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Emotional and memory deficits also constitute reliable outcome measures to assess efficacy of treatments in the <jats:italic>mdx<\/jats:italic> mouse lacking the muscle and neuronal full\u2010length dystrophins. The present study aimed to evaluate whether these deficits could be alleviated by the restoration of brain dystrophin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We performed intracerebroventricular administration of a new potent tricyclo\u2010DNA antisense oligonucleotide (tcDNA\u2010ASO) containing a full phosphodiester backbone conjugated to a palmitic acid moiety (tcDNA\u2010ASO), designed to skip the mutated exon 23 of <jats:italic>mdx<\/jats:italic> mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We first show that the tcDNA\u2010ASO rescues expression of brain dystrophin to 10\u201330% of wild\u2010type levels and significantly reduces the abnormal unconditioned fear responses in <jats:italic>mdx<\/jats:italic> mice in a dose\u2010dependent manner, 5\u2009weeks post\u2010injection. Exon skipping efficiency, ASO biodistribution, protein restoration and effect on the fear response were optimal with a dose of 400\u2009\u03bcg at 6\u20137\u2009weeks post\u2010injection, with synaptic\u2010like expression in brain tissues such as the hippocampus and amygdala. Furthermore, this dose of tcDNA\u2010ASO restored long\u2010term memory retention of <jats:italic>mdx<\/jats:italic> mice in an object recognition task, but only had minor effects on fear conditioning.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>These results suggest for the first time that postnatal re\u2010expression of brain dystrophin could reverse or at least alleviate some cognitive deficits associated with Duchenne muscular dystrophy. ANN NEUROL 2022;92:213\u2013229<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.26409","type":"journal-article","created":{"date-parts":[[2022,5,19]],"date-time":"2022-05-19T13:39:27Z","timestamp":1652967567000},"page":"213-229","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Partial Restoration of Brain Dystrophin and Behavioral Deficits by Exon Skipping in the Muscular Dystrophy X\u2010Linked (<i>mdx<\/i>) Mouse"],"prefix":"10.1002","volume":"92","author":[{"given":"Faouzi","family":"Zarrouki","sequence":"first","affiliation":[{"name":"UVSQ, Inserm, END\u2010ICAP Universit\u00e9 Paris\u2010Saclay  Versailles France"},{"name":"CNRS, Institut des Neurosciences Paris Saclay Universit\u00e9 Paris\u2010Saclay  Saclay France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karima","family":"Relizani","sequence":"additional","affiliation":[{"name":"UVSQ, Inserm, END\u2010ICAP Universit\u00e9 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