{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T05:30:40Z","timestamp":1790227840931,"version":"4.1.0"},"reference-count":64,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,8,7]],"date-time":"2018-08-07T00:00:00Z","timestamp":1533600000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,8,7]],"date-time":"2018-08-07T00:00:00Z","timestamp":1533600000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Abnormal hippocampal neural plasticity has been implicated in behavioural abnormalities and complex neuropsychiatric conditions, including bipolar disorder (BD). However, the determinants of this neural alteration remain unknown. This work tests the hypothesis that the neurotransmitter serotonin (5-HT) is a key determinant of hippocampal neuroplasticity, and its absence leads to maladaptive behaviour relevant for BD. Depletion of brain 5-HT in\n                    <jats:italic>Tph2<\/jats:italic>\n                    mutant mice resulted in reduced behavioural despair, reduced anxiety, marked aggression and lower habituation in novel environments, reminiscent of bipolar-associated manic behaviour. Treatment with valproate produced a substantial improvement of the mania-like behavioural phenotypes displayed by\n                    <jats:italic>Tph2<\/jats:italic>\n                    mutants. Brain-wide fMRI mapping in mutants revealed functional hippocampal hyperactivity in which we also observed dramatically increased neuroplasticity. Importantly, remarkable correspondence between the transcriptomic profile of the\n                    <jats:italic>Tph2<\/jats:italic>\n                    mutant hippocampus and neurons from bipolar disorder patients was observed. Chronic stress reversed the emotional phenotype and the hippocampal transcriptional landscape of\n                    <jats:italic>Tph2<\/jats:italic>\n                    mutants. These changes were associated with inappropriate activation of transcriptional adaptive response to stress as assessed by gene set enrichment analyses in the hippocampus of\n                    <jats:italic>Tph2<\/jats:italic>\n                    mutant mice. These findings delineate 5-HT as a critical determinant in BD associated maladaptive emotional responses and aberrant hippocampal neuroplasticity, and support the use of\n                    <jats:italic>Tph2<\/jats:italic>\n                    \u2212\/\u2212 mice as a new research tool for mechanistic and therapeutic research in bipolar disorder.\n                  <\/jats:p>","DOI":"10.1038\/s41598-018-30291-2","type":"journal-article","created":{"date-parts":[[2018,8,1]],"date-time":"2018-08-01T10:47:13Z","timestamp":1533120433000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Serotonin depletion causes valproate-responsive manic-like condition and increased hippocampal neuroplasticity that are reversed by stress"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0485-8544","authenticated-orcid":false,"given":"Giacomo","family":"Maddaloni","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Migliarini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Napolitano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Giorgi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Nazzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Biasci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"De Felice","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Gritti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Cavaccini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Galbusera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Franceschi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Lessi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco La","family":"Ferla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Aretini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara Maria","family":"Mazzanti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaella","family":"Tonini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Gozzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Usiello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0844-8139","authenticated-orcid":false,"given":"Massimo","family":"Pasqualetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,8,7]]},"reference":[{"key":"30291_CR1","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1038\/nrn849","volume":"3","author":"JJ Kim","year":"2002","unstructured":"Kim, J. J. & Diamond, D. M. The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci 3, 453\u2013462 (2002).","journal-title":"Nat Rev Neurosci"},{"key":"30291_CR2","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1038\/sj.npp.1301574","volume":"33","author":"C Pittenger","year":"2008","unstructured":"Pittenger, C. & Duman, R. S. Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 33, 88\u2013109 (2008).","journal-title":"Neuropsychopharmacology"},{"key":"30291_CR3","doi-asserted-by":"publisher","first-page":"1353","DOI":"10.1038\/nn.4086","volume":"18","author":"BS McEwen","year":"2015","unstructured":"McEwen, B. S. et al. Mechanisms of stress in the brain. Nat Neurosci 18, 1353\u20131363 (2015).","journal-title":"Nat Neurosci"},{"key":"30291_CR4","doi-asserted-by":"publisher","first-page":"1171","DOI":"10.1038\/mp.2013.175","volume":"19","author":"JD Gray","year":"2014","unstructured":"Gray, J. D., Rubin, T. G., Hunter, R. G. & McEwen, B. S. Hippocampal gene expression changes underlying stress sensitization and recovery. Mol Psychiatry 19, 1171\u20131178.10 (2014).","journal-title":"Mol Psychiatry"},{"key":"30291_CR5","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1002\/hipo.20744","volume":"21","author":"AM Magarinos","year":"2011","unstructured":"Magarinos, A. M. et al. Effect of brain-derived neurotrophic factor haploinsufficiency on stress-induced remodeling of hippocampal neurons. Hippocampus 21, 253\u2013264 (2011).","journal-title":"Hippocampus"},{"key":"30291_CR6","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/nrn2639","volume":"10","author":"SJ Lupien","year":"2009","unstructured":"Lupien, S. J., McEwen, B. S., Gunnar, M. R. & Heim, C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 10, 434\u2013445 (2009).","journal-title":"Nat Rev Neurosci"},{"key":"30291_CR7","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1124\/pr.111.005108","volume":"64","author":"AE Autry","year":"2012","unstructured":"Autry, A. E. & Monteggia, L. M. Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 64, 238\u2013258 (2012).","journal-title":"Pharmacol Rev"},{"key":"30291_CR8","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1038\/nature10287","volume":"476","author":"JS Snyder","year":"2011","unstructured":"Snyder, J. S., Soumier, A., Brewer, M., Pickel, J. & Cameron, H. A. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature 476, 458\u2013461 (2011).","journal-title":"Nature"},{"key":"30291_CR9","doi-asserted-by":"publisher","first-page":"2376","DOI":"10.1038\/npp.2009.75","volume":"34","author":"M Boldrini","year":"2009","unstructured":"Boldrini, M. et al. Antidepressants increase neural progenitor cells in the human hippocampus. Neuropsychopharmacology 34, 2376\u20132389 (2009).","journal-title":"Neuropsychopharmacology"},{"key":"30291_CR10","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1016\/j.biopsych.2012.04.024","volume":"72","author":"M Boldrini","year":"2012","unstructured":"Boldrini, M. et al. Hippocampal angiogenesis and progenitor cell proliferation are increased with antidepressant use in major depression. Biol Psychiatry 72, 562\u201371 (2012).","journal-title":"Biol Psychiatry"},{"key":"30291_CR11","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/0006-8993(92)91597-8","volume":"588","author":"Y Watanabe","year":"1992","unstructured":"Watanabe, Y., Gould, E. & McEwen, B. S. Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res 588, 341\u2013345 (1992).","journal-title":"Brain Res"},{"key":"30291_CR12","doi-asserted-by":"publisher","first-page":"18201","DOI":"10.1073\/pnas.0509232102","volume":"102","author":"R Pawlak","year":"2005","unstructured":"Pawlak, R. et al. Tissue plasminogen activator and plasminogen mediate stress-induced decline of neuronal and cognitive functions in the mouse hippocampus. Proc Natl Acad Sci USA 102, 18201\u201318206 (2005).","journal-title":"Proc Natl Acad Sci USA"},{"key":"30291_CR13","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1038\/nature15526","volume":"527","author":"J Mertens","year":"2015","unstructured":"Mertens, J. et al. Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature 527, 95\u201399 (2015).","journal-title":"Nature"},{"key":"30291_CR14","doi-asserted-by":"publisher","DOI":"10.1038\/tp.2012.56","volume":"2","author":"NM Walton","year":"2012","unstructured":"Walton, N. M. et al. Detection of an immature dentate gyrus feature in human schizophrenia\/bipolar patients. Transl Psychiatry 2, e135, https:\/\/doi.org\/10.1038\/tp.2012.56 (2012).","journal-title":"Transl Psychiatry"},{"key":"30291_CR15","doi-asserted-by":"publisher","first-page":"318596","DOI":"10.1155\/2013\/318596","volume":"2013","author":"H Hagihara","year":"2013","unstructured":"Hagihara, H., Takao, K., Walton, N. M., Matsumoto, M. & Miyakawa, T. Immature dentate gyrus: an endophenotype of neuropsychiatric disorders. Neural Plast 2013, 318596, https:\/\/doi.org\/10.1155\/2013\/318596 (2013).","journal-title":"Neural Plast"},{"key":"30291_CR16","doi-asserted-by":"publisher","first-page":"202","DOI":"10.3389\/fncel.2017.00202","volume":"11","author":"G Maddaloni","year":"2017","unstructured":"Maddaloni, G. et al. Development of Serotonergic Fibers in the Post-Natal Mouse Brain. Front Cell Neurosci. 11, 202, https:\/\/doi.org\/10.3389\/fncel.2017.00202 (2017).","journal-title":"Front Cell Neurosci."},{"issue":"Suppl 1","key":"30291_CR17","doi-asserted-by":"publisher","first-page":"S1","DOI":"10.1097\/00004850-200206001-00002","volume":"17","author":"DJ Nutt","year":"2002","unstructured":"Nutt, D. J. The neuropharmacology of serotonin and noradrenaline in depression. Int Clin Psychopharmacol 17(Suppl 1), S1\u201312 (2002).","journal-title":"Int Clin Psychopharmacol"},{"key":"30291_CR18","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1126\/science.1083328","volume":"301","author":"L Santarelli","year":"2003","unstructured":"Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805\u2013809 (2003).","journal-title":"Science"},{"key":"30291_CR19","doi-asserted-by":"publisher","first-page":"1178","DOI":"10.1177\/0269881114553646","volume":"28","author":"M Morais","year":"2014","unstructured":"Morais, M. et al. The effects of chronic stress on hippocampal adult neurogenesis and dendritic plasticity are reversed by selective MAO-A inhibition. J Psychopharmacol 28, 1178\u20131183 (2014).","journal-title":"J Psychopharmacol"},{"key":"30291_CR20","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.bbr.2014.06.005","volume":"277","author":"V Mosienko","year":"2015","unstructured":"Mosienko, V. et al. Life without brain serotonin: reevaluation of serotonin function with mice deficient in brain serotonin synthesis. Behav Brain Res 277, 78\u201388 (2015).","journal-title":"Behav Brain Res"},{"key":"30291_CR21","doi-asserted-by":"publisher","DOI":"10.1038\/srep20338","volume":"6","author":"NN Song","year":"2016","unstructured":"Song, N. N. et al. Reducing central serotonin in adulthood promotes hippocampal neurogenesis. Sci Rep 6, 20338, https:\/\/doi.org\/10.1038\/srep20338 (2016).","journal-title":"Sci Rep"},{"key":"30291_CR22","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.scr.2016.12.018","volume":"19","author":"NN Song","year":"2017","unstructured":"Song, N. N. et al. Enhanced dendritic morphogenesis of adult hippocampal newborn neurons in central 5-HT-deficient mice. Stem Cell Res 19, 6\u201311 (2017).","journal-title":"Stem Cell Res"},{"key":"30291_CR23","doi-asserted-by":"publisher","first-page":"9828","DOI":"10.1523\/JNEUROSCI.1469-16.2016","volume":"36","author":"MS Whitney","year":"2016","unstructured":"Whitney, M. S. et al. Adult Brain Serotonin Deficiency Causes Hyperactivity, Circadian Disruption, and Elimination of Siestas. J Neurosci 36, 9828\u20139842 (2016).","journal-title":"J Neurosci"},{"key":"30291_CR24","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.1038\/mp.2012.128","volume":"18","author":"S Migliarini","year":"2013","unstructured":"Migliarini, S., Pacini, G., Pelosi, B., Lunardi, G. & Pasqualetti, M. Lack of brain serotonin affects postnatal development and serotonergic neuronal circuitry formation. Mol Psychiatry 18, 1106\u20131118 (2013).","journal-title":"Mol Psychiatry"},{"key":"30291_CR25","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.vascn.2009.03.003","volume":"59","author":"S Flaisher-Grinberg","year":"2009","unstructured":"Flaisher-Grinberg, S. & Einat, H. A possible utilization of the mice forced swim test for modeling manic-like increase in vigor and goal-directed behavior. J Pharmacol Toxicol Methods 59, 141\u2013145 (2009).","journal-title":"J Pharmacol Toxicol Methods"},{"key":"30291_CR26","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1038\/nature11740","volume":"493","author":"KM Tye","year":"2013","unstructured":"Tye, K. M. et al. Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature 493, 537\u2013541 (2013).","journal-title":"Nature"},{"key":"30291_CR27","doi-asserted-by":"publisher","first-page":"11043","DOI":"10.1523\/JNEUROSCI.1682-10.2010","volume":"30","author":"F Napolitano","year":"2010","unstructured":"Napolitano, F. et al. Role of aberrant striatal dopamine D1 receptor\/cAMP\/protein kinase A\/DARPP32 signaling in the paradoxical calming effect of amphetamine. J Neurosci 30, 11043\u201311056 (2010).","journal-title":"J Neurosci"},{"key":"30291_CR28","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1016\/j.cell.2014.03.039","volume":"157","author":"S Chung","year":"2014","unstructured":"Chung, S. et al. Impact of circadian nuclear receptor REV-ERBalpha on midbrain dopamine production and mood regulation. Cell 157, 858\u2013868 (2014).","journal-title":"Cell"},{"key":"30291_CR29","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/j.neuroscience.2015.08.041","volume":"321","author":"RW Logan","year":"2016","unstructured":"Logan, R. W. & McClung, C. A. Animal models of bipolar mania: The past, present and future. Neuroscience 321, 163\u2013188 (2016).","journal-title":"Neuroscience"},{"key":"30291_CR30","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1093\/schbul\/sbp114","volume":"35","author":"I Gaisler-Salomon","year":"2009","unstructured":"Gaisler-Salomon, I., Schobel, S. A., Small, S. A. & Rayport, S. How high-resolution basal-state functional imaging can guide the development of new pharmacotherapies for schizophrenia. Schizophr Bull 35, 1037\u20131044 (2009).","journal-title":"Schizophr Bull"},{"key":"30291_CR31","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.neuroimage.2012.12.015","volume":"69","author":"A Gozzi","year":"2013","unstructured":"Gozzi, A., Agosta, F., Massi, M., Ciccocioppo, R. & Bifone, A. Reduced limbic metabolism and fronto-cortical volume in rats vulnerable to alcohol addiction. Neuroimage 69, 112\u2013119 (2013).","journal-title":"Neuroimage"},{"key":"30291_CR32","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/nrn3379","volume":"14","author":"H Park","year":"2013","unstructured":"Park, H. & Poo, M. M. Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci 14, 7\u201323 (2013).","journal-title":"Nat Rev Neurosci"},{"key":"30291_CR33","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1007\/s00406-015-0611-3","volume":"266","author":"G Kronenberg","year":"2016","unstructured":"Kronenberg, G. et al. Increased brain-derived neurotrophic factor (BDNF) protein concentrations in mice lacking brain serotonin. Eur Arch Psychiatry Clin Neurosci 266, 281\u2013284 (2016).","journal-title":"Eur Arch Psychiatry Clin Neurosci"},{"key":"30291_CR34","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1016\/S0896-6273(00)80378-5","volume":"19","author":"H Kang","year":"1997","unstructured":"Kang, H., Welcher, A. A., Shelton, D. & Schuman, E. M. Neurotrophins and time: different roles for TrkB signaling in hippocampal long-term potentiation. Neuron 19, 653\u2013664 (1997).","journal-title":"Neuron"},{"key":"30291_CR35","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/S0896-6273(01)00443-3","volume":"32","author":"SL Patterson","year":"2001","unstructured":"Patterson, S. L. et al. Some forms of cAMP-mediated long-lasting potentiation are associated with release of BDNF and nuclear translocation of phospho-MAP kinase. Neuron 32, 123\u2013140 (2001).","journal-title":"Neuron"},{"key":"30291_CR36","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","volume":"102","author":"A Subramanian","year":"2005","unstructured":"Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102, 15545\u201315550 (2005).","journal-title":"Proc Natl Acad Sci USA"},{"key":"30291_CR37","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1016\/j.cpr.2011.01.004","volume":"31","author":"RE Bender","year":"2011","unstructured":"Bender, R. E. & Alloy, L. B. Life stress and kindling in bipolar disorder: review of the evidence and integration with emerging biopsychosocial theories. Clin Psychol Rev 31, 383\u2013398 (2011).","journal-title":"Clin Psychol Rev"},{"key":"30291_CR38","doi-asserted-by":"publisher","first-page":"1561","DOI":"10.1016\/S0140-6736(15)00241-X","volume":"387","author":"I Grande","year":"2016","unstructured":"Grande, I., Berk, M., Birmaher, B. & Vieta, E. Bipolar disorder. Lancet 387, 1561\u20131572 (2016).","journal-title":"Lancet"},{"key":"30291_CR39","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1111\/j.1399-5618.2012.01006.x","volume":"14","author":"J Ballester","year":"2012","unstructured":"Ballester, J. et al. Is bipolar disorder specifically associated with aggression? Bipolar Disord 14, 283\u2013290 (2012).","journal-title":"Bipolar Disord"},{"key":"30291_CR40","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1038\/mp.2014.163","volume":"20","author":"PW Gold","year":"2015","unstructured":"Gold, P. W. The organization of the stress system and its dysregulation in depressive illness. Mol Psychiatry 20, 32\u201347 (2015).","journal-title":"Mol Psychiatry"},{"key":"30291_CR41","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/S0896-6273(02)00653-0","volume":"34","author":"EJ Nestler","year":"2002","unstructured":"Nestler, E. J. et al. Neurobiology of depression. Neuron 34, 13\u201325 (2002).","journal-title":"Neuron"},{"key":"30291_CR42","doi-asserted-by":"publisher","first-page":"1110","DOI":"10.1038\/nn1969","volume":"10","author":"A Sahay","year":"2007","unstructured":"Sahay, A. & Hen, R. Adult hippocampal neurogenesis in depression. Nat Neurosci 10, 1110\u20131115 (2007).","journal-title":"Nat Neurosci"},{"key":"30291_CR43","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1016\/S0006-3223(01)01083-6","volume":"50","author":"B Chen","year":"2001","unstructured":"Chen, B., Dowlatshahi, D., MacQueen, G. M., Wang, J. F. & Young, L. T. Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry 50, 260\u2013265 (2001).","journal-title":"Biol Psychiatry"},{"key":"30291_CR44","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1523\/JNEUROSCI.23-01-00349.2003","volume":"23","author":"T Saarelainen","year":"2003","unstructured":"Saarelainen, T. et al. Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J Neurosci 23, 349\u2013357 (2003).","journal-title":"J Neurosci"},{"key":"30291_CR45","doi-asserted-by":"publisher","first-page":"9104","DOI":"10.1523\/JNEUROSCI.20-24-09104.2000","volume":"20","author":"JE Malberg","year":"2000","unstructured":"Malberg, J. E., Eisch, A. J., Nestler, E. J. & Duman, R. S. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 20, 9104\u20139110 (2000).","journal-title":"J Neurosci"},{"key":"30291_CR46","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1007\/s11920-007-0054-2","volume":"9","author":"RE Scheffer","year":"2007","unstructured":"Scheffer, R. E. Concurrent ADHD and bipolar disorder. Curr Psychiatry Rep. 9, 415\u2013419 (2007).","journal-title":"Curr Psychiatry Rep."},{"key":"30291_CR47","unstructured":"Barkley, R. A. Attention Deficit Hyperactivity Disorder in Adults: The Latest Assessment and Treatment Strategies in vol. vi. Sudbury Jones and Bartlett Publishers, p. 81 (2010)."},{"key":"30291_CR48","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1038\/nm.2330","volume":"17","author":"H Won","year":"2011","unstructured":"Won, H. et al. GIT1 is associated with ADHD in humans and ADHD-like behaviors in mice. Nat Med 17, 566\u2013572 (2011).","journal-title":"Nat Med"},{"key":"30291_CR49","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1001\/archpsyc.64.5.543","volume":"64","author":"KR Merikangas","year":"2007","unstructured":"Merikangas, K. R. et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry 64, 543\u2013552 (2007).","journal-title":"Arch Gen Psychiatry"},{"key":"30291_CR50","doi-asserted-by":"publisher","first-page":"980","DOI":"10.1038\/sj.mp.4001557","volume":"9","author":"M Harvey","year":"2004","unstructured":"Harvey, M. et al. Support for the involvement of TPH2 gene in affective disorders. Mol Psychiatry 9, 980\u2013981 (2004).","journal-title":"Mol Psychiatry"},{"key":"30291_CR51","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1097\/YPG.0b013e3280111877","volume":"17","author":"M Harvey","year":"2007","unstructured":"Harvey, M., Gagne, B., Labbe, M. & Barden, N. Polymorphisms in the neuronal isoform of tryptophan hydroxylase 2 are associated with bipolar disorder in French Canadian pedigrees. Psychiatr Genet 17, 17\u201322 (2007).","journal-title":"Psychiatr Genet"},{"key":"30291_CR52","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1176\/ajp.156.1.136","volume":"156","author":"JB Vincent","year":"1999","unstructured":"Vincent, J. B. et al. Genetic association analysis of serotonin system genes in bipolar affective disorder. Am J Psychiatry 156, 136\u2013138 (1999).","journal-title":"Am J Psychiatry"},{"key":"30291_CR53","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1136\/jmg.40.10.781","volume":"40","author":"YM Lin","year":"2003","unstructured":"Lin, Y. M., Yang, H. C., Lai, T. J., Fann, C. S. & Sun, H. S. Receptor mediated effect of serotonergic transmission in patients with bipolar affective disorder. J Med Genet 40, 781\u2013786 (2003).","journal-title":"J Med Genet"},{"key":"30291_CR54","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1093\/hmg\/ddm286","volume":"17","author":"S Cichon","year":"2008","unstructured":"Cichon, S. et al. Brain-specific tryptophan hydroxylase 2 (TPH2): a functional Pro206Ser substitution and variation in the 5\u2032-region are associated with bipolar affective disorder. Hum Mol Genet 17, 87\u201397 (2008).","journal-title":"Hum Mol Genet"},{"key":"30291_CR55","doi-asserted-by":"publisher","first-page":"574","DOI":"10.1038\/sj.mp.4001328","volume":"8","author":"M Anguelova","year":"2003","unstructured":"Anguelova, M., Benkelfat, C. & Turecki, G. A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: I. Affective disorders. Mol Psychiatry 8, 574\u2013591 (2003).","journal-title":"Mol Psychiatry"},{"key":"30291_CR56","doi-asserted-by":"publisher","first-page":"1473","DOI":"10.1038\/mp.2016.261","volume":"22","author":"YR Yang","year":"2017","unstructured":"Yang, Y. R. et al. Forebrain-specific ablation of phospholipase Cgamma1 causes manic-like behavior. Mol Psychiatry 22, 1473\u20131482 (2017).","journal-title":"Mol Psychiatry"},{"key":"30291_CR57","doi-asserted-by":"publisher","first-page":"10164","DOI":"10.1073\/pnas.0703806104","volume":"104","author":"FM Benes","year":"2007","unstructured":"Benes, F. M. et al. Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars. Proc Natl Acad Sci USA 104, 10164\u201310169 (2007).","journal-title":"Proc Natl Acad Sci USA"},{"key":"30291_CR58","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1016\/j.neubiorev.2007.10.005","volume":"32","author":"F Kapczinski","year":"2008","unstructured":"Kapczinski, F. et al. Allostatic load in bipolar disorder: implications for pathophysiology and treatment. Neurosci Biobehav Rev 32, 675\u2013692 (2008).","journal-title":"Neurosci Biobehav Rev"},{"key":"30291_CR59","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1111\/acps.12581","volume":"134","author":"IC Passos","year":"2016","unstructured":"Passos, I. C., Mwangi, B., Vieta, E., Berk, M. & Kapczinski, F. Areas of controversy in neuroprogression in bipolar disorder. Acta Psychiatr Scand 134, 91\u2013103 (2016).","journal-title":"Acta Psychiatr Scand"},{"key":"30291_CR60","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1176\/ajp.149.8.999","volume":"149","author":"RM Post","year":"1992","unstructured":"Post, R. M. Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J Psychiatry 149, 999\u20131010 (1992).","journal-title":"Am J Psychiatry"},{"key":"30291_CR61","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1038\/mp.2015.142","volume":"22","author":"S Alboni","year":"2017","unstructured":"Alboni, S. et al. Fluoxetine effects on molecular, cellular and behavioral endophenotypes of depression are driven by the living environment. Mol Psychiatry 22, 552\u2013561.58 (2017).","journal-title":"Mol Psychiatry"},{"key":"30291_CR62","doi-asserted-by":"publisher","first-page":"e3301","DOI":"10.1371\/journal.pone.0003301","volume":"3","author":"KV Savelieva","year":"2008","unstructured":"Savelieva, K. V. et al. Genetic disruption of both tryptophan hydroxylase genes dramatically reduces serotonin and affects behavior in models sensitive to antidepressants. Plos One 3, e3301 (2008).","journal-title":"Plos One"},{"key":"30291_CR63","doi-asserted-by":"publisher","DOI":"10.1038\/tp.2012.44","volume":"2","author":"V Mosienko","year":"2012","unstructured":"Mosienko, V. et al. Exaggerated aggression and decreased anxiety in mice deficient in brain serotonin. Transl Psychiatry 2, e122 (2012).","journal-title":"Transl Psychiatry"},{"key":"30291_CR64","doi-asserted-by":"publisher","first-page":"2429","DOI":"10.1007\/s00213-015-3879-0","volume":"232","author":"L Gutknecht","year":"2015","unstructured":"Gutknecht, L. et al. Interaction of brain 5-HT synthesis deficiency, chronic stress and sex differentially impact emotional behavior in Tph2 knockout mice. Psychopharmacology (Berl) 232, 2429\u20132441 (2015).","journal-title":"Psychopharmacology (Berl)"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-30291-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-30291-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-30291-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T03:12:18Z","timestamp":1671592338000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-30291-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,8,7]]},"references-count":64,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["30291"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-30291-2","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/123646","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,8,7]]},"assertion":[{"value":"23 November 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 July 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 August 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"11847"}}