn. Mem."],"accepted":{"date-parts":[[2026,7,15]]},"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:p>\n                    Fragile X syndrome (FXS) is a leading inherited cause of intellectual disability. FXS is caused by a trinucleotide repeat expansion in the\n                    <jats:italic>fragile X messenger ribonucleoprotein 1<\/jats:italic>\n                    (\n                    <jats:italic>fmr1<\/jats:italic>\n                    ) gene, which results in transcriptional silencing, and loss of its protein product, FMRP. One symptom of FXS is cognitive inflexibility, but there is no generally accepted way to test this in rodents. Tests of reversal learning or extinction paradigms have been used as measures of cognitive flexibility, but these are indirect, require substantial training and experimenter effort, and often yield inconsistent results. This study tests male and female\n                    <jats:italic>Fmr1<\/jats:italic>\n                    knockout (KO) and wild-type (WT) mice in a \u201cpuzzle box\u201d specifically designed to assess cognitive flexibility. The Puzzle Box is a two-chambered apparatus with a brightly illuminated area and an enclosed goal area. Novel obstacles block the underpass to the goal area, requiring that mice adopt new strategies. Results reveal that female, but not male,\n                    <jats:italic>Fmr1<\/jats:italic>\n                    KO mice exhibit impaired performance compared to WT controls. Analysis of behavioral measures during novel obstacle presentation revealed a behavioral phenotype consistent with increased anxiety-like and hyperactivity behaviors, as well as altered engagement with novel obstacle conditions, in female\n                    <jats:italic>Fmr1<\/jats:italic>\n                    KO mice compared to WT controls. Overall, the Puzzle Box test shows promise as a rapid screening test for cognitive flexibility impairments in FXS or other rodent models of neurological disorders.\n                  <\/jats:p>","DOI":"10.1101\/lm.054216.126","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T19:20:13Z","timestamp":1785784813000},"page":"a054216","source":"Crossref","is-referenced-by-count":0,"title":["Assessment of sex-dependent cognitive flexibility in a mouse model of fragile X syndrome"],"prefix":"10.1101","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8733-7447","authenticated-orcid":false,"given":"Patricia S.","family":"Pirbhoy","sequence":"first","affiliation":[{"name":"Reeve-Irvine Research Center, University of California, Irvine, School of Medicine, Irvine, California 92697, USA"},{"name":"Department of Anatomy and Neurobiology, University of California, Irvine, School of Medicine, Irvine, California 92697, USA"},{"name":"Department of Neurobiology and Behavior, University of California Irvine, Irvine, California 92697, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7069-8756","authenticated-orcid":false,"given":"Oswald","family":"Steward","sequence":"additional","affiliation":[{"name":"Reeve-Irvine Research Center, University of California, Irvine, School of Medicine, Irvine, California 92697, USA"},{"name":"Department of Anatomy and Neurobiology, University of California, Irvine, School of Medicine, Irvine, California 92697, USA"},{"name":"Department of Neurobiology and Behavior, University of California Irvine, Irvine, California 92697, USA"},{"name":"Department of Neurosurgery, University of California Irvine, School of Medicine, Irvine, California 92697, 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