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Neuromodulatory systems in the brain\u2014including those involving serotonin and dopamine\u2014exhibit daily oscillations in neural activity and help shape circadian rhythms. Disrupted neuromodulation can cause circadian abnormalities that are thought to underlie several neuropsychiatric disorders, including bipolar mania and schizophrenia, for which a mechanistic understanding is still lacking. Here, we show that genetically depleting serotonin in Tph2 knockout mice promotes manic-like behaviors and disrupts daily oscillations of the dopamine biosynthetic enzyme tyrosine hydroxylase (TH) in midbrain dopaminergic nuclei. Specifically, while TH mRNA and protein levels in the Substantia Nigra (SN) and Ventral Tegmental Area (VTA) of wild-type mice doubled between the light and dark phase, TH levels were high throughout the day in Tph2 knockout mice, suggesting a hyperdopaminergic state. Analysis of TH expression in striatal terminal fields also showed blunted rhythms. Additionally, we found low abundance and blunted rhythmicity of the neuropeptide cholecystokinin (Cck) in the VTA of knockout mice, a neuropeptide whose downregulation has been implicated in manic-like states in both rodents and humans. Altogether, our results point to a previously unappreciated serotonergic control of circadian dopamine signaling and propose serotonergic dysfunction as an upstream mechanism underlying dopaminergic deregulation and ultimately maladaptive behaviors.<\/jats:p>","DOI":"10.3390\/ijms25126475","type":"journal-article","created":{"date-parts":[[2024,6,12]],"date-time":"2024-06-12T06:47:30Z","timestamp":1718174850000},"page":"6475","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Impact of Serotonin Deficiency on Circadian Dopaminergic Rhythms"],"prefix":"10.3390","volume":"25","author":[{"given":"Giacomo","family":"Maddaloni","sequence":"first","affiliation":[{"name":"Unit of Cell and Developmental Biology, Department of Biology, University of Pisa, 56127 Pisa, Italy"},{"name":"Harvard Medical School, Department of Genetics, Harvard University, 77 Avenue Louis Pasteur, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6399-436X","authenticated-orcid":false,"given":"Noemi","family":"Barsotti","sequence":"additional","affiliation":[{"name":"Unit of Cell and Developmental Biology, Department of Biology, University of Pisa, 56127 Pisa, Italy"},{"name":"Centro per l\u2019Integrazione della Strumentazione Scientifica dell\u2019Universit\u00e0 di Pisa (CISUP), 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2741-269X","authenticated-orcid":false,"given":"Sara","family":"Migliarini","sequence":"additional","affiliation":[{"name":"Unit of Cell and Developmental Biology, Department of Biology, University of Pisa, 56127 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Giordano","sequence":"additional","affiliation":[{"name":"Unit of Cell and Developmental Biology, Department of Biology, University of Pisa, 56127 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Nazzi","sequence":"additional","affiliation":[{"name":"Unit of Cell and Developmental Biology, Department of Biology, University of Pisa, 56127 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Picchi","sequence":"additional","affiliation":[{"name":"Unit of Cell and Developmental Biology, Department of Biology, University of Pisa, 56127 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Errico","sequence":"additional","affiliation":[{"name":"CEINGE Biotecnologie Avanzate Franco Salvatore, 80131 Naples, Italy"},{"name":"Department of Agricultural Sciences, University of Naples \u201cFederico II\u201d, 80055 Portici, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Usiello","sequence":"additional","affiliation":[{"name":"CEINGE Biotecnologie Avanzate Franco Salvatore, 80131 Naples, Italy"},{"name":"Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0844-8139","authenticated-orcid":false,"given":"Massimo","family":"Pasqualetti","sequence":"additional","affiliation":[{"name":"Unit of Cell and Developmental Biology, Department of Biology, University of Pisa, 56127 Pisa, Italy"},{"name":"Centro per l\u2019Integrazione della Strumentazione Scientifica dell\u2019Universit\u00e0 di Pisa (CISUP), 56126 Pisa, Italy"},{"name":"Center for Neuroscience and Cognitive Systems@UniTn, Istituto Italiano di Tecnologia, 38068 Rovereto, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/nrn3743","article-title":"Light as a Central Modulator of Circadian Rhythms, Sleep and Affect","volume":"15","author":"LeGates","year":"2014","journal-title":"Nat. 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