Abnormal Development of Monoaminergic Neurons Is Implicated in Mood Fluctuations and Bipolar Disorder

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-HT2C 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.

Chronic treatment with mood stabilizer lithium inhibits amphetamine-induced risk-taking manic-like behaviors

“…Chronic lithium treatment was reported to reduce Otx2 overexpression and reduce increased centre activity of mice in the OFT [19]. A genomewide association study shows an association between neurocan gene and BD.…”

“…OFT [19,24,26], elevated zero maze test [27] or EPM test [10,25,26] in animals. These tests were also used for studying anxiety.…”

“…Increased engagement in risk-taking behaviors is found in psychiatric disorders such as BD, schizophrenia and substance abuse [15,22], and has been studied in animal models for psychiatric disorders [19,24,30,27]. Repeated amphetamine treatment was found to increase risk-taking behavior [14,34].…”

“…However it is not clear if amphetamine-increased risk-taking behavior can be inhibited by lithium treatment. The open field test (OFT), elevated zero maze test or elevated plus maze (EPM) test were previously used to analyze the effect of lithium on risk-taking behaviors in various animal models [10,19,[24][25][26][27]. Wire-beam bridge (WBB) test was used to analyze risk-taking behavior by measuring the tendency of mice to reach for a foodrewarding goal through an unrailed bridge above ground [6].…”

Sex-specific hippocampal 5-hydroxymethylcytosine is disrupted in response to acute stress

“…Putative binding factors were predicted using SpaMo directly from the DREME suite software package and are listed in the tables shown with their putative transcription factors. The literature (Ref) links of each TF to psychiatric disorders are shown: Scz (schizophrenia); BP (Bipolar Disorder); MDD (Major Depressive Disorder); Epi (Epilepsy); ND (Neuronal Differentiation); OCD (Obsessive Compulsive Disorder) (Aston et al, 2005; Basmanav et al, 2015; Butts et al, 2014; Castilhos et al, 2014; Chen et al, 2014b; Chiang et al, 2015; Forero et al, 2016; Forrest et al, 2013; Goes et al, 2015; Grados et al, 2014; Gurung and Prata, 2015; Hattori et al, 2014; Johansson et al, 2016; Jukic et al, 2015; Keyes et al, 2015; Kim et al, 2014; Le-Niculescu et al, 2009; Lisowski et al, 2013; Mencarelli et al, 2008; Nestadt et al, 2012; Rivolta et al, 2014; Rotheram-Fuller et al, 2010; Schlaudraff et al, 2014; Shi et al, 2016; Wang et al, 2014; Wei et al, 2015; Wockner et al, 2014). …”