Abnormal development of monoaminergic neurons is implicated in mood fluctuations and bipolar disorder
Apstrakt
Subtle mood fluctuations are normal emotional experiences, whereas drastic mood swings can be a manifestation of bipolar disorder (BPD). Despite their importance for normal and pathological behavior, the mechanisms underlying endogenous mood instability are largely unknown. During embryogenesis, the transcription factor Otx2 orchestrates the genetic networks directing the specification of dopaminergic (DA) and serotonergic (5-HT) neurons. Here we behaviorally phenotyped mouse mutants overexpressing Otx2 in the hindbrain, resulting in an increased number of DA neurons and a decreased number of 5-HT neurons in both developing and mature animals. Over the course of 1 month, control animals exhibited stable locomotor activity in their home cages, whereas mutants showed extended periods of elevated or decreased activity relative to their individual average. Additional behavioral paradigms, testing for manic-and depressive-like behavior, demonstrated that mutants showed an increase in intra-...individual fluctuations in locomotor activity, habituation, risk-taking behavioral parameters, social interaction, and hedonic-like behavior. Olanzapine, lithium, and carbamazepine ameliorated the behavioral alterations of the mutants, as did the mixed serotonin receptor agonist quipazine and the specific 5-HT 2C receptor agonist CP-809101. Testing the relevance of the genetic networks specifying monoaminergic neurons for BPD in humans, we applied an interval-based enrichment analysis tool for genome-wide association studies. We observed that the genes specifying DA and 5-HT neurons exhibit a significant level of aggregated association with BPD but not with schizophrenia or major depressive disorder. The results of our translational study suggest that aberrant development of monoaminergic neurons leads to mood fluctuations and may be associated with BPD.
Izvor:
Neuropsychopharmacology, 2015, 40, 4, 839-848Izdavač:
- Nature Publishing Group
Finansiranje / projekti:
- National Institute for Psychobiology in Israel—Founded by the Charles E. Smith Family (grant 209-11-12 to CB)
- The Israeli Ministry of Health, Chief Scientist Office (grant 3-7433 to CB)
- Israeli Science Foundation (grant 1391/11 to CB)
DOI: 10.1038/npp.2014.244
ISSN: 0893-133X
WoS: 000349509000006
Scopus: 2-s2.0-84925496969
Institucija/grupa
PharmacyTY - JOUR AU - Jukić, Marin AU - Carrillo-Roa, T AU - Bar, M AU - Becker, G AU - Jovanović, V.M AU - Zega, K AU - Binder, E.B AU - Brodski, C PY - 2015 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2488 AB - Subtle mood fluctuations are normal emotional experiences, whereas drastic mood swings can be a manifestation of bipolar disorder (BPD). Despite their importance for normal and pathological behavior, the mechanisms underlying endogenous mood instability are largely unknown. During embryogenesis, the transcription factor Otx2 orchestrates the genetic networks directing the specification of dopaminergic (DA) and serotonergic (5-HT) neurons. Here we behaviorally phenotyped mouse mutants overexpressing Otx2 in the hindbrain, resulting in an increased number of DA neurons and a decreased number of 5-HT neurons in both developing and mature animals. Over the course of 1 month, control animals exhibited stable locomotor activity in their home cages, whereas mutants showed extended periods of elevated or decreased activity relative to their individual average. Additional behavioral paradigms, testing for manic-and depressive-like behavior, demonstrated that mutants showed an increase in intra-individual fluctuations in locomotor activity, habituation, risk-taking behavioral parameters, social interaction, and hedonic-like behavior. Olanzapine, lithium, and carbamazepine ameliorated the behavioral alterations of the mutants, as did the mixed serotonin receptor agonist quipazine and the specific 5-HT 2C receptor agonist CP-809101. Testing the relevance of the genetic networks specifying monoaminergic neurons for BPD in humans, we applied an interval-based enrichment analysis tool for genome-wide association studies. We observed that the genes specifying DA and 5-HT neurons exhibit a significant level of aggregated association with BPD but not with schizophrenia or major depressive disorder. The results of our translational study suggest that aberrant development of monoaminergic neurons leads to mood fluctuations and may be associated with BPD. PB - Nature Publishing Group T2 - Neuropsychopharmacology T1 - Abnormal development of monoaminergic neurons is implicated in mood fluctuations and bipolar disorder VL - 40 IS - 4 SP - 839 EP - 848 DO - 10.1038/npp.2014.244 ER -
@article{ author = "Jukić, Marin and Carrillo-Roa, T and Bar, M and Becker, G and Jovanović, V.M and Zega, K and Binder, E.B and Brodski, C", year = "2015", abstract = "Subtle mood fluctuations are normal emotional experiences, whereas drastic mood swings can be a manifestation of bipolar disorder (BPD). Despite their importance for normal and pathological behavior, the mechanisms underlying endogenous mood instability are largely unknown. During embryogenesis, the transcription factor Otx2 orchestrates the genetic networks directing the specification of dopaminergic (DA) and serotonergic (5-HT) neurons. Here we behaviorally phenotyped mouse mutants overexpressing Otx2 in the hindbrain, resulting in an increased number of DA neurons and a decreased number of 5-HT neurons in both developing and mature animals. Over the course of 1 month, control animals exhibited stable locomotor activity in their home cages, whereas mutants showed extended periods of elevated or decreased activity relative to their individual average. Additional behavioral paradigms, testing for manic-and depressive-like behavior, demonstrated that mutants showed an increase in intra-individual fluctuations in locomotor activity, habituation, risk-taking behavioral parameters, social interaction, and hedonic-like behavior. Olanzapine, lithium, and carbamazepine ameliorated the behavioral alterations of the mutants, as did the mixed serotonin receptor agonist quipazine and the specific 5-HT 2C receptor agonist CP-809101. Testing the relevance of the genetic networks specifying monoaminergic neurons for BPD in humans, we applied an interval-based enrichment analysis tool for genome-wide association studies. We observed that the genes specifying DA and 5-HT neurons exhibit a significant level of aggregated association with BPD but not with schizophrenia or major depressive disorder. The results of our translational study suggest that aberrant development of monoaminergic neurons leads to mood fluctuations and may be associated with BPD.", publisher = "Nature Publishing Group", journal = "Neuropsychopharmacology", title = "Abnormal development of monoaminergic neurons is implicated in mood fluctuations and bipolar disorder", volume = "40", number = "4", pages = "839-848", doi = "10.1038/npp.2014.244" }
Jukić, M., Carrillo-Roa, T., Bar, M., Becker, G., Jovanović, V.M, Zega, K., Binder, E.B,& Brodski, C.. (2015). Abnormal development of monoaminergic neurons is implicated in mood fluctuations and bipolar disorder. in Neuropsychopharmacology Nature Publishing Group., 40(4), 839-848. https://doi.org/10.1038/npp.2014.244
Jukić M, Carrillo-Roa T, Bar M, Becker G, Jovanović V, Zega K, Binder E, Brodski C. Abnormal development of monoaminergic neurons is implicated in mood fluctuations and bipolar disorder. in Neuropsychopharmacology. 2015;40(4):839-848. doi:10.1038/npp.2014.244 .
Jukić, Marin, Carrillo-Roa, T, Bar, M, Becker, G, Jovanović, V.M, Zega, K, Binder, E.B, Brodski, C, "Abnormal development of monoaminergic neurons is implicated in mood fluctuations and bipolar disorder" in Neuropsychopharmacology, 40, no. 4 (2015):839-848, https://doi.org/10.1038/npp.2014.244 . .