Neuroscience and Biobehavioral Reviews 99 (2019) 117–127

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Neuroscience and Biobehavioral Reviews

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Review article The evolutionarily conserved role of in CNS disorders and T behavioral regulation: Translational lessons from zebrafish Rafael Genarioa,1, Ana C.V.V. Giacominia,b,1, Konstantin A. Demind,f, Bruna E. dos Santosa, Natalia I. Marchioria, Angrey D. Volging, Alim Bashirzadeg,h, Tamara G. Amstislavskayag,h, ⁎ ⁎⁎ Murilo S. de Abreua,c, , Allan V. Kalueffe,f,g,i,j,k, a Bioscience Institute, University of Passo Fundo (UPF), Passo Fundo, RS, Brazil b Postgraduate Program in Environmental Sciences, University of Passo Fundo (UPF), Passo Fundo, Brazil c The International Zebrafish Neuroscience Research Consortium (ZNRC), Slidell, LA,USA d Institute of Experimental Medicine, Almazov National Medical Research Centre, Ministry of Healthcare of Russian Federation, St. Petersburg, Russia e School of Pharmacy, Southwest University, Chongqing, China f Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia g Laboratory of Translational Biopsychiatry, Research Institute of Physiology and Basic Medicine, Novosibirsk, Russia h Department of Neuroscience, Novosibirsk State University, Novosibirsk, Russia i Ural Federal University, Ekaterinburg, Russia j Granov’s Russian Scientific Research Center of Radiology and Surgical Technologies, Ministry of Healthcare of Russian Federation, Pesochny, Russia k Almazov National Medical Research Centre, Ministry of Healthcare of Russian Federation, St. Petersburg, Russia

ARTICLE INFO ABSTRACT

Keywords: Melatonin is an important hormone regulating circadian rhythm, neuroprotection and neuroimmune processes. Melatonin However, its exact physiological roles in brain mechanisms remain poorly understood. Here, we summarize the Animal model mounting evidence implicating melatonin in brain disorders and behavior, based on clinical and experimental Genetic model studies in-vivo. In addition to rodent models, the zebrafish (Danio rerio) is becoming increasingly utilized in Behavioral regulation biomedical and neuroscience research. Here, we discuss melatonin neurobiology of zebrafish, and parallel these CNS findings with clinical and rodent data. We also discuss the genomic effects of melatonin in zebrafish, andem- phasize the growing utility of zebrafish models to study melatonin neurobiology and drug discovery.

1. Introduction Dubocovich et al., 1997; Nonno et al., 1998; Sugden et al., 1997; Teh and Sugden, 1998)) and Mtnr1b (Ki = 0.18-0.48 nM (Beresford et al., 1998; Melatonin (methoxyindole, n-acetyl-5-methoxytryptamine) is a pineal Dubocovich et al., 1997; Nonno et al., 1998; Sugden et al., 1997; Teh and gland hormone secreted at night under normal light/dark conditions Sugden, 1998)), expressed in different organs, including the brain. (Gastel et al., 1998; Reiter, 1991). Its production follows the stimulation Through these receptors, melatonin regulates circadian rhythm, sleep, of the postganglionic nerve terminals of the sympathetic nervous system, hunger and temperature (Brzezinski et al., 2005; Scheer and Czeisler, releasing norepinephrine that activates pinealocytes to produce melatonin 2005) as well as the expression of several important circadian genes, in- (Pandi-Perumal et al., 2008; Schomerus and Korf, 2006; Simonneaux, cluding Clock1a, Per1b and Per2 in mammalian brain and some other 2003). To a much lesser extent, melatonin is produced by the retina, la- organs (Khan et al., 2016). Normal circadian rhythm is critical for the crimal gland, gastrointestinal tract, skin and ovary (Ahmad et al., 2016; health of an organism (Evans and Davidson, 2013), as its disturbances Reiter et al., 2014). Melatonin is not stored in the producing cells, and is often trigger psychiatric disorders, such as depression and anxiety released after biosynthesis, peaking during the night (Arendt, 1995; (Billiard et al., 1994; Germain and Kupfer, 2008; Kaplan and Harvey, Schomerus and Korf, 2006; Tan et al., 2015; Wurtman et al., 1963). In 2009; Liu et al., 2007; Tapia-Osorio et al., 2013). mammals, physiological effects of melatonin are exerted through several Melatonin has several other critical physiological roles, exerting melatonin receptors, Mtnr1a (Ki = 0.08-0.88 nM (Beresford et al., 1998; anti-inflammatory (Celinski et al., 2014; Gonciarz et al., 2012, 2011),

⁎ Corresponding authors at: Bioscience Institute, University of Passo Fundo, Passo Fundo, Brazil. ⁎⁎ Corresponding authors at: School of Pharmacy, Southwest University, Chongqing, China. E-mail addresses: [email protected] (M.S. de Abreu), [email protected] (A.V. Kalueff). 1 Shared first authorship https://doi.org/10.1016/j.neubiorev.2018.12.025 Received 7 November 2018; Received in revised form 12 December 2018; Accepted 20 December 2018 Available online 03 January 2019 0149-7634/ © 2019 Elsevier Ltd. All rights reserved. R. Genario, et al. Neuroscience and Biobehavioral Reviews 99 (2019) 117–127 antioxidant (Ahmad et al., 2016), anti-cancer (Asghari et al., 2017; psychiatric illnesses (Kupfer, 2015), and melatonin shows anxiolytic Mills et al., 2005; Reiter et al., 2014; Srinivasan et al., 2008), immuno- effects (Wilhelmsen et al., 2011) in oncological (Hansen et al., 2014) modulating (Ángeles Esteban et al., 2013; Carrillo-Vico et al., 2013) and pediatric patients (Marseglia et al., 2015a). Depression is also a and pancreas-regulating effects (Mulder et al., 2009; Peschke, 2008; common CNS disorder (MÉNard et al., 2016) often associated with low Peschke et al., 2006). Anti-inflammatory effects of melatonin involve production, aberrant metabolism of melatonin (Crasson et al., 2004; reducing pro-inflammatory cytokines interleukins (IL) IL-1, IL-6 and Khaleghipour et al., 2012) and altered Mtnr1a and Mtnr1b tumor necrosis factor alpha (TNF-α) in plasma, brain and other organs signaling (Cardinali et al., 2012). In patients with the delayed sleep (Celinski et al., 2014; Gonciarz et al., 2012, 2011). Here, we summarize phase syndrome, melatonin supplementation improves sleep and re- the mounting evidence on the critical role of melatonin in CNS dis- duces depressive symptoms (Rahman et al., 2010), whereas anti- orders and behavior in both clinical and experimental studies in-vivo, depressant effects of buspirone are potentiated by melatonin in patients focusing on important translational lessons what can be learnt from with major depression (Fava et al., 2012), also improving their cogni- animal models. tive performance (Targum et al., 2015). Neurodegenerative diseases are characterized by overt cognitive 2. Clinical effects of melatonin in CNS disorders deficits (Poletti et al., 2012; Seeley et al., 2009) due to apoptosis and neurodegeneration (Wang, 2005). Presenting as progressive motor, One of the best-studied clinical effects of melatonin is its pro-hyp- cognitive and emotional deficits, Huntington's disease (Reilmann et al., notic action (Altun and Ugur-Altun, 2007; Reiter, 2003). Melatonin 2014; Walker, 2007) is often accompanied by reduced plasma levels of supplementation can be used as the main treatment of insomnia, to melatonin (Kalliolia et al., 2014) and aberrant metabolism of its pre- normalize the circadian cycle (Auld et al., 2017; Cardinali et al., 2016; cursor tryptophan (Stoy et al., 2005). Amyotrophic lateral sclerosis Golombek et al., 2015). For example, melatonin is used in patients with (ALS) is a fatal neurodegenerative disease linked to progressive de- secondary insomnia (Auld et al., 2017; Brzezinski et al., 2005; generation of motor neurons (Kiernan et al., 2011; Nagase et al., 2016; Golombek et al., 2015), whereas melatonin-related drugs (e.g., ra- Robberecht, 2000). In ALS patients, high doses of melatonin reduce melteon (Kuriyama et al., 2014) and (Kupfer, 2006)) im- oxidative damage and delay neurodegeneration (Weishaupt et al., prove sleep quality. Additionally, melatonin can serve as a therapy for 2006). Other neurodegenerative disorders responding to therapeutic neurodegenerative disorders (Dowling et al., 2005; Zhang et al., 2016), effects of melatonin include Parkinson's (Hwang, 2013), Alzheimer’s depression (Bouwmans et al., 2018; Cardinali et al., 2012), epilepsy diseases (Smith et al., 2000) and multiple sclerosis (Gilgun-Sherki et al., (Jain et al., 2015) and autism (Andersen et al., 2008; Malow et al., 2004), collectively supporting an important neuroprotective role of this 2012)(Table 1). hormone in vivo (Furio et al., 2007; Zhang et al., 2016). Furthermore, melatonin exerts therapeutic effects in neonatal hy- Melatonin is an efficient antioxidant that easily penetrates through poxic-ischemic encephalopathy, due to its neuroprotective effects as an biological membranes and exerts pleiotropic actions on multiple cells antioxidant and agent that reduces brain injury in these patients (Aly (Milczarek et al., 2010). This hormone also plays an important role in et al., 2015). Melatonin also improves the overall quality of life, in- gestation. For example, women with abnormally functioning placentae creasing the rate of survival and reducing tumor progression in patients during severe preeclampsia display lower melatonin levels (Marseglia with inoperable brain metastases (Lissoni et al., 1994). Melatonin et al., 2015b; Nakamura et al., 2001). The high perinatal susceptibility supplementation improves mood and cognitions in patients with de- to oxidative stress suggests that prophylactic use of antioxidants like mentia (Jean-Louis et al., 1998), Alzheimer's disease (Wade et al., melatonin may help prevent or reduce oxidative stress-related diseases 2014) and insomnia (Xu et al., 2015). in newborns (Gitto et al., 2013). Indeed, short-term melatonin therapy Anxiety spectrum disorders are highly prevalent and debilitating is highly effective and safe in reducing complications during pregnancy

Table 1 A brief summary of positive clinical effects of melatonin on CNS disorders.

Patients CNS disorder Treatment Effects References

Children Epilepsy 9 mg for 4 weeks Reduced insomnia (Jain et al., 2015) Autism 0.75-6 mg for 1.8 years Reduced insomnia (Andersen et al., 2008) Autism 1-3 mg for 14 weeks Reduced insomnia (Malow et al., 2012) Developmental disabilities 5 mg for 6 weeks Reduced sleep latency (Dodge and Wilson, 2001) Neurodevelopmental disorders 0.5-12 mg for 12 weeks Improved sleep quality (Gringras et al., 2012) Neurodevelopmental disorders 0.5-12 mg for 12 weeks Reduced sleep latency (Appleton et al., 2012) Chronic idiopathic insomnia 5 mg for 4 weeks Improved health status and sleep quality (Smits et al., 2003) Children and adults Tuberous sclerosis 5 mg for 5 weeks Improved total sleep time (O’Callaghan et al., 1999) Tuberous sclerosis 5 and 10 mg for 8 weeks Reduced sleep latency (Hancock et al., 2005) Mental disabilities and epileptic seizures 3-9 mg for 2 months Improved sleep/wake cycle, reduced epileptic (Coppola et al., 2004) seizures Adults Delayed sleep phase syndrome 5 mg for 4 weeks Reduced depression and improved sleep quality (Rahman et al., 2010) Traumatic brain injury 2 mg for 4 weeks Improved sleep quality and reduced anxiety (Grima et al., 2018) Fibromyalgia 10 mg for 6 weeks Reduced pain (de Zanette et al., 2014) Multiple sclerosis 3 mg for 12 months Improved cognitive performance (Roostaei et al., 2015) Adults and elderly Parkinson’s disease 5 and 50 mg for 2 weeks Improved sleep quality (Dowling et al., 2005) Parkinson’s disease 3 mg for 4 weeks Improved subjective quality of sleep (Medeiros et al., 2007) Schizophrenia and tardive dyskinesia 10 mg for 6 weeks Reduced tardive dyskinesia (Shamir et al., 2001) Schizophrenia 3-12 mg for 15 days Improved sleep architecture, mood and daytime (Kumar and Kalonia, 2007) functioning Primary insomnia 2 mg for 3 weeks Improved sleep architecture, mood and quality of life (Wade et al., 2007) Elderly Mild cognitive impairment 3-9 mg for 9–18 months Improved sleep quality and cognitive performance (Furio et al., 2007) Mild cognitive impairment 6 mg for 10 days Improved sleep quality, memory and mood (Jean‐Louis et al., 1998) Alzheimer’s disease 2 mg for 24 weeks Improved sleep quality and cognitive function (Wade et al., 2014) Dementia 3 mg for 4 weeks Improved sleep quality and cognitive function (Asayama et al., 2003) Amyotrophic lateral sclerosis 300 mg/day for 24 Reduced oxidative markers and promoted (Weishaupt et al., 2006) months neuroprotection

118 R. Genario, et al. Neuroscience and Biobehavioral Reviews 99 (2019) 117–127 and in the perinatal period, thus becoming an attractive therapy in animal model organisms. Complementing melatonin data in rodents, pregnancy and as a promising neuroprotective agent in perinatal as- resent findings support its role in neurobehavioral regulation inother phyxia (Marseglia et al., 2015b). vertebrates, including birds (Cassone and Brooks, 1991; Dawson et al., Genetic variance in melatonin-related genes has also been linked to 2001), reptiles (Firth et al., 2009; Tosini et al., 2001), amphibians CNS pathogenesis. For example, mutations of circadian genes regulated (Isorna et al., 2004; Tavolaro et al., 1995) and fishes (Falcón et al., by melatonin (e.g., per2, per3, clock, arntl) and its receptor genes 2007; Falcon et al., 2010; Iigo et al., 2003). For example, stress and (Mtnr1a, Mtnr1b) have been associated with autism (Jonsson et al., stress hormones (e.g., cortisol) affect pineal melatonin production in 2010; Yang et al., 2016). Sleep disorders are also linked to circadian rainbow trout, Oncorhynchus mykiss (López-Patiño et al., 2014). Mela- genes, including mutations in the per3 gene (Archer et al., 2010; tonin treatment enhances serotoninergic and dopaminergic metabolism Ebisawa et al., 2001) and polymorphisms in the AANAT gene (Hohjoh in the hypothalamus of this fish, and lowers plasma cortisol and aber- et al., 2003), whereas polymorphisms of genes related to melatonin rant monoaminergic metabolism following stress (Conde-Sieira et al., signaling (Mtnr1a and Mtnr1b) and biosynthesis (e.g., AANAT and 2014). Collectively, this emphasizes the importance of studying the role ASMT) are implicated in schizophrenia (Park et al., 2011), depression of melatonin in CNS mechanisms in-depth utilizing various alternative (Gałecka et al., 2011; Gałecki et al., 2010) and a promising attention organisms, including fish models. deficit hyperactivity disorder (ADHD) (Chaste et al., 2011). 4. Effects of melatonin in zebrafish models 3. CNS effects of melatonin in rodents and other models 4.1. Neurobehavioral effects of melatonin in zebrafish Animal models are a valuable tool to probe neurobiological me- chanisms of normal and pathological brain functions. Paralleling clin- A small tropical freshwater teleost fish, the zebrafish (Danio rerio) ical findings, the role of melatonin in sleep and cognitive regulation has has recently gained popularity in neuroscience as a low-cost, geneti- been established in rodent models (Fuller et al., 2006; Sugden, 1983). cally tractable vertebrate species with high physiological and genetic For example, melatonin supplementation improves cognitive perfor- homology to (Kalueff et al., 2014a, b). Zebrafish express well- mance in sleep-deprived animals, also increasing hippocampal anti- developed behavioral phenotypes, and respond to a wide range of CNS oxidant protection and lowering oxidative stress (Alzoubi et al., 2016; drugs (Cachat et al., 2010; Egan et al., 2009; Giacomini et al., 2016), Kumar and Singh, 2009; Silva et al., 2004). Similarly, melatonin de- including melatonin (Lima-Cabello et al., 2014; Zhdanova et al., 2008). monstrates overt sedative/pro-hypnotic effects in rodents (Sugden, Various models of CNS diseases have already been established in zeb- 1983), likely through the modulation of the gamma aminobutyric acid rafish, ranging from neurodegenerative to affective, psychotic and (GABA) system (Wang et al., 2003). neurodevelopmental disorders (Kalueff et al., 2014b; Meshalkina et al., The neuroprotective action of melatonin suggests its potential role in 2018; Norton, 2013). Taken together, this emphasizes the growing experimental models of neurodegenerative disorders (Feng et al., 2006; utility of zebrafish in CNS disease modeling and studying physiological Patki and Lau, 2011). For example, in a rat Parkinson's model evoked by and behavioral adaptations (Lima-Cabello et al., 2014; Zhdanova et al., rotenone, melatonin exerts both neuroprotective (reducing dopaminergic 2001, 2008). injury) and antidepressant activity (e.g., lowering immobility in the forced Zebrafish possess a well-developed melatonin system in the brain swim ‘despair’ test) (Bassani et al., 2014). In a transgenic mouse model of (Lima-Cabello et al., 2014), and produce it in the pineal gland and in Alzheimer's disease, melatonin reduces anxiety- and depression-like beha- the retina, like mammals (Falcón et al., 2007). The biosynthesis of vior (Nie et al., 2017), strikingly paralleling clinical data on therapeutic melatonin involves an enzymatic conversion from tryptophan, which efficacy of melatonin discussed earlier Table 1. Melatonin also protects serves as the precursor. It is first converted to serotonin (5-hydro- against the neurotoxin 6-hydroxydopamine (6-OHDA), inhibiting the pro- xytryptophan) followed by catalyzing by the arylalkylamine-N-acetyl- duction of free radicals in rodent brain (Borah and Mohanakumar, 2009; transferase (AANAT) into N-acetyl-serotonin (Klein et al., 1997). This Simola et al., 2007) and lowering its hypoxia- and ischemia-related oxi- dark-dependent step is next followed by the methylation of N-acetyl dative stress (Carloni et al., 2008; Qiu and Xu, 2016). Similarly, melatonin serotonin by hydroxyindole-O-methyltransferase (HIOMT) to produce protects against other neurotoxins, such as phosphamidon (Sharma et al., melatonin (Bégay et al., 1998; Falcon et al., 2010). Zebrafish possess 2013), isoflurane (Liu et al., 2013) and scopolamine (Wang et al., 2013). two aanat genes, aanat1 and aanat2 (Appelbaum et al., 2006), likely Furthermore, melatonin and related drugs reduce anxiety in rodents due to teleost-specific genome duplications (Falcón et al., 2007). (Karakas et al., 2011; Tian et al., 2010), especially in the models of Aanat1 is expressed in the retina, and aanat2 expressed in the pineal chronic stress and/or disturbed circadian rhythms (Golombek et al., 1993; gland and, at a low level, in the retina (Falcón, 1999; Falcón et al., Kopp et al., 2000; Papp et al., 2006). Likewise, melatonin reduces rodent 2007). Many of the pineal melatonin effects are mediated via Mtnr1a depression-like behaviors (Detanico et al., 2009; Raghavendra et al., and Mtnr1b (Chai et al., 2013), highly conserved in vertebrates (Falcón 2000; Sun et al., 2017; Tian et al., 2010) and attenuates behavioral and et al., 2007). In teleost fishes, Mtnr1a and Mtnr1b receptors localize in neuroendocrine consequences of prolonged stress (Detanico et al., 2009; the pituitary, telencephalon, diencephalon, mesencephalon and rhom- Haridas et al., 2013). For example, in the chronic mild stress (CMS) bencephalon (Gaildrat and Falcón, 2000; Herrera-Pérez et al., 2010; model, chronic melatonin attenuates the effects of a 21-day CMS onsu- Maitra and Hasan, 2016). Zebrafish Mtnr1a and Mtnr1b receptors show crose intake and locomotion in male rats (Kopp et al., 1999). Melatonin high homology with their and rodent orthologues (75% and reduces serum corticosterone levels and anxiety-like behavior induced by 74% Mtnr1a; 69% and 62% Mtnr1b genetic sequence homology vs. chronic immobilization stress, increasing the release of oxytocin, ser- humans and mice, respectively), as assessed by the BLAST database otonin and noradrenaline in the frontal cortex (Gomaa et al., 2017). analyses (Table 2). Notably, zebrafish genome consist of 6 Mtnr para- Anxiolytic-like effects of melatonin in rodent models involve the GABA- logues (Mtnr1aa, Mtnr1ab, Mtnr1a-like, Mtnr1ba, Mtnr1bb and Mtnr1c ergic system, a primary target for many commonly used, clinically active (Villarreal et al., 2017), two of which (Mtnr1aa and Mtnr1ab) share the anxiolytics (Golombek et al., 1993). Furthermore, administration of this same putative epitope sequence (Villarreal et al., 2017), Table 2. Thus, hormone attenuates detrimental effects of chronic stress on rodent sexual zebrafish may serve not only as supplementary, but also ascom- behavior (Brotto et al., 2001), accompanied by reducing a pro-in- plementary tools to study the complex genetic mechanisms of sleep flammatory cytokine interleukin IL-4 and boosting an anti-inflammatory deficits and other CNS disorders. cytokine IL-10 (Kalinichenko et al., 2014). Collectively, this calls for further probing melatonin-related CNS The importance of targeting evolutionarily conserved, core me- mechanisms and behavioral processes in zebrafish. For example, they chanisms of melatonin activity necessitates widening the spectrum of have recently emerged as an important novel model of sleep and

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Table 2 Melatonin-related genes in zebrafish (accessed in www.ensembl.org, searching for melatonin-related genes in zebrafish) and their human and mouse orthologues, based on the National Center for Biotechnology Information (NCBI) Genetic Testing Registry (GTR) database with % homology calculated based on identity using the HomoloGene database (www.ncbi.nlm.nih.gov/homologene).

Genes Symbols Main neurobiological functions % Homology

Zebrafish vs Human Zebrafish vs Mouse Human vs Mouse

Melatonin receptor 1 A (a and b) Mtnr1aa, Mtnr1ab Control of reproductive and circadian actions of 75 74 84 melatonin 1 A-like* Mtnr1 Al Control of reproductive and circadian actions of 77 74 – melatonin Melatonin receptor 1Ba** Mtnr1Ba Control of reproductive and circadian actions of 60 59 81 melatonin Melatonin receptor 1Bb Mtnr1Bb Control of reproductive and circadian actions of 69 62 melatonin Melatonin receptor 1C*** Mtnr1C Control of reproductive and circadian actions of – – – melatonin Arylalkylamine N-acetyltransferase 1 Aanat1 Biosynthesis of melatonin 67 71 85 Arylalkylamine N-acetyltransferase 2 Aanat2 Biosynthesis of melatonin 62 64 85 Dopa decarboxylase Ddc Biosynthesis of dopamine 72 74 89 Acetylserotonin O-methyltransferase Asmt Biosynthesis of melatonin 47 36 48 Hypocretin/ 2 Hcrtr2 Regulation of feeding behavior 71 72 94 Tryptophan hydroxylase 1a Tph1a Biosynthesis of serotonin 80 78 89 Tryptophan hydroxylase 1b Tph1b Biosynthesis of serotonin 77 75 89 Tryptophan hydroxylase 2 Tph2 Biosynthesis of serotonin 74 77 93 Average homology rate, % 69.25 68 83.7

* Compared to Mtnr1 A human/mouse homologues respectively. ** Using Q90456 Uniprot sequence to compare vs. HomoloGene P49286 sequence for Human or Q3SXF8 for Mouse Mtnr1B receptors in BLAST (www.blast.ncbi. nlm.nih.gov/) due to the lack of this gene in the Homologene database. *** Not present in human or mouse.

Fig. 1. Effects of melatonin treat- ment in adult zebrafish under light housing, tested in the 15-min novel tank test. Endpoints assessed following 0.232 mg/L melatonin exposure for 24 h included distance traveled (U = 168; p = 0.3949), entries to the top (U = 80.5; p = 0.0009), time in top zone (U = 107; p = 0.0112). Data are expressed as mean + SEM, significance (P) assessed by an unpaired Mann- Whitney U test (n = 20 per group).

Table 3 Summary of the effects of melatonin on the expression of zebrafish CNSgenes.

Gene Biological function References

Increased expression Arylalkylamine N-acetyltransferase 1 Control of biosynthesis of melatonin (Khan et al., 2016) Arylalkylamine N-acetyltransferase 2 Control of biosynthesis of melatonin Leptin receptor Regulation of body weight and food intake (Piccinetti et al., 2010) 4 Regulation of body weight and food intake PTEN induced putative kinase 1 Mitochondrial protection, autophagic cell control and oxidative protection (Díaz-Casado et al., 2016) Protein DJ-1-like Locomotion, autophagy, cellular protection and oxidative protection Mitochondrial E3 ubiquitin protein ligase 1 Mitochondrial function and autophagy control Reduced expression Ghrelin Regulation of body weight and food intake (Piccinetti et al., 2010) Neuropeptide Y Stress response, food intake, circadian rhythms 1 Control of mood, cognition, food intake, behavior and pain responses circadian rhythms (Cahill and Research, 2002; Elbaz et al., 2013; 2001), inducing neuroprotective and antioxidant effects (Han et al., Zhdanova, 2011), including various models of sleep deprivation (Rihel 2017; Lima-Cabello et al., 2014), protecting against toxins (e.g., a et al., 2010; Zhdanova, 2006) – directly modulated by melatonin. Ex- Parkinsonic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine posed to constant luminosity, zebrafish also display cognitive deficits (MPTP) (Díaz-Casado et al., 2016) and alleviating the evoked oxidative (Pinheiro-da-Silva et al., 2017) and anxiety (Singh et al., 2013) cor- stress, apoptosis and locomotor deficits (Han et al., 2017). rected by melatonin (Fig. 1). Melatonin also attenuates cognitive defi- Given shared effects of melatonin on anxiety in humans and rodents, cits caused by aging, which, in turn, is associated with lower production examining its acute action in zebrafish is warranted. To address this of melatonin (Zhdanova et al., 2008). Like in mammals, this hormone question, we utilized 40 adult zebrafish (˜50/50 male/female ratio) of also exerts robust pro-hypnotic effects in zebrafish (Zhdanova et al., the wild-type short-fin strain housed for 24 h at the University of Passo

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Fig. 2. A general overview of melatonin effects on human and animal CNS pathogenetic processes. In clinical patients, the left side of the brain summarizes theeffects of melatonin, and the right half of the brain presents detrimental effects caused by CNS disorders.

Table 4 increases top activity (entries to top and time in top), thereby demon- Selected open translational questions concerning melatonin role in CNS dis- strating robust anxiolytic-like effects in this zebrafish model (Fig. 1). orders. Such effects in zebrafish would generally be in line with a pro-hypnotic Questions action of melatonin already reported in these fish (Zhdanova, 2005), since many anxiolytic agents (including melatonin) display anxiolysis at Clinical and conceptual low and hypnotic/sedative effects at higher doses. Likewise, chronic 2- • Which does come first - melatonin deficits or CNS disorder? week administration of melatonin in zebrafish reverses anxiogenic ef- • What are neuronal, genetic and physiological endpoints linking melatonin deficits to CNS disorders, and vice versa? fects of radiation (Nirwane et al., 2016). • What are neurodevelopmental effects of melatonin? Furthermore, circadian rhythms modulate learning and memory in • Are there epigenetic mechanisms involved in melatonin-related CNS disorders? vertebrate and invertebrate models (Gerstner and Yin, 2010). For ex- • What are physiological and behavioral effects of melatonin receptors antagonist? ample, zebrafish trained in a modified active avoidance conditioning • How does correcting monoamine signaling affect melatonin signaling? • Why both the lack of and excessive sleep are detrimental, and how does melatonin paradigm during their active phase (daytime) under a light/dark cycle play a role in these deficits? learn faster compared to training during the nighttime, suggesting that • Is there a significant molecular interplay between melatonin and* GABA -ergic melatonin may indeed inhibit memory consolidation (Rawashdeh et al., system? 2007). Melatonin also affects reproduction and follicular maturation in • Are there significant side effects of melatonin supplementation? zebrafish (Carnevali et al., 2011, 2010; Danilova et al., 2004). Under • Can melatonin supplementation evoke abuse-like states and/or withdrawal-like states (upon cessation)? darkness housing, zebrafish exhibit higher levels of melatonin inthe • How can melatonin receptors antagonists be used clinically, and what are their brain and ovary, increasing gonadotrophin releasing hormone produc- physiological effects? tion (Yumnamcha et al., 2017). Melatonin also regulates zebrafish • How do the lack or excess of melatonin alters common endophenotypes related to feeding behavior and metabolism, causing an anorexic effect by sti- psychiatric diseases? • How do melatonin receptors differ in their CNS effects, especially among species? mulating synthesis of leptin (a satiety hormone) and inhibiting an or- • What are effects of chronic melatonin exposure in humans? How do they differfrom exigenic hormone ghrelin (Montalbano et al., 2018; Piccinetti et al., acute effects? 2010). Model-specific In addition to melatonin, novel melatonergic drugs have recently • What is unique role of zebrafish melatonin receptor C that is not observed in humans been developed. For example, (a selective Mtnr1a and and rodents? • How do the lack or excess of melatonin after common endophenotypes related to Mtnr1b agonist) injected into the suprachiasmatic nucleus causes hy- psychiatric diseases? polocomotion and immobility in adult zebrafish (Gupta et al., 2014), • What are effects of chronic melatonin exposure in animal models? How dothey whereas, like in other model species, many effects of melatonin can be differ from acute treatment? blocked in zebrafish by its receptor antagonists, such as • How do personality traits predict animal responsivity to melatonin treatments? • Are there robust and stable individual differences in zebrafish behavioral responses (Danilova et al., 2004; Rawashdeh et al., 2007; Ren et al., 2015; to melatonin? Zhdanova, 2011). • Does sensitivity to hypnotic effects of GABA-ergic drugs correlate with zebrafish responses to melatonergic drugs? • What are strain and sex differences in melatonin effects in zebrafish, andinthe 4.2. Melatonin-related genomic responses in zebrafish brain patterns of melatonin-related gene expression? • Are there specific tests for screening melatonin-related phenotypes in zebrafish? Like in mammals, melatonin interacts with various CNS genes re- * GABA – gamma aminobutyric acid. lated to circadian rhythm and complex behaviors of zebrafish (Lima- Cabello et al., 2014). For example, in addition to reduced food intake, zebrafish treated with melatonin display up-regulated expression of Fundo (Brazil) under a 14-h light/10-h dark photoperiod. Zebrafish anorexigenic molecules leptin and melanocortin receptor 4 (MC4R) and behaviors were assessed in the novel tank test, the most sensitive down-regulated orexigenic factors ghrelin, neuropeptide Y (NPY) and aquatic paradigm for measuring zebrafish affective behaviors (Kysil cannabinoid receptor 1 (CB1) (Piccinetti et al., 2010). In zebrafish et al., 2017). Examining the effects of melatonin on zebrafish behavior, embryos, melatonin co-administered with MPTP prevents Parkinson- we compared control and melatonin-treated (0.232 mg/L for 24 h) like pathogenesis by restoring parkin/PINK1/DJ-1/MUL1 gene expres- zebrafish behaviors in this test, showing that melatonin significantly sion, thereby normalizing the activity of this pathway, and also

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Fig. 3. A complex molecular network of zebrafish melatonin-regulated genes. The network was constructed based on genes listed in Tables 2 and 3 using STRING database (www.string-db.org/) based on known molecular interactions of the respective gene protein products’, for moderate effect and excluded text- mining data. of the biosynthesis of serotonin (a precursor of melatonin) and melatonin receptors form a compact cluster including tryptophan hydroxylase 1b (tph1b), tryptophan hydroxylase 1a (tph1a) and tryptophan hydroxylase 2 (tph2) proteins co-modulating serotonin signaling and melatonin biosynthesis. The arylalkylamine N-acetyltransferase 1 (aanat1) and arylalkylamine N-acetyltransferase 2 (aanat2) proteins co-modulate melatonin signaling, paralleled by interplay between melatonin receptors, neuropeptide Y and cannabinoid receptor 1. rescuing locomotion (Díaz-Casado et al., 2016). Likewise, melatonin directed research with the help of zebrafish models. Analyses of such modulates apoptotic genes, diminishing apoptosis and preventing genomic targets of zebrafish melatonin-regulated genes (Table 2 and 3) swimming deficits in a zebrafish model of fenvalerate neurotoxicity in-silico reveal a complex molecular network in which tryptophan hy- (Han et al., 2017). Table 3 summarizes a wide range of effects of droxylase 1b (tph1b), tryptophan hydroxylase 1a (tph1a) and trypto- melatonin on zebrafish CNS genes. Finally, zebrafish may also represent phan hydroxylase 2 (tph2) proteins co-modulate serotonin signaling, useful genetic models to study central effects of melatonin. For instance, consequently influencing melatonin biosynthesis (Fig. 3). The same is transgenic zebrafish where the molecular clock is selectively blocked in true for the aanat1 and aanat2 proteins that interact and modulate the pineal melatonin-producing cells, show disrupted melatonin pro- melatonin signaling (Fig. 3). duction (Ben-Moshe Livne et al., 2016). Collectively, this not only de- However, the zebrafish, like any other potentially useful model or- monstrates a wide spectrum of genes related to melatonin action in ganism, has its limitations, as has been critically evaluated elsewhere zebrafish brain, and but also supports the utility of zebrafish genetic (Kalueff et al., 2014b; Meshalkina et al., 2017). For example, zebrafish models to probe melatonin neurobiology in this organism. Combined express multiple orthologous ‘melatonin’ genes which share only ap- with the growing availability of modern genetic tools in zebrafish proximately 70% of homology with those in mammals (Table 2). In (Howe et al., 2016; Liu et al., 2017), this line of inquiry becomes im- addition, as already mentioned, zebrafish underwent another, teleost- portant. specific genome duplication that may complicate studying some genes, but can offer interesting opportunities for studying some other, espe- 5. Conclusion cially crucial ‘viable’, genes (Kalueff et al., 2014b; Meshalkina et al., 2018). Overall, clinical and experimental data reveal a complex picture of Furthermore, melatonin also demonstrates likely epigenetic reg- mechanisms and biological targets regulated by melatonin in the brain ulation of gene expression that may underlie its CNS effects. For ex- (Fig. 2). Together with high genetic homology of melatonin-related ample, chronic treatment with melatonin causes histone hyperacetyla- genes (Table 2), this supports shared, evolutionarily conserved role of tion in rat neural stem cells (Niles et al., 2013), and similar epigenetic melatonin in neurobehavioral regulation in zebrafish, rodents and hu- effects may exist in zebrafish. Likewise, since neurodegenerative dis- mans. Although our current knowledge of CNS effects of this hormone eases alter histone acetylation (Mattson, 2003), the epigenetic mod- is still limited (Table 4), we recognize the promise of animals models for ulation of melatonin Mtnr1a and Mtnr1b receptors (especially in brain probing these effects (Lima-Cabello et al., 2014; Ping et al., 2018), areas where they are lost because of ageing, injury or disease), may be a based on robust sensitivity of rodents and zebrafish to genetic and promising therapeutic strategy (Bahna and Niles, 2018), meriting fur- pharmacological modulation in all major neurobehavioral domains ther testing in both rodent and zebrafish models (Fig. 4). (Fig. 2). Finally, melatonin supplementation is widely used clinically as a The growing number of genes modulated by melatonin in zebrafish safe and effective treatment of insomnia and circadian rhythms (Auld brain (Table 3) further supports this notion, calling for new target- et al., 2017; Golombek et al., 2015). Therefore, it may be an effective

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Fig. 4. A complex molecular network constructed using STITCH database (www.stitch.embl.de/) based on known molecular interactions of melatonin (denoted by an arrow) with moderate effect and excluded data-mining data. Several clusters include melatonin receptor-related genes, two asmt genes, cytochrome 450-associated genes, adenylate cyclase related genes (involved in melatonin signaling transduction) and diverse, but closely related large group of neurochemical and other proteins, including serotonin, adenosine and dopamine receptors that differentially modulate melatonin effects. alternative over other CNS drugs, such as benzodiazepines, currently example, in severe dementia, it is difficult to establish an effective dose, widely used to treat depression, anxiety and sleep deficits (Cardinali and therefore pharmacological treatments tend to fail in improving et al., 2016; Sonnenberg et al., 2012), but possessing markedly more sleep quality and slowing down cognitive deterioration (Defrancesco serious side effects, compared to melatonin. In addition to melatonin et al., 2015). In addition, polypharmacy and chronic drug use may per se, other melatonin-related drugs may also be effective in treating decrease the effectiveness of subsequent treatments. For instance, insomnia and improving sleep quality (Kupfer, 2006; Kuriyama et al., melatonin has no effects on benzodiazepine withdrawal (Wright et al., 2014). 2015). Another factor to consider is the genetic polymorphisms of However, some differences in pharmacological response may also melatonin receptors (Park et al., 2011) and key enzymes of synthesis exist between experimental and clinical studies, factoring into potential and biotransformation that may affect its therapeutic response in pa- problems with data translatability. One possible explanation for these tients and/or impact therapeutic action of melatonin supplementation differences can be that experimental studies (e.g., of melatonin) gen- (Rossignol and Frye, 2011). Finally, modulating evolutionarily con- erally evaluate the drug individually, whereas in clinical research the served melatonin-related mechanisms discussed here in a wide range of drug is associated with several other drugs, due to other disorders model organisms (Fig. 2) may foster the search for effective treatments presented by the patient and/or polypharmacy (Jellinger and Attems, on various CNS disorders, including sleep, eating, affective and neu- 2015; Müller-Rebstein et al., 2017; Sganga et al., 2015). Such phar- rodegenerative disorders. Combined with high- and medium- macological interactions may decrease the efficiency of the treatment throughput potential of zebrafish models (Fontana et al., 2018; Kalueff and make it difficult to determine the effective dose of each drug. For et al., 2014a; Stewart et al., 2014), this line of research may lead to

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