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A number of studies have demonstrated functionality of DA neurons originating from hESCs when grafted to the striatum of rodent and non\u2010human primate models of PD. However, several questions remain in regard to their axonal outgrowth potential and capacity to integrate into host circuitry. Here, ventral midbrain (VM) patterned hESC\u2010derived progenitors were grafted into the midbrain of 6\u2010hydroxydopamine\u2010lesioned rats, and analyzed at 6, 18, and 24\u2009weeks for a time\u2010course evaluation of specificity and extent of graft\u2010derived fiber outgrowth as well as potential for functional recovery. To investigate synaptic integration of the transplanted cells, we used rabies\u2010based monosynaptic tracing to reveal the origin and extent of host presynaptic inputs to grafts at 6 weeks. The results reveal the capacity of grafted neurons to extend axonal projections toward appropriate forebrain target structures progressively over 24\u2009weeks. The timing and extent of graft\u2010derived dopaminergic fibers innervating the dorsolateral striatum matched reduction in amphetamine\u2010induced rotational asymmetry in the animals where recovery could be observed. Monosynaptic tracing demonstrated that grafted cells integrate with host circuitry 6 weeks after transplantation, in a manner that is comparable with endogenous midbrain connectivity. Thus, we demonstrate that VM patterned hESC\u2010derived progenitors grafted to midbrain have the capacity to extensively innervate appropriate forebrain targets, integrate into the host circuitry and that functional recovery can be achieved when grafting fetal or hESC\u2010derived DA neurons to the midbrain.<\/jats:p>","DOI":"10.1002\/cne.24500","type":"journal-article","created":{"date-parts":[[2018,7,14]],"date-time":"2018-07-14T14:35:44Z","timestamp":1531578944000},"page":"2133-2146","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":69,"title":["Target\u2010specific forebrain projections and appropriate synaptic inputs of hESC\u2010derived dopamine neurons grafted to the midbrain of parkinsonian rats"],"prefix":"10.1002","volume":"526","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2686-458X","authenticated-orcid":false,"given":"Tiago","family":"Cardoso","sequence":"first","affiliation":[{"name":"Developmental and Regenerative Neurobiology, Department of Experimental Medical Science Lund University  Lund Sweden"},{"name":"Lund Stem Cell Center Lund University  Lund Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew F.","family":"Adler","sequence":"additional","affiliation":[{"name":"Developmental and Regenerative Neurobiology, Department of Experimental Medical Science Lund University  Lund Sweden"},{"name":"Lund Stem Cell Center Lund University  Lund Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bengt","family":"Mattsson","sequence":"additional","affiliation":[{"name":"Developmental and Regenerative Neurobiology, Department of Experimental Medical Science Lund University  Lund Sweden"},{"name":"Lund Stem Cell Center Lund University  Lund Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deirdre B.","family":"Hoban","sequence":"additional","affiliation":[{"name":"Developmental and Regenerative Neurobiology, Department of Experimental Medical Science Lund University  Lund Sweden"},{"name":"Lund Stem Cell Center Lund University  Lund Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Nolbrant","sequence":"additional","affiliation":[{"name":"Developmental and Regenerative Neurobiology, Department of Experimental Medical Science Lund University  Lund Sweden"},{"name":"Lund Stem Cell Center Lund University  Lund Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny Nelander","family":"Wahlestedt","sequence":"additional","affiliation":[{"name":"Developmental and Regenerative Neurobiology, Department of Experimental Medical Science Lund University  Lund Sweden"},{"name":"Lund Stem Cell Center Lund University  Lund Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnete","family":"Kirkeby","sequence":"additional","affiliation":[{"name":"Developmental and Regenerative Neurobiology, Department of Experimental Medical Science Lund University  Lund Sweden"},{"name":"Danish Stem Cell Center (DanStem) University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shane","family":"Grealish","sequence":"additional","affiliation":[{"name":"Developmental and Regenerative Neurobiology, Department of Experimental Medical Science Lund University  Lund Sweden"},{"name":"Lund Stem Cell Center Lund University  Lund Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders","family":"Bj\u00f6rklund","sequence":"additional","affiliation":[{"name":"Developmental and Regenerative Neurobiology, Department of Experimental Medical Science Lund University  Lund Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malin","family":"Parmar","sequence":"additional","affiliation":[{"name":"Developmental and Regenerative Neurobiology, Department of Experimental Medical Science Lund University  Lund Sweden"},{"name":"Lund Stem Cell Center Lund University  Lund Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,7,31]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/510195a"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1177\/40.10.1527370"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2015.123"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2017.09.014"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.07.015"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(80)90692-7"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00243848"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2016.03.014"},{"key":"e_1_2_6_10_1","first-page":"29","article-title":"Intracerebral grafting of neuronal cell suspensions. 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