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To address this, we examined mice with a stroke in the left medial prefrontal cortex (mPFC) resulting in persistent anxiety-like and depression-like behaviors and memory deficits as a model of post-stroke depression. Chronic treatment with FLX (but not exercise) completely reversed the behavioral phenotype and partially reversed changes in FosB-labeled cells in the mPFC, nucleus accumbens, septum, hippocampus, basolateral amygdala (BLA), and dorsal raphe. In these regions, 5-HT or norepinephrine (NE) innervation was quantified by staining for 5-HT or NE transporters, respectively. 5-HT synapses and synaptic triads were identified as synaptophysin-stained sites on 5-HT axons located proximal to gephyrin-stained or PSD95-stained spines. A week after stroke, 5-HT innervation was greatly reduced at the stroke site (left cingulate gyrus (CG) of the mPFC) and the left BLA. Chronically, 5-HT and NE innervation was reduced at the left CG, nucleus accumbens, and BLA, with no changes in other regions. In these areas, pre-synaptic and post-synaptic 5-HT synapses and triads to inhibitory (gephyrin+) sites were reduced, while 5-HT contacts at excitatory (PSD95+) sites were reduced in the CG and prelimbic mPFC. Chronic FLX, but not exercise, reversed these reductions in 5-HT innervation but incompletely restored NE projections. Changes in 5-HT innervation were verified using YFP staining in mice expressing YFP-tagged channelrhodopsin in 5-HT neurons. Thus, FLX-induced 5-HT axonal neuroplasticity of forebrain projections may help mediate recovery from brain injury.<\/jats:p>","DOI":"10.1038\/s41398-020-01008-9","type":"journal-article","created":{"date-parts":[[2020,9,30]],"date-time":"2020-09-30T18:38:00Z","timestamp":1601491080000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Fluoxetine-induced recovery of serotonin and norepinephrine projections in a mouse model of post-stroke depression"],"prefix":"10.1038","volume":"10","author":[{"given":"Amin","family":"Zahrai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faranak","family":"Vahid-Ansari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mireille","family":"Daigle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1809-3554","authenticated-orcid":false,"given":"Paul R.","family":"Albert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,9,30]]},"reference":[{"key":"1008_CR1","doi-asserted-by":"publisher","first-page":"1575","DOI":"10.1016\/S0140-6736(13)61611-6","volume":"382","author":"HA Whiteford","year":"2013","unstructured":"Whiteford, H. 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