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However, these previous studies assessed gene expression in all neurons regardless of their activity state during heroin seeking. Using Fos as a marker of neural activity, we describe distinct molecular alterations induced in activated versus non\u2010activated neurons during cue\u2010induced heroin seeking after prolonged withdrawal. We trained rats to self\u2010administer heroin for 10\u00a0days (6\u00a0h\/day) and assessed cue\u2010induced heroin seeking in extinction tests after 14 or 30\u00a0days. We used fluorescent\u2010activated cell sorting (<jats:styled-content style=\"fixed-case\">FACS<\/jats:styled-content>) to purify Fos\u2010positive and Fos\u2010negative neurons from PFC 90\u00a0min after extinction testing. Flow cytometry showed that Fos\u2010immunoreactivity was increased in less than 10% of sparsely distributed <jats:styled-content style=\"fixed-case\">PFC<\/jats:styled-content> neurons. <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content> levels of the immediate early genes <jats:italic>fosB<\/jats:italic>,<jats:italic> arc<\/jats:italic>,<jats:italic> egr1<\/jats:italic>, and <jats:italic>egr2<\/jats:italic>, as well as <jats:italic>npy<\/jats:italic> and <jats:italic>map2k6<\/jats:italic>, were increased in Fos\u2010positive, but not Fos\u2010negative, neurons. In support of these findings, double\u2010label immunohistochemistry indicated substantial coexpression of neuropeptide Y (<jats:styled-content style=\"fixed-case\">NPY<\/jats:styled-content>)\u2010 and Arc\u2010immunoreactivity in Fos\u2010positive neurons. Our data indicate that cue\u2010induced relapse to heroin seeking after prolonged withdrawal induces unique molecular alterations within activated <jats:styled-content style=\"fixed-case\">PFC<\/jats:styled-content> neurons that are distinct from those observed in the surrounding majority of non\u2010activated neurons.<\/jats:p>","DOI":"10.1111\/jnc.12074","type":"journal-article","created":{"date-parts":[[2012,10,31]],"date-time":"2012-10-31T23:31:36Z","timestamp":1351726296000},"page":"100-108","source":"Crossref","is-referenced-by-count":41,"title":["Unique gene alterations are induced in <scp>FACS<\/scp>\u2010purified Fos\u2010positive neurons activated during cue\u2010induced relapse to heroin seeking"],"prefix":"10.1111","volume":"124","author":[{"given":"Sanya","family":"Fanous","sequence":"first","affiliation":[{"name":"Behavioral Neuroscience Branch IRP\/NIDA\/NIH\/DHHS Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle H.","family":"Guez\u2010Barber","sequence":"additional","affiliation":[{"name":"Behavioral Neuroscience Branch IRP\/NIDA\/NIH\/DHHS Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan M.","family":"Goldart","sequence":"additional","affiliation":[{"name":"Behavioral Neuroscience Branch IRP\/NIDA\/NIH\/DHHS Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regina","family":"Schrama","sequence":"additional","affiliation":[{"name":"Behavioral Neuroscience Branch IRP\/NIDA\/NIH\/DHHS Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence R. 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