{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T02:22:47Z","timestamp":1788056567059,"version":"build-2784847793"},"reference-count":59,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82171531"],"award-info":[{"award-number":["82171531"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82102031"],"award-info":[{"award-number":["82102031"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81671347"],"award-info":[{"award-number":["81671347"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82371558"],"award-info":[{"award-number":["82371558"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Bipolar Disorders"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Accumulative research indicates key roles of the peripheral inflammation system and hippocampal function in major mood disorders. The complement system modulates inflammatory function and is abnormal in mood disorders, but its precise neural pathway remains unclear. This study investigates the interrelations among complement component 3 (C3) levels, hippocampal function, and mood symptoms among offspring of bipolar disorder (BD) parents who carry familial risk of mood disorders.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>\n                      We recruited unaffected BD offspring with (symptomatic offspring, SO,\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u200931) or without (asymptomatic offspring, AO,\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u200939) subthreshold symptoms, and matched healthy controls (HC,\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u200941). Peripheral C3 levels were measured, and resting\u2010state fMRI was conducted to assess hippocampal functional connectivity (FC). Spectral dynamic causal modeling (spDCM) was conducted to verify the directionality of the hippocampal FC.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The SO group exhibited significantly lower peripheral C3 levels (\n                      <jats:italic>F<\/jats:italic>\n                      <jats:sub>2,108<\/jats:sub>\n                      \u2009=\u200923.651,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) and reduced left hippocampus\u2010left cerebellum FC (\n                      <jats:italic>F<\/jats:italic>\n                      <jats:sub>2,108<\/jats:sub>\n                      \u2009=\u20098.541,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) compared to both the AO and HC groups. Furthermore, the left hippocampus\u2010left cerebellum FC partially mediated the relationship between C3 levels and depressive symptoms in the SO group (bootstrapping 95% CI\u2009=\u2009\u22124.1168 to \u22120.1569), but not in AO (bootstrapping 95% CI\u2009=\u2009\u22120.3479 to 0.1317) or HC (bootstrapping 95% CI\u2009=\u2009\u22120.3297 to 0.0885). The left hippocampus\u2010left cerebellum FC was bidirectional in all 3 groups.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings indicate a C3\u2010hippocampus\u2010depressive symptom pathway might underpin the particular high vulnerability of individuals with both familial and symptomatic risks of mood disorders. This evidence provides new neuroinflammatory markers and targets for early identification and intervention of these individuals.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bdi.70056","type":"journal-article","created":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T05:38:38Z","timestamp":1756791518000},"page":"461-471","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Role of the Complement\n                    <scp>C3<\/scp>\n                    \u2010Hippocampus Pathway in Relation With Mood Symptoms in Offspring of Parents With Bipolar Disorder"],"prefix":"10.1111","volume":"27","author":[{"given":"Shiyun","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Affective Disorder The Affiliated Brain Hospital of Guangzhou Medical University  Guangzhou People's Republic of China"},{"name":"Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China Guangzhou Medical University  Guangzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongwan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Affective Disorder The Affiliated Brain Hospital of Guangzhou Medical University  Guangzhou People's Republic of China"},{"name":"Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China Guangzhou Medical University  Guangzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Affective Disorder The Affiliated Brain Hospital of Guangzhou Medical University  Guangzhou People's Republic of China"},{"name":"Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China Guangzhou Medical University  Guangzhou People's Republic of China"},{"name":"Department of Psychology The University of Hong Kong  Hong Kong People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1768-5793","authenticated-orcid":false,"given":"Wenjin","family":"Zou","sequence":"additional","affiliation":[{"name":"Department of Affective Disorder The Affiliated Brain Hospital of Guangzhou Medical University  Guangzhou People's Republic of China"},{"name":"Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China Guangzhou Medical University  Guangzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyue","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Affective Disorder The Affiliated Brain Hospital of Guangzhou Medical University  Guangzhou People's Republic of China"},{"name":"Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China Guangzhou Medical University  Guangzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weicong","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Affective Disorder The Affiliated Brain Hospital of Guangzhou Medical University  Guangzhou People's Republic of China"},{"name":"Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China Guangzhou Medical University  Guangzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyong","family":"Chen","sequence":"additional","affiliation":[{"name":"Lecong Hospital of Shunde  Foshan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suk\u2010Yu","family":"Yau","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Sciences, Faculty of Health and Social Sciences The Hong Kong Polytechnic University  Hong Kong People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangguang","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Affective Disorder The Affiliated Brain Hospital of Guangzhou Medical University  Guangzhou People's Republic of China"},{"name":"Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China Guangzhou Medical University  Guangzhou People's Republic of China"},{"name":"Lecong Hospital of Shunde  Foshan People's Republic of China"},{"name":"School of Health and Life Sciences University of Health and Rehabilitation Sciences  Qingdao People's Republic of 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