Mol. Cells 2017; 40(7): 450-456
Published online July 31, 2017
https://doi.org/10.14348/molcells.2017.0065
© The Korean Society for Molecular and Cellular Biology
Correspondence to : *Correspondence: kyungjin@dgist.ac.kr
Mammalian physiology and behavior are regulated by an internal time-keeping system, referred to as circadian rhythm. The circadian timing system has a hierarchical organization composed of the master clock in the suprachiasmatic nucleus (SCN) and local clocks in extra-SCN brain regions and peripheral organs. The circadian clock molecular mechanism involves a network of transcription-translation feedback loops. In addition to the clinical association between circadian rhythm disruption and mood disorders, recent studies have suggested a molecular link between mood regulation and circadian rhythm. Specifically, genetic deletion of the circadian nuclear receptor
Keywords circadian rhythm, dopaminergic system, mood disorder, Parkinson’s disease, REV-ERBα
The circadian time-keeping system evolved from cyanobacteria to humans, and drives circadian rhythm over a 24-h period to anticipate and respond to environmental changes in accordance with sunrise and sunset. Molecular clocks, found in nearly all tissues, are organized in a hierarchical system, with the master clock located in the hypothalamic suprachiasmatic nucleus (SCN) of the anterior hypothalamus and local clocks located in both extra-SCN brain regions and peripheral organs. The master clock synchronizes the internal timing of peripheral clocks to drive circadian control of physiology and behavior.
Chronic disturbances in circadian rhythmicity in patients with mood disorders were noted over 50 years ago (Wirz-Justice, 2006). Patients with mood disorders, including major depressive disorder (MDD), bipolar disorder (BPD), and seasonal affective disorder (SAD), exhibit disrupted circadian rhythmicity in body temperature, hormone secretions, e.g., cortisol and melatonin, blood pressure, and sleep-wake cycles (Albrecht, 2013; Wirz-Justice, 2006). Human genetic and animal studies have shown molecular links between circadian rhythm and mood disorders (McCarthy and Welsh, 2012). The central neurotransmitter system has been implicated in mood regulation via a variety of biochemical and signal transduction processes (McClung, 2007; Russo and Nestler, 2013). Identification of molecular clockwork components has provided a link between the circadian clock and the monoamine system (Albrecht, 2017).
There is an association between circadian rhythm and emotional regulation in neurodegenerative diseases, such as Parkinson’s disease (PD) (Wulff et al., 2010). PD is characterized by progressive degeneration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc), leading to motor dysfunction (Dauer and Przedborski, 2003). Patients with PD also display non-motor and circadian rhythm-related symptoms, such as mood dysregulation, specifically depression, anxiety, and apathy (Chaudhuri and Schapira, 2009; Videnovic et al., 2014). However, the etiology of mood disorders in PD has not been elucidated, and drug development has been limited (Aarsland et al., 2011). We review the literature concerning mood regulation in healthy and PD states from a chronobiological view.
The mammalian circadian clock is a hierarchical time-keeping system. The master clock, which acts as the circadian pacemaker, is located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. Local clocks exist in extra-SCN brain regions and peripheral organs (Balsalobre et al., 1998; Yamazaki et al., 2000). The master clock synchronizes internal clock timing to external photic zeitgebers from light input via the retina, and peripheral clocks mediate circadian control of physiology and behavior by adjustment from the SCN via endocrine and systemic cues (Dibner et al., 2010).
The daily timing of physiological processes is influenced by peripheral oscillators. Transcriptome-profiling supports this notion; more than 10% of total mRNA shows circadian expression patterns in the liver (Akhtar et al., 2002; Storch et al., 2002; Zhang et al., 2014). By comparing the degree of circadian regulation in different tissues, it has been shown that most circadian gene transcripts are expressed in a tissue-specific manner, and that the circadian phase of gene transcripts is distinct (Panda et al., 2002; Storch et al., 2002).
The circadian clock consists of a network of transcription-translation feedback loops that generate endogenous circadian rhythm. In the core feedback loop, the positive elements include members of the basic helix-loop-helix (bHLH)-PAS (Period-ARNT-Single-minded) domain-containing transcription factor family, CLOCK (or NPAS), and BMAL1 (Bunger et al., 2000; King et al., 1997). CLOCK and BMAL1 heterodimerize and activate transcription of target genes containing E-box
Another regulatory loop controls
Under pathological conditions, decreased circadian amplitude – the difference between peaks and troughs of circadian rhythms – is often observed (Gloston et al., 2017). Rev-erb α is a key molecule for determining amplitude. F-box protein FBX7 ubiquitinates and degrades phosphorylated REV-ERBα by cyclin-dependent kinase 1 (CDK1) to regulate clock amplitude (Zhao et al., 2016). ROR promotes chromatin decondensation during the activation phase of the circadian cycle to facilitate REV-ERB binding to open chromatin during the inactivation phase to maintain circadian amplitude (Zhu et al., 2015).
Patients with mood disorders often display abnormal rhythmicity of body temperature, cortisol and melatonin levels, blood pressure, and sleep/wake cycles suggesting circadian rhythm disruption (Wirz-Justice, 2006). Sundown syndrome, also referred to as “nocturnal delirium,” is characterized by worsening of behaviors such as agitation, aggression, restlessness, and delirium, particularly during the late afternoon/early evening, implying a strong association between circadian rhythm and mood regulation (Bedrosian and Nelson, 2013). Genome-wide association studies have identified circadian gene polymorphisms that influence psychiatric disease susceptibility. These circadian gene variants include
Several animal studies support the influence of circadian clock genes on mood regulation in brain regions implicated in emotion.
In the midbrain, the circadian nuclear receptor REV-ERBα is a crucial modulator of mood-related behaviors (Chung et al., 2014).
Mood is controlled by complex neural circuits and various neurotransmitters. Many brain regions that contribute to mood, including the hippocampus, prefrontal cortex (PFC), VTA, nucleus accumbens (NAc), amygdala, hypothalamus, and lateral habenula, interact with each other via circuits in the DAergic, noradrenergic, serotonergic, glutamatergic, and GABAergic pathways (Nestler and Carlezon, 2006).
The DAergic system is implicated in mood regulation (Chung et al., 2014; Hampp et al., 2008; Roybal et al., 2007). DAergic neurons in the VTA innervate the PFC and the NAc, which are referred to as the mesocortical and mesolimbic pathways, respectively. The mesocorticolimbic pathway is important for the control of motivation, emotion, and reward functions (Renard et al., 2001; Wise, 1998; Yadid et al., 2001). Abnormalities in this circuit induce addiction, affective disorders, schizophrenia, and attention-deficit hyperactive disorder (Grace, 2016; Hyman and Malenka, 2001; Volkow et al., 2009). The nigrostriatal pathway from the substantia nigra (SN) to dorsal striatum (also known as the caudate-putamen) is another DAergic pathway associated with motor function; degeneration of this circuit can induce PD (Cheng et al., 2010).
DAergic neurons in the SN and VTA have distinct anatomical, molecular, and electrophysiological characteristics, though some projection patterns have been shown to overlap (Brichta and Greengard, 2014). Few DAergic projections originating from the SN innervate the ventral striatum, while some VTA projections innervate the dorsal striatum. DAergic projections to the amygdala and PFC come from both SN and VTA (Björklund and Dunnett, 2007). The SN and VTA receive afferent inputs from brain regions involved in mood regulation, such as the central amygdala and dorsal raphe (Watabe-Uchida et al., 2012). Based on the partially shared input-output networks, we speculate that the functions of the SN and VTA may not be mutually exclusive.
Notably, both the SN and VTA harbor functional clockwork, and the key activities of these regions oscillate in a circadian manner. Core clock genes, including
PD is a neurodegenerative disorder that results from DAergic neuronal death in the SNpc (Dauer and Przedborski, 2003), resulting in motor deficits as well as non-motor symptoms, such as mood dysregulation. DAergic neuron degeneration is more concentrated in the SNpc ventral tier than the SNpc dorsal tier and VTA, suggesting that SN and VTA DAergic neurons have different susceptibilities to degeneration in PD (Brichta and Greengard, 2014). Ventral SNpc DAergic neurons innervate not only the striatum (Cebrián and Prensa, 2010) but also the PFC (Björklund and Dunnett, 2007), which is implicated in PD with depression (Aarsland et al., 2011). Thus, the SNpc ventral tier may be implicated in both the motor and non-motor symptoms of PD. Approximately 45% of patients with PD experience depression (Burn, 2002; Chaudhuri and Schapira, 2009), and 50% have comorbid anxiety (Brown et al., 2011). Although the etiology of mood disorders in PD is unclear, dysfunctional monoaminergic neurotransmission is widely observed (Braak et al., 2003; Halliday et al., 1990; Zarow et al., 2003). However, direct evidence for the contribution of serotonin to mood disturbances in PD is lacking (Leentjens et al., 2006). Selective serotonin reuptake inhibitors (SSRIs), classic antidepressants, lack efficacy in patients with PD (Weintraub et al., 2005). Levodopa (L-DOPA) treatment, a well-known antiparkinsonian drug, does not improve anxiety and depression in patients with PD (Kim et al., 2009; Richard et al., 2004). Pramipexole (DA agonist) and nortriptyline (tricyclic antidepressant that acts as a serotonin and norepinephrine reuptake inhibitor but has side effects) are the only effective drugs for depression in PD (Aarsland et al., 2011). Therefore, therapeutic approaches that control the upstream regulators of the DA system, such as REV-ERBα, may hold promise.
Local inhibition of REV-ERBα activity by injection of a potent REV-ERBα antagonist SR8278 (Kojetin et al., 2011) into the ventral midbrain induces a hyperdopaminergic state, caused by disappearance of REV-ERBα repression of TH expression. SR8278-injected mice also exhibit mania-like behaviors, including decreased depressive- and anxiety-like phenotypes at dusk, leading to disappearance of the circadian pattern of mood-related behaviors (Chung et al., 2014; Fig. 2A). Conversely, 6-hydroxydopamine (6-OHDA)-injected mice (animal model of PD) exhibit a hypodopaminergic state owing to DAergic neuronal death in the SNpc and increased depressive and anxiety-like phenotypes at dawn, resulting in disruption of the circadian pattern of mood-related behaviors (unpublished data: Fig. 2A). Changes in mood-related behaviors in SR8278- and 6-OHDA-injected animals can be dissociated from locomotor dysfunction. SR8278-infused mice show an array of mania-like behaviors that cannot be attributed to increased locomotion (Chung et al., 2014). Mice injected unilaterally with 6-OHDA intrastriatally exhibit motor coordination problems, though not regarding voluntary locomotion (Heuer et al., 2012; Roedter et al., 2001). These suggest that appropriate circadian oscillation of DA levels is necessary to elicit circadian mood-related behaviors (Fig. 2B).
Mood disorder, which is often accompanied by sundown syndrome, and disruption of circadian rhythmicity are both common in neurodegenerative diseases, including Alzheimer’s disease (AD) and PD (Bliwise et al., 1995; Wulff et al., 2010). Clinical studies have shown disrupted rest-activity cycles, changes in blood pressure and heart rate rhythm, abnormal hormone secretion, and non-motor symptoms in PD (Videnovic and Willis, 2016). Conversely, circadian abnormalities in PD may also influence pathological processes, e.g., circadian disruption exacerbates motor deficits and DAergic neuronal loss in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of PD (Lauretti et al., 2017). Circadian clock protein deficiency leads to vulnerability to oxidative injury and neurodegeneration in various animal models (Musiek, 2015). Thus, the mechanisms linking molecular clocks and various non-motor symptoms and neurodegeneration in PD should be investigated further. Clock-targeted therapeutics might be beneficial for treating neurodegenerative diseases.
We reviewed the role of the circadian clock in mood-related behaviors in healthy and pathological states. Pharmacological treatments to improve mood disorders, such as SSRIs, lithium, or valproic acid, shift the phase or modulate the circadian rhythm period (Johnsson et al, 1983; McClung et al., 2007; Sprouse et al., 2006). Lithium, a mood stabilizer used to treat BPD, inhibits glycogen synthase kinase-3 beta (GSK3β), which phosphorylates and stabilizes REV-ERBα (Yin et al., 2006). REV-ERBα influences mood regulation through circadian control of the DAergic system (Chung et al., 2014), suggesting that REV-ERBα is a potential therapeutic target for PD with comorbid mood disorders. Small molecules targeting the molecular clock, e.g., a synthetic antagonist of REV-ERB (Kojetin et al., 2011), are being evaluated. REV-ERB agonists alter circadian gene expression in various peripheral tissues and brain regions, and cause diverse physiological changes, especially in sleep architecture and emotional behaviors in mice (Banerjee et al., 2014; Solt et al., 2012). Future studies should characterize the mechanisms of diverse clock-targeting molecules that have therapeutic potential for treating clock-related diseases.
While we mainly highlighted the contribution of the DAergic system to the circadian rhythm of mood regulation and its implication in mood disorders accompanied with PD, we cannot rule out the contribution of other brain circuits. For example, the lateral preoptic area and paraventricular nucleus are enriched with DAergic neurons regulated by photoperiods (Dulcis et al., 2013). The lateral habenula may act as a link between the circadian DAergic system and daily mood regulation in terms of regulating DA release through projections to the SN and VTA (Hikosaka, 2010). Other candidates include the bed nucleus of the stria terminalis, central amygdala, basolateral amygdala, dentate gyrus, and paraventricular thalamic nucleus (Amir and Stewart, 2009; Colavito et al., 2015). Therefore, it is important to understand the role of circadian rhythm in other neuronal circuits and brain regions involved in mood regulation.
Mol. Cells 2017; 40(7): 450-456
Published online July 31, 2017 https://doi.org/10.14348/molcells.2017.0065
Copyright © The Korean Society for Molecular and Cellular Biology.
Jeongah Kim1,2, Sangwon Jang1, Han Kyoung Choe1, Sooyoung Chung3, Gi Hoon Son4, and Kyungjin Kim1,5,*
1Department of Brain and Cognitive Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Korea, 2Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Korea, 3Department of Brain and Cognitive Sciences, Scranton College, Ewha Womans University, Seoul 03760, Korea, 4Department of Biomedical Sciences, College of Medicine, Korea University, Seoul 02473, Korea, 5Korea Brain Research Institute (KBRI), Daegu 41068, Korea
Correspondence to:*Correspondence: kyungjin@dgist.ac.kr
Mammalian physiology and behavior are regulated by an internal time-keeping system, referred to as circadian rhythm. The circadian timing system has a hierarchical organization composed of the master clock in the suprachiasmatic nucleus (SCN) and local clocks in extra-SCN brain regions and peripheral organs. The circadian clock molecular mechanism involves a network of transcription-translation feedback loops. In addition to the clinical association between circadian rhythm disruption and mood disorders, recent studies have suggested a molecular link between mood regulation and circadian rhythm. Specifically, genetic deletion of the circadian nuclear receptor
Keywords: circadian rhythm, dopaminergic system, mood disorder, Parkinson’s disease, REV-ERBα
The circadian time-keeping system evolved from cyanobacteria to humans, and drives circadian rhythm over a 24-h period to anticipate and respond to environmental changes in accordance with sunrise and sunset. Molecular clocks, found in nearly all tissues, are organized in a hierarchical system, with the master clock located in the hypothalamic suprachiasmatic nucleus (SCN) of the anterior hypothalamus and local clocks located in both extra-SCN brain regions and peripheral organs. The master clock synchronizes the internal timing of peripheral clocks to drive circadian control of physiology and behavior.
Chronic disturbances in circadian rhythmicity in patients with mood disorders were noted over 50 years ago (Wirz-Justice, 2006). Patients with mood disorders, including major depressive disorder (MDD), bipolar disorder (BPD), and seasonal affective disorder (SAD), exhibit disrupted circadian rhythmicity in body temperature, hormone secretions, e.g., cortisol and melatonin, blood pressure, and sleep-wake cycles (Albrecht, 2013; Wirz-Justice, 2006). Human genetic and animal studies have shown molecular links between circadian rhythm and mood disorders (McCarthy and Welsh, 2012). The central neurotransmitter system has been implicated in mood regulation via a variety of biochemical and signal transduction processes (McClung, 2007; Russo and Nestler, 2013). Identification of molecular clockwork components has provided a link between the circadian clock and the monoamine system (Albrecht, 2017).
There is an association between circadian rhythm and emotional regulation in neurodegenerative diseases, such as Parkinson’s disease (PD) (Wulff et al., 2010). PD is characterized by progressive degeneration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc), leading to motor dysfunction (Dauer and Przedborski, 2003). Patients with PD also display non-motor and circadian rhythm-related symptoms, such as mood dysregulation, specifically depression, anxiety, and apathy (Chaudhuri and Schapira, 2009; Videnovic et al., 2014). However, the etiology of mood disorders in PD has not been elucidated, and drug development has been limited (Aarsland et al., 2011). We review the literature concerning mood regulation in healthy and PD states from a chronobiological view.
The mammalian circadian clock is a hierarchical time-keeping system. The master clock, which acts as the circadian pacemaker, is located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. Local clocks exist in extra-SCN brain regions and peripheral organs (Balsalobre et al., 1998; Yamazaki et al., 2000). The master clock synchronizes internal clock timing to external photic zeitgebers from light input via the retina, and peripheral clocks mediate circadian control of physiology and behavior by adjustment from the SCN via endocrine and systemic cues (Dibner et al., 2010).
The daily timing of physiological processes is influenced by peripheral oscillators. Transcriptome-profiling supports this notion; more than 10% of total mRNA shows circadian expression patterns in the liver (Akhtar et al., 2002; Storch et al., 2002; Zhang et al., 2014). By comparing the degree of circadian regulation in different tissues, it has been shown that most circadian gene transcripts are expressed in a tissue-specific manner, and that the circadian phase of gene transcripts is distinct (Panda et al., 2002; Storch et al., 2002).
The circadian clock consists of a network of transcription-translation feedback loops that generate endogenous circadian rhythm. In the core feedback loop, the positive elements include members of the basic helix-loop-helix (bHLH)-PAS (Period-ARNT-Single-minded) domain-containing transcription factor family, CLOCK (or NPAS), and BMAL1 (Bunger et al., 2000; King et al., 1997). CLOCK and BMAL1 heterodimerize and activate transcription of target genes containing E-box
Another regulatory loop controls
Under pathological conditions, decreased circadian amplitude – the difference between peaks and troughs of circadian rhythms – is often observed (Gloston et al., 2017). Rev-erb α is a key molecule for determining amplitude. F-box protein FBX7 ubiquitinates and degrades phosphorylated REV-ERBα by cyclin-dependent kinase 1 (CDK1) to regulate clock amplitude (Zhao et al., 2016). ROR promotes chromatin decondensation during the activation phase of the circadian cycle to facilitate REV-ERB binding to open chromatin during the inactivation phase to maintain circadian amplitude (Zhu et al., 2015).
Patients with mood disorders often display abnormal rhythmicity of body temperature, cortisol and melatonin levels, blood pressure, and sleep/wake cycles suggesting circadian rhythm disruption (Wirz-Justice, 2006). Sundown syndrome, also referred to as “nocturnal delirium,” is characterized by worsening of behaviors such as agitation, aggression, restlessness, and delirium, particularly during the late afternoon/early evening, implying a strong association between circadian rhythm and mood regulation (Bedrosian and Nelson, 2013). Genome-wide association studies have identified circadian gene polymorphisms that influence psychiatric disease susceptibility. These circadian gene variants include
Several animal studies support the influence of circadian clock genes on mood regulation in brain regions implicated in emotion.
In the midbrain, the circadian nuclear receptor REV-ERBα is a crucial modulator of mood-related behaviors (Chung et al., 2014).
Mood is controlled by complex neural circuits and various neurotransmitters. Many brain regions that contribute to mood, including the hippocampus, prefrontal cortex (PFC), VTA, nucleus accumbens (NAc), amygdala, hypothalamus, and lateral habenula, interact with each other via circuits in the DAergic, noradrenergic, serotonergic, glutamatergic, and GABAergic pathways (Nestler and Carlezon, 2006).
The DAergic system is implicated in mood regulation (Chung et al., 2014; Hampp et al., 2008; Roybal et al., 2007). DAergic neurons in the VTA innervate the PFC and the NAc, which are referred to as the mesocortical and mesolimbic pathways, respectively. The mesocorticolimbic pathway is important for the control of motivation, emotion, and reward functions (Renard et al., 2001; Wise, 1998; Yadid et al., 2001). Abnormalities in this circuit induce addiction, affective disorders, schizophrenia, and attention-deficit hyperactive disorder (Grace, 2016; Hyman and Malenka, 2001; Volkow et al., 2009). The nigrostriatal pathway from the substantia nigra (SN) to dorsal striatum (also known as the caudate-putamen) is another DAergic pathway associated with motor function; degeneration of this circuit can induce PD (Cheng et al., 2010).
DAergic neurons in the SN and VTA have distinct anatomical, molecular, and electrophysiological characteristics, though some projection patterns have been shown to overlap (Brichta and Greengard, 2014). Few DAergic projections originating from the SN innervate the ventral striatum, while some VTA projections innervate the dorsal striatum. DAergic projections to the amygdala and PFC come from both SN and VTA (Björklund and Dunnett, 2007). The SN and VTA receive afferent inputs from brain regions involved in mood regulation, such as the central amygdala and dorsal raphe (Watabe-Uchida et al., 2012). Based on the partially shared input-output networks, we speculate that the functions of the SN and VTA may not be mutually exclusive.
Notably, both the SN and VTA harbor functional clockwork, and the key activities of these regions oscillate in a circadian manner. Core clock genes, including
PD is a neurodegenerative disorder that results from DAergic neuronal death in the SNpc (Dauer and Przedborski, 2003), resulting in motor deficits as well as non-motor symptoms, such as mood dysregulation. DAergic neuron degeneration is more concentrated in the SNpc ventral tier than the SNpc dorsal tier and VTA, suggesting that SN and VTA DAergic neurons have different susceptibilities to degeneration in PD (Brichta and Greengard, 2014). Ventral SNpc DAergic neurons innervate not only the striatum (Cebrián and Prensa, 2010) but also the PFC (Björklund and Dunnett, 2007), which is implicated in PD with depression (Aarsland et al., 2011). Thus, the SNpc ventral tier may be implicated in both the motor and non-motor symptoms of PD. Approximately 45% of patients with PD experience depression (Burn, 2002; Chaudhuri and Schapira, 2009), and 50% have comorbid anxiety (Brown et al., 2011). Although the etiology of mood disorders in PD is unclear, dysfunctional monoaminergic neurotransmission is widely observed (Braak et al., 2003; Halliday et al., 1990; Zarow et al., 2003). However, direct evidence for the contribution of serotonin to mood disturbances in PD is lacking (Leentjens et al., 2006). Selective serotonin reuptake inhibitors (SSRIs), classic antidepressants, lack efficacy in patients with PD (Weintraub et al., 2005). Levodopa (L-DOPA) treatment, a well-known antiparkinsonian drug, does not improve anxiety and depression in patients with PD (Kim et al., 2009; Richard et al., 2004). Pramipexole (DA agonist) and nortriptyline (tricyclic antidepressant that acts as a serotonin and norepinephrine reuptake inhibitor but has side effects) are the only effective drugs for depression in PD (Aarsland et al., 2011). Therefore, therapeutic approaches that control the upstream regulators of the DA system, such as REV-ERBα, may hold promise.
Local inhibition of REV-ERBα activity by injection of a potent REV-ERBα antagonist SR8278 (Kojetin et al., 2011) into the ventral midbrain induces a hyperdopaminergic state, caused by disappearance of REV-ERBα repression of TH expression. SR8278-injected mice also exhibit mania-like behaviors, including decreased depressive- and anxiety-like phenotypes at dusk, leading to disappearance of the circadian pattern of mood-related behaviors (Chung et al., 2014; Fig. 2A). Conversely, 6-hydroxydopamine (6-OHDA)-injected mice (animal model of PD) exhibit a hypodopaminergic state owing to DAergic neuronal death in the SNpc and increased depressive and anxiety-like phenotypes at dawn, resulting in disruption of the circadian pattern of mood-related behaviors (unpublished data: Fig. 2A). Changes in mood-related behaviors in SR8278- and 6-OHDA-injected animals can be dissociated from locomotor dysfunction. SR8278-infused mice show an array of mania-like behaviors that cannot be attributed to increased locomotion (Chung et al., 2014). Mice injected unilaterally with 6-OHDA intrastriatally exhibit motor coordination problems, though not regarding voluntary locomotion (Heuer et al., 2012; Roedter et al., 2001). These suggest that appropriate circadian oscillation of DA levels is necessary to elicit circadian mood-related behaviors (Fig. 2B).
Mood disorder, which is often accompanied by sundown syndrome, and disruption of circadian rhythmicity are both common in neurodegenerative diseases, including Alzheimer’s disease (AD) and PD (Bliwise et al., 1995; Wulff et al., 2010). Clinical studies have shown disrupted rest-activity cycles, changes in blood pressure and heart rate rhythm, abnormal hormone secretion, and non-motor symptoms in PD (Videnovic and Willis, 2016). Conversely, circadian abnormalities in PD may also influence pathological processes, e.g., circadian disruption exacerbates motor deficits and DAergic neuronal loss in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of PD (Lauretti et al., 2017). Circadian clock protein deficiency leads to vulnerability to oxidative injury and neurodegeneration in various animal models (Musiek, 2015). Thus, the mechanisms linking molecular clocks and various non-motor symptoms and neurodegeneration in PD should be investigated further. Clock-targeted therapeutics might be beneficial for treating neurodegenerative diseases.
We reviewed the role of the circadian clock in mood-related behaviors in healthy and pathological states. Pharmacological treatments to improve mood disorders, such as SSRIs, lithium, or valproic acid, shift the phase or modulate the circadian rhythm period (Johnsson et al, 1983; McClung et al., 2007; Sprouse et al., 2006). Lithium, a mood stabilizer used to treat BPD, inhibits glycogen synthase kinase-3 beta (GSK3β), which phosphorylates and stabilizes REV-ERBα (Yin et al., 2006). REV-ERBα influences mood regulation through circadian control of the DAergic system (Chung et al., 2014), suggesting that REV-ERBα is a potential therapeutic target for PD with comorbid mood disorders. Small molecules targeting the molecular clock, e.g., a synthetic antagonist of REV-ERB (Kojetin et al., 2011), are being evaluated. REV-ERB agonists alter circadian gene expression in various peripheral tissues and brain regions, and cause diverse physiological changes, especially in sleep architecture and emotional behaviors in mice (Banerjee et al., 2014; Solt et al., 2012). Future studies should characterize the mechanisms of diverse clock-targeting molecules that have therapeutic potential for treating clock-related diseases.
While we mainly highlighted the contribution of the DAergic system to the circadian rhythm of mood regulation and its implication in mood disorders accompanied with PD, we cannot rule out the contribution of other brain circuits. For example, the lateral preoptic area and paraventricular nucleus are enriched with DAergic neurons regulated by photoperiods (Dulcis et al., 2013). The lateral habenula may act as a link between the circadian DAergic system and daily mood regulation in terms of regulating DA release through projections to the SN and VTA (Hikosaka, 2010). Other candidates include the bed nucleus of the stria terminalis, central amygdala, basolateral amygdala, dentate gyrus, and paraventricular thalamic nucleus (Amir and Stewart, 2009; Colavito et al., 2015). Therefore, it is important to understand the role of circadian rhythm in other neuronal circuits and brain regions involved in mood regulation.
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