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Although AN is associated with the highest mortality rate among psychiatric disorders, there have been few neuropathological studies on this topic. This study aims to identify alterations of the reward circuitry regions, especially in the nucleus accumbens (NAcc), using AN brain tissues.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The neuronal networks in AN cases and controls were examined by immunohistochemistry directed at tyrosine hydroxylase (TH; dopaminergic neuron marker) and glial fibrillary acidic protein (GFAP; astrocyte marker). We also immunochemically analyzed frozen samples presenting astrogliosis, especially in the NAcc and striatum.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Histologically, neuronal deformation with cytoplasmic shrinkage was seen in reward\u2010related brain regions, such as the orbitofrontal cortex\/anterior cingulate cortex. The NAcc showed massive GFAP\u2010positive astrocytes and dot\u2010like protrusions of astrocytes in the shell compartment. In the shell, TH and GFAP immunoreactivities revealed prominent astrogliosis within striosomes, which receive projection from the ventral tegmental area (VTA). The numbers of GFAP\u2010positive astrocytes in the NAcc (<jats:italic>P\u2009=<\/jats:italic>\u00a00.0079) and VTA (<jats:italic>P\u2009=<\/jats:italic>\u00a00.0025) of AN cases were significantly higher than those of controls. Strongly immunoreactive 18\u2009to\u200925 kDa bands, which might represent degradation products, were detected only in the NAcc of AN cases. Clinically, all cases presented cognitive rigidity, which might reflect a deficit of the reward pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings suggest impaired dopaminergic innervation between the NAcc and VTA in AN. Functional dysconnectivity in the reward\u2010related network might induce neuropsychiatric symptoms associated with AN.<\/jats:p><\/jats:sec>","DOI":"10.1111\/pcn.13340","type":"journal-article","created":{"date-parts":[[2022,2,15]],"date-time":"2022-02-15T14:09:05Z","timestamp":1644934145000},"page":"187-194","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Neuropathological investigation of patients with prolonged anorexia nervosa"],"prefix":"10.1111","volume":"76","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1989-2398","authenticated-orcid":false,"given":"Ito","family":"Kawakami","sequence":"first","affiliation":[{"name":"Dementia Research Project Tokyo Metropolitan Institute of Medical Science  Tokyo Japan"},{"name":"Department of Psychiatry Tokyo Metropolitan Matsuzawa Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4588-4474","authenticated-orcid":false,"given":"Shuji","family":"Iritani","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Nagoya University Graduate School of Medicine  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichi","family":"Riku","sequence":"additional","affiliation":[{"name":"Institute for Medical Science of Aging Aichi Medical University  Nagakute Japan"},{"name":"Department of Neurology Nagoya University  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kentaro","family":"Umeda","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Tokyo Metropolitan Matsuzawa Hospital  Tokyo Japan"},{"name":"Department of Psychiatry Nagoya University Graduate School of Medicine  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mina","family":"Takase","sequence":"additional","affiliation":[{"name":"Dementia Research Project Tokyo Metropolitan Institute of Medical Science  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Dementia Research Project Tokyo Metropolitan Institute of Medical Science  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Niizato","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Tokyo Metropolitan Matsuzawa Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomio","family":"Arai","sequence":"additional","affiliation":[{"name":"Department of Pathology Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Institute for Medical Science of Aging Aichi Medical University  Nagakute Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Oshima","sequence":"additional","affiliation":[{"name":"Department of Psychiatry Tokyo Metropolitan Matsuzawa Hospital  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masato","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Dementia Research Project Tokyo Metropolitan Institute of Medical Science  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,3,7]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.books.9780890425596"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.157.3.393"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cortex.2014.02.020"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.med.050208.200745"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2682"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/erv.2216"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(00)03643-6"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1097\/JCP.0b013e3182970469"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2015.172"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2016.16060671"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2005.05.003"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02916248"},{"key":"e_1_2_11_14_1","first-page":"816","article-title":"Pathology of neurological & psychiatric aspects of various deficiency manifestations with digestive & neuro\u2010endocrine disorders: Study of the changes of the central nervous system in 2 cases of anorexia in young girls (so\u2010called mental anorexia)","volume":"58","author":"Martin F","year":"1958","journal-title":"Acta Neurol. 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