Skip to main content
Download PDF

Neural function of Bmal1: an overview

Cell & Bioscience volume 13, Article number: 1 (2023) Cite this article

Abstract

Bmal1 (Brain and muscle arnt-like, or Arntl) is a bHLH/PAS domain transcription factor central to the transcription/translation feedback loop of the biologic clock. Although Bmal1 is well-established as a major regulator of circadian rhythm, a growing number of studies in recent years have shown that dysfunction of Bmal1 underlies a variety of psychiatric, neurodegenerative-like, and endocrine metabolism-related disorders, as well as potential oncogenic roles. In this review, we systematically summarized Bmal1 expression in different brain regions, its neurological functions related or not to circadian rhythm and biological clock, and pathological phenotypes arising from Bmal1 knockout. This review also discusses oscillation and rhythmicity, especially in the suprachiasmatic nucleus, and provides perspective on future progress in Bmal1 research.

Introduction

Bmal1 (Brain and muscle arnt-like), also known as Arntl, is a bHLH/PAS domain transcription factor that serves as a core factor in the transcription/translation feedback loop (TTFL) of the biological clock. Bmal1 forms a heterodimer with the protein product encoded by the Clock gene. This heterodimer in turn binds genes with E-box elements such as Per 1, Per 2, Per 3, Cry 1, and Cry 2 to activate their transcription. PER and CRY proteins can inhibit CLOCK/BMAL1 heterodimer activity [1, 2], which leads to formation of a negative feedback loop. Recent and ongoing advances in gene targeting technology have enabled closer study of several pathological Bmal1 deletion phenotypes. These studies collectively support that Bmal1 deletion or conditional knockdown/knockout can cause circadian rhythm-related disorders, as well as other disease phenotypes that strikingly resemble psychiatric disorders (e.g., depression, schizophrenia, etc.) and neurodegeneration (e.g., Parkinson's syndrome, etc.) [3,4,5,6,7]. In addition, conditional knockdown/knockout of Bmal1 has also been linked with behavioral abnormalities that occur even while maintaining a normal circadian rhythm [8,9,10]. However, the mechanisms by which defects in this gene can lead to these neurological diseases have remained unclear, suggesting an incomplete understanding of the genetic basis of the biological clock. Thus, considerable research attention has focused on identifying previously unrecognized functions of the biological clock genes such as Bmal1.

Pleiotropy refers to the formation of multiple traits conferred or influenced by a single gene, and thus involves a multiple physiological and can thus simultaneously affect a variety of physiological systems. As a core transcription factor in the TTFL, Bmal1 participates in maintaining the molecular biological clock of cells and can also mediate the development of a variety of diseases. In this paper, we systematically review studies investigating Bmal1 expression in the brain, the neurological function(s) of Bmal1, and pathological phenotypes arising from Bmal1 deficiency to comprehensively understand its effects.

Overview of Bmal1

Genetic data suggest that Bmal1 is an important component of the mammalian circadian pacemaker [11, 12]. In mammals, the biological clock system is a hierarchy of multiple oscillators at the organismal, cellular, and molecular levels. At the organismal level, the suprachiasmatic nucleus (SCN) is the apical, central pacemaker that integrates light information and ultimately regulates the rhythms of gene expression, physiology and behavior. At the cellular level, the SCN consists of multiple oscillatory neurons that are coupled into a circadian unit [13, 14]. Overall, biological rhythms and biological clock genes are thus regulated by a complex network of interactions. Synchronization of the biological clock is calibrated by intercellular coupling following signaling from the central pacemaker, which involves neuronal electrical activity, modulation of activators, synaptic transmission, and transmission of information between the SCN and other brain regions and/or peripheral nerves. Knockout of Bmal1 can abolish circadian rhythms in behavior, blood pressure, and heart rate [11, 12], although this effect is not necessarily observed in a small number of tissues such as fibroblasts [15].

In terms of gross phenotype, mice lacking Bmal1 display decreased body size and weight [16, 17], as well as abnormal knee joint morphology and calcified tendons [18], indicating that the growth and development of these animals can be greatly affected by Bmal1. In addition to impaired growth, Bmal1 global knockout also leads to significantly lower survival rates in mice [17] and display several signs of premature aging, including sarcopenia, cataracts, subcutaneous fat loss, and organ atrophy [16]. The mechanisms responsible for Bmal1 deficiency-related aging may involve mammalian target of rapamycin (mTOR) signaling, sirtuins, or nicotinamide adenine dinucleotide (NAD+) [19,20,21]. Bmal1 is gradually depleted from the nucleus during cellular senescence in human and cynomolgus monkeys. In addition, Bmal1 has been shown to function in maintaining genomic stability, inhibiting LINE1 transposase activation and antagonizing cellular senescence, which cumulatively suggest that Bmal1 may inactivate LINE1 that drives aging in primate cells [22]. Furthermore, Bmal1 knockout was found to induce ovarian dysplasia, significantly reduce follicle and corpora lutea counts, and impair steroid production in female mice. In Bmal1 knockout male mice, testes, seminal vesicles, and seminiferous tubules are generally reduced in diameter [23,24,25]. These results suggest a key role for Bmal1 in reproductive endocrinology and fertility, although we lack an understanding of the underlying mechanisms.

Inflammatory and intracellular immune dysfunction are also strongly associated with defects in Bmal1. Knockout of Bmal1 leads to increased accumulation of reactive oxygen species in macrophages and promotes the accumulation of the hypoxia-responsive protein, HIF-1α, which affects glucose absorption and glycolytic processes, ultimately stimulating pro-inflammatory cytokine IL-1β production [26,27,28]. Additionally, Bmal1 can decrease transcription of chemokine ligand 2 to attenuate the number of Ly6Chi monocytes and inflammation [29]. These above findings show that Bmal1 is an important mediator linking the biological clock with the immune system by limiting inflammatory response. Bmal1 function is also reportedly relevant to hyperglycemia and hypoinsulinemia, most likely through (1) transcriptional regulation of cAMP-responsive element-binding protein H and apolipoprotein AIV to control larger lipoprotein production [30], (2) regulation of β-cell development and function [31, 32], and (3) regulatory contributions to maintaining metabolic homeostasis to ensure normal mitochondrial function [33, 34].

The relationship between Bmal1 and tumors is complicate, and its effects may be bidirectional. For example, it has been demonstrated to inhibit cell growth in some cancers, such as neuroblastoma [35], tongue squamous cell carcinoma [36], spontaneous hepatocellular carcinoma [37] and lung tumors [38]. However, Bmal1 has also been reported as an oncogene [39, 40], such as in acute myeloid leukemia models, where it was shown to be essential for the growth of leukemia stem cell (leukemia stem cell are responsible for disease development and spread). Moreover, disruption of Bmal1 expression results in anti-leukemic effects [39]. It should be noted that the positive effects of Bmal1 on tumor growth are very closely related to its function in the regulation of metabolism. In conjunction with other clock genes, Bmal1 is necessary for metabolic processes in cells by controlling how nutrients and metabolites are utilized in a time-specific manner to support cell proliferation and biomass production [41]. This collective evidence suggests the possibility that Bmal1 could serve as a potential therapeutic target for tumors.

In addition to these functions, a growing body of evidence supports an important role of Bmal1 in neurological disorders, especially psychiatric disorders (e.g., depression, schizophrenia) [3, 42] and neurodegenerative pathologies (e.g., Parkinson's syndrome, Alzheimer's disease, etc.) [4, 5, 7]. However, the mechanisms involved are remarkably broad and complex. A brief overview of the basic functions of Bmal1 is shown in Fig. 1, and a comprehensive perspective of Bmal1 in neural function is provided in sections below.

Fig. 1
figure 1

A brief overview of the basic functions of Bmal1. Bmal1 has important roles in circadian rhythm, vision/image processing, the neurological basis of behaviors, endocrine/exocrine glands, liver/biliary system, homeostasis/metabolism, oncogenesis and tumorprogression, respiratory system, immune system, growth and aging, skeletal system development. Radiographs are from [18]

Full size image

Bmal1-mediated neuronal activity and neural circuits

BMAL1 is a major positive feedback regulator of the biological clock, so current research on its relationship with neuronal activity has focused on the SCN. The SCN consists of multiple neuron types including vasoactive intestinal polypeptide (VIP) and Arginine Vasopressin (AVP) positive neurons [43, 44]. Indeed, almost every neuron in the SCN synthesizes γ-aminobutyric acid (GABA), and GABA signaling plays a dominant role in SCN neuronal activity [45,46,47,48]. Overall, the neuronal activity and transmission between SCN neurons, mediated by TTFL, are relevant to the spontaneous firing rate (SFR) of SCN neurons and intracellular calcium concentration [49] (Fig. 2).

Fig. 2
figure 2

Bmal1-mediated neuronal activity and involved neural circuits. A simplified overview of the relationship between the TTFL and neuronal activity. SCN neuronal activity is controlled by a combination of ion channels and signaling pathways. SCN neurons communicate through synapses, various activation factors, and possibly gap junctions to produce rhythms. Astrocyte regulation of rhythms relies on the regulation of glial transmitters such as Glu, ATP, ASP, and Gly. The regulation of Glu release is closely related to oscillations of the GABAergic network. TTFL: Transcription/Translation Feedback Loop; Glu: glutamate; VIP: Vasoactive intestinal polypeptide; GRP: Gastrin Releasing Peptide; AVP: Arginine Vasopressin; GABA: γ-aminobutyric acid; ASP: Aspartic Acid; Gly: Glycine; VPAC2: Vasoactive Intestinal Peptide Receptor 2; VGCC: Voltage-Gated Calcium Channel; NMDAR: N-methyl-d-aspartate receptor; GABAR: γ-aminobutyric acid receptor; GAT: GABA transporter

Full size image

Electrical activity and activator signaling pathways in SCN neurons

SCN neuronal activity is biologically rhythmic, with the rhythm generated by a combination of ion channels and signaling pathways. First, cyclic changes in the physiological activity of central pacemaker cells occurring over a 24-h period have been observed in both mammals and drosophila. At night, the SFR and input resistance of SCN neurons are lower than during the day in rodents, whereas depolarization of the resting membrane potential is more pronounced in the daytime phase than at night [50,51,52,53,54,55]. In the morning, sodium conductance through NA/NA Leak Channel Non-Selective Protein ion channels depolarizes these neurons. Currents are driven by the rhythmic expression of nematode cation channel localization factor-1, which links the molecular clock to ion channel function. At night, basal potassium currents peak, silencing the clock neurons [56]. Calcium-activated potassium channels (BK channels) are inactivated through their N-type β2 subunits, and inactivation of BK currents during the day reduces their steady-state current levels. At night, the inactivation decreases, thereby increasing the BK current. It is reasonable to speculate that the biological clock may regulate circadian changes in cellular excitability by inactivating gating channels [57]. In addition, inhibiting potassium channel (Kv4.1, Kv4.2) gene expression also leads to an increase SFR in SCN and thus a shorter rhythm cycle [58, 59]. In addition to the role of ion channels, longer day length can alter the expression pattern of chloride transporters. Intracellular chloride accumulation leads to greater production of excitatory GABA synaptic inputs by modulating the strength and polarity of the ionotropic γ-aminobutyric acid receptor (GABAAR)-mediated synaptic inputs. In contrast, blocking either GABAAR signaling, or chloride transporter activity disrupts changes in the phase and cycle induced by light stimuli [60].

Dynamic fluctuations in calcium ions (Ca2+) also play a key role in the regulation of biological clock oscillations, especially biological clock gene transcription [61]. Individual neurons in cultured SCN sections exhibit strong circadian fluctuations in response to intracellular Ca2+ concentration [62], and Ca2+ influx can eliminate the rhythmic expression of biological clock genes. These phenomena suggest that diurnal variation in membrane potential triggered by the cyclic transmembrane influx of Ca2+ has an important role in the rhythmic expression of clock genes [63]. In addition, CaMKII (calmodulin-dependent protein kinase II) also participates in synchronization between individual neuronal clocks. For instance, in Rat-1 cells expressing a Bmal1-luc reporter exposed to 20 µM KN93 (CaMKII inhibitor), the bioluminescence rhythm is substantially attenuated. Knockdown of CamkIIγ and CamkIIδ by siRNA can also significantly attenuate the amplitude of the Bmal1-luc rhythm in NIH3T3 fibroblasts. CaMKII-mediated phosphorylation of CLOCK (i.e., Bmal1 is not phosphorylated) facilitates its interaction with Bmal1 and enhances E-box-dependent gene expression [64]. The peak in Bmal1 transcription occurs before the highest level of action potential, while neuronal activity and Bmal1-driven transcription of the biological clock concurrently increase at the beginning of each daily cycle [14].

Apart from Ca2+ and CaMKII, the cyclic adenosine monophosphate (cAMP) signaling pathway is also an important pathway involved in coupling membrane potential and clock gene expression. Several studies have demonstrated that cAMP levels are rhythmic in the SCN. The cAMP peak occurs during the day in the SCN, prior to the rhythmic peak of the neuronal activity. Transcriptional activity of the cAMP response element is also strongly rhythmic in the SCN [65,66,67]. Casein kinase and signaling by RAS-dependent mitogen-activated protein kinases (MAPKs) is also relevant to rhythmicity. Protein kinase C (PKC) and receptor for activated C kinase-1 (RACK 1) have also been identified as components of the biological clock. These Ca2+-sensitive signal molecules are recruited to the BMAL1 complex in the nucleus. Overexpression or deletion of RACK1 or PKC may affect the suppression of CLOCK-BMAL1 transcriptional activity and circadian period [68]. Thus, these signaling pathways can also act as 'cytoplasmic' oscillators. In conclusion, neuronal electrical activity, intracellular activator signaling pathways, and the transcription of biological clock genes, such as Bmal1 are closely related, and they together mediate biological clock rhythms in the SCN. However, whether these interactions also occur in cells outside of the SCN has not yet been reported.

Inter-neuronal oscillation and neural circuitry

Communication between neurons also follows a biological rhythm. Parvalbumin (PV)-positive neuron-specific deletion of Bmal1 results in a reduced expression of PV and decreased visual acuity in the visual cortex, whereas Bmal1 knockout in forebrain pyramidal neurons of TLCN-Cre mice does not, suggesting that Bmal1 plays an important role in the functional maturation of the PV circuit [69]. In addition, Bmal1 knockout in astrocytes leads to impaired circadian motor behavior, cognition and prolongs the circadian cycle of SCN clock gene expression, suggesting that circadian rhythms in SCN astrocytes regulate the daily rhythms of the SCN and behavior, like rhythmic activity in SCN neurons. The rhythmic oscillations of the SCN are associated with inter-neuronal transmission, whereas astrocytes are associated with maintenance of the rhythmic cycle [48, 70]. Studies have shown that conditional knockout of Bmal1 in astrocytes does not completely disrupt the rhythm of SCN clock gene expression but can delay the cycle by 30 min [70]. Similar findings were obtained in mice with astrocyte-specific knockout of other biological clock genes [71]. It is also noteworthy that Bmal1-deficient mice exhibit impaired formation of actin stress fibers in astrocytes, leading to morphological changes that can negatively impact synaptic function [72].

In order to produce coherent rhythms, SCN neurons communicate through synapses [73], various active factors [74, 75], and possibly gap junctions [76]. Although individual SCN neurons can act as independent circadian oscillators [13], SCN network connections contribute to enhancing overall cellular rhythmicity [77]. In SCN neurons, a variety of cellular processes follow circadian rhythms, including clock gene expression, Ca2+ flux, neuronal firing rates, and neuropeptide release. Furthermore, coupling between SCN neurons requires the involvement of a variety of molecules, including GABA, VIP, and Gastrin Releasing Peptide [78]. This functional coupling is not restricted to neurons, astrocytes also play an important role in neuron-neuron coupling. Synapses in the SCN are "tripartite", consisting of presynaptic axon terminals, postsynaptic membranes, and astrocytes containing GABA transporters [48, 79]. The regulation of rhythm by astrocytes relies on control of glial transmitters such as glutamate (Glu), Adenosine Triphosphate (ATP), Aspartic Acid (ASP), and Glycine (Gly) [80,81,82,83]. The coordination of Glu release is closely related to oscillations in GABAergic network. By using microdialysis, rhythmic changes in GABA were detected in the SCN, which functions as the central pacemaker, as well as in other brain regions [84]. Glu can also transmit retinal light information to the SCN via retinal hypothalamic projections [85, 86]. At night, active astrocytes release Glu, which activates the presynaptic NR2C subunit-containing N-methyl-d-aspartic acid receptor (NMDAR). In turn, NMDAR stimulates the release of GABA, consequently reducing SCN neuronal activity at night [71], and also triggering periodic oscillations in intracellular Ca2+ levels [87]. Investigations of the transcriptional regulatory mechanisms for this oscillation showed that phosphorylation of serine residues in BMAL1 increased in response to Glu stimulation and BMAL1 protein level [88]. Depletion of VIP or VPAC2 knockout both result in the loss of rhythm in SCN brain slices [89], while incubating these SCN slices with wild-type murine SCN brain slices can rescue rhythm in VIP-/VPAC2-deficient SCN tissue [75]. GABA signaling forms connections among neurons in the SCN and helps maintain rhythmic oscillations [90], although antagonizing GABA signaling in normal SCN brain slices does not disrupt the rhythm, and only in the absence of VIP signaling accelerate the loss of rhythm. This finding suggests that VIP signaling may facilitate GABA signaling to antagonize the rhythm. Furthermore, the mechanisms of this GABA-VIP signaling pathway may also play a role in the regulation of intracellular signaling feedback loops by cAMP and Ca2+ [45]. These collective findings thus indicate that the maintenance of rhythm is determined by a balance between VIP and GABA signaling. Overall, oscillation and the neural circuit responsible for rhythm is an extremely complex network. While studies examining the networks between SCN neurons and other cells remain limited, further investigation is also needed to determine the specific influence on transmission and mechanisms through which Bmal1 participates in other neural circuits.

Expression of Bmal1 in different cell types in the brain

Based on genomic data from the Allen Institute for Brain Science (ALLEN BRAIN MAP) [91]. Bmal1 expression patterns in the human brain are similar at different age stage. Specifically, Bmal1 is more abundantly expressed in brain regions such as the parietal/occipital/frontal/temporal lobes, nucleus accumbens, to a lesser extent in the thalamus, cerebellar cortex, striatum, with relatively low expression in the mesencephalon, cerebellum, corpus callosum and other white matter regions (Fig. 3A). By contrast, Bmal1 is most abundantly expressed in the isocortex, thalamus and cerebellum in mice, followed by the cortical subplate and hippocampal formation.

Fig. 3
figure 3

Expression of Bmal1 on different cell types in the brain. A Distribution of Bmal1 in different regions from six normal human samples (aged 24–57), with green and red in the heatmap indicating low and high expression, respectively. The data were obtained from https://portal.brain-map.org/. B–J Expression of Bmal1 in different brain regions of mice. Horizontal axis represents transcripts per 100,000 in each cluster; ordinates represent subsets of cells identified with different markers, with special markers indicated in parentheses. The data were obtained from DropViz website [142]

Full size image

During the perinatal period in mice, Bmal1 was found to be enriched in the cerebral cortex, peaking on postnatal day 3. In utero electroporation combined with RNAi interference experiments in mice revealed that Bmal1 knockdown in neurons delays their radial migration in the embryonic cortex. Furthermore, reduced Bmal1 expression throughout the brain disrupts axonal projections from the corpus callosum to the lateral cerebral hemisphere ipsilaterally [92]. A variety of factors, including Glu, Ca2+, cyclic AMP-dependent protein kinase (PKA), and diacylglycerol-dependent protein kinase are involved in coordinating Bmal1 transcription and translation during development [9, 88, 93].

Single-cell RNA sequencing (scRNA-seq) analysis in adult mouse brains [94] revealed abundant Bmal1 expression in both neurons and glial cells, also with especially high transcript levels in Purkinje cells. Bmal1 expression varies across different brain regions but with no difference between excitatory and inhibitory neurons (Fig. 3B–J. See the original article for the distribution in specific cell subpopulations). Among specific neurons in different brain regions, scRNA-seq showed that PV-positive interneurons (GAD1/2+, PV+) in prefrontal cortex (PFC) has highest Bmal1 expression, twice more than that in excitatory neurons (SLC17A+), SST-positive interneurons (GAD1/2+, SST+) and astrocytes (Gja1+). In several brain regions, higher Bmal1 expression is a feature of inhibitory neurons, such as inhibitory neurons (GAD1/2+) and fibroblasts in the posterior cortex, GAD1/2+ inhibitory neurons in the striatum, GAD1/2+ inhibitory neurons and mural cells in the cerebellum. Whereas in the hippocampus, Bmal1 expression is higher in excitatory neurons (SLC17A+) and astrocytes (Gja1+) than inhibitory neurons, while the thalamus has Bmal1 expressed equally in different cell types.

The detection of Bmal1 in rat brain by using two neuropeptides (substance P and enkephalin) co-expressed with Bmal1 and the other clock gene, Per2, found Bmal1 in almost all neurons (~ 90%) in the forebrain (dorsal striatum, nucleus ambiguus, amygdala, and terminal cortex), while Per2 is expressed in a slightly lower proportion of neurons. In the olfactory bulb, Bmal1 and Per2 are expressed only in a smaller proportion of cells [95]. Overall, Bmal1 is widely expressed in the mammalian brain and is notably abundant in both neurons and glial cells, which likely participates in neuronal development.

Bmal1 in neurological diseases

Several studies have found associations between clock genes and neurological diseases. For instance, genes with rhythmic oscillations in their expression, like Bmal1, exhibit altered peak timing and phasing in depressed patients [96]. A similar pattern was found in the pineal gland and cingulate cortex of Alzheimer's disease (AD) patients and in leukocytes of Parkinson's disease (PD) patients [4, 97, 98]. Similarly, a reduction in the amplitude of expression rhythms of genes such as Bmal1 was detected in the saliva of patients with bipolar disorder [99]. Single nucleotide polymorphism (SNP) analysis found polymorphisms in Bmal1 and other genes that were potentially associated with increased risk of seasonal affective disorder and AD [100,101,102], while genome-wide association studies revealed a large overlap (> 80%) in the genetic factors involved in bipolar disorder, depression and schizophrenia, including hundreds of significant genetic loci [103], several of which were related to clock genes. A report on SNP markers by the Psychiatric Genomics Consortium (Bipolar Disorder and Schizophrenia Working Group) stated that a SNP in Bmal1 could help to differentiate genetic risk for bipolar disorder and schizophrenia [104]. This SNP in Bmal1 was also correlated with morbidity in bipolar disorder and schizophrenia [3, 105, 106].

Aligning well with these above findings, epigenetic mechanisms are known to be related to the regulation of the circadian clock. Aberrant DNA methylation of Bmal1 was observed in bipolar disorder and AD patients [107, 108]. In addition, the first primate model of deficiency for a core rhythm gene was generated by CRISPR/Cas9-mediated knockout of Bmal1 in macaque, which resulted in schizophrenia-like symptoms, further supporting a possible role of Bmal1 in neurological disorders [42]. In humans, robust evidence indicates that chronotherapy is highly effective for treating mood disorders [109]. For example, agomelatine was recently developed as a new antidepressant targeting the biological clock [110]. Activation of Bmal1 is also a biological target for lithium in the treatment of bipolar disorder [111]. These diverse lines of evidence suggest that Bmal1 may play a causative role in mental disorders, some of which phenotypically resemble neurological disorders.

Bmal1 has also been observed to influence different interactions responsible for the onset of neurological disease in animals. For instance, autistic-like behavior has been linked to deficiency of Bmal1, with hyperactivation of mammalian target of rapamycin complex 1 (mTORC1) signaling implicated as a likely important contributing pathway [10, 112]. In chronic unpredictable mild stress model rats, clock gene expression in brain subregions hippocampus and nucleus ambiguous, as well as liver, are altered following stress induction, with Bmal1 and Per2 levels showing particularly high fluctuations in response to stress [113]. Rats exposed to forced activity (simulating night-shift work), showed no significant changes in their clock-related genes expression in hippocampus, but the phosphorylation of BMAL1 and its regulator S6 kinase beta-1 was significantly reduced in PFC. Thus, simulating night-shift work rats have a disruption in the post-transcriptional regulatory pathway controlling clock genes mRNA translation in PFC, and this disruption may also be associated with impaired arousal during night work [114].

Circadian rhythm plays an important role in immune function, and its disruption has been linked to the etiology of depression. Evidence suggests that chemokines, the production of which are controlled by Clock, contribute to neuroinflammation-induced depression, therefore implying that clock genes may also serve as regulators of neuroinflammation [115]. Dopamine (DA) D2 receptor-mediated signaling can enhance the CLOCK:BMAL1 complex capacity for transcriptional activation of its targets [116], while AHI1 (frequently associated with abnormal neurodevelopment and mental disturbance) is known to bind RORα and repress BMAL1 expression, subsequently inhibiting Rev-Erbα expression and increasing tyrosine hydroxylase expression [117]. These studies provide an intriguing connection between abnormalities in circadian rhythm in mental disorders and the dopaminergic hypothesis. Overall, Bmal1 may be responsible for the onset and progression of several psychiatric disorders through multiple pathways.

Alternatively, Bmal1 regulates neuroinflammation in the brain to maintain functionality of the DA signaling pathway, whereas disruption of this balance has been proposed as causative factor in the onset of PD [118]. In transgenic dominant negative Bmal1 mice, hippocampal regulation of memory retrieval via DA and PKA-induced GluA1 phosphorylation [9], suggesting that Bmal1 could be relevant to neurodegenerative pathologies through DA signaling pathway. Apart from DA signaling, Bmal1 deletion in mice was shown to result in activation of astrocyte proliferation [119], causing the development of abnormal pathological phenotypes such as memory impairment and hyperactivity [120]. By contrast, elevation of Bmal1 expression leads to impaired astrocyte function via inhibition of aerobic glycolysis [121]. Additionally, methylation of CpG sites in the Bmal1 promoter can lead to its epigenetic silencing, which has been linked with the pathological progression of AD [122, 123]. Post-translationally, accelerated BMAL1 degradation also leads to circadian rhythm disruption in AD mouse model [124]. Currently, considerable research efforts are dedicated to defining the role of Bmal1 in AD and its potential as a therapeutic target, which has been well-reviewed by Ashish Sharma and colleagues [125].

Pathological phenotypes arising from Bmal1 deletion

Major advances in gene editing have facilitated the establishment of Bmal1 knockout animal models to enable deeper investigation of its neurobiological functions. In various Bmal1 knockout mice model, its deletion triggered not only circadian rhythm-related disorders, but also psychiatric disorders, memory impairment, and other neurological disorders with different disease phenotypes associated with specific brain regions and/or cell subpopulations subjected to conditional deletion (see Table 1 for details). In addition to biological clock disruption, consequently altering behavioral rhythms and biological clock gene expression, global Bmal1 knockout also leads to degeneration of synaptic terminals, impaired functional connectivity in the cortex, oxidative damage to neurons, and impaired expression of several redox defense genes [120]. Behaviorally, these Bmal1 knockout mice display hyperactivity, deficiency in short- and long-term memory formation in novel environments [126], impairment of social behaviors and increased stereotyped behavior [10, 112]. In mice with Bmal1 knockdown by intra-cerebroventricular injection of siRNA, both activity and waking time are reduced, while sleep in the dark phase and immobilization in tail suspension tests increased [8]. Since SCN serves as the master clock brain region coordinating biological clock, specific labeling or pathological changes following chemogenetic interference with Bmal1 in this area can be highly informative of its function, as reported in numerous studies. Mice with Bma1 knockdown by viral injection in the SCN exhibited depressive- and anxiety-like behavioral changes, like slower escape from stress in learned helplessness, increased immobility time in tail suspension tests, and less time spent in the bright box in light–dark transition test, as well as increased body weight and an overall decrease in corticosterone release with an abnormal release rhythm [127]. Synaptotagmin10 (Syt10) is highly expressed in the SCN but is expressed at relatively low levels in other regions, make it as a perfect marker for SCN cells. Bmal1 expression was reduced by 65% in heterozygous Syt10-Cre mice (Syt10-Cre+/−; Bmal1loxp/loxp), which did not result in circadian arrhythmia, whereas Bmal1 transcript levels decreased by 83% in homozygous Syt10-Cre mice (Syt10-Cre+/+; Bmal1loxp/loxp) that was accompanied by arrhythmia [128]. In addition, by crossing Neuromedin S-Cre mice (specific labelling of SCN neurons) with Bmal1loxp/loxp, mice showed a ~ 32% reduction in Bmal1 mRNA levels in the SCN and resulted in disturbance in circadian rhythm-associated behavior [129].

Table 1 Recent advances in abnormal Bmal1 expression and phenotype research through gene editing
Full size table

A growing number of studies have found that Bmal1 knockdown in different cell types also results in a variety of different pathological states. Using CaMKII: CaMKII-Cre or CaMKII-tTA mice to induce specific deletion of forebrain excitatory neurons while preserving the integrity of Bmal1 in the SCN revealed significant memory impairment without anxiety or depression-like behavior. And several findings suggested that memory impairment may be related to molecules involved in DA/cAMP signaling in the hippocampus [9, 130, 131]. Bmal1 knockout in the forebrain and in most SCN cells by crossing CamKIIalpha iCre BAC with Bmal1 loxp mice resulted in progeny with aberrations in their circadian rhythm-related behaviors, characterized by abolished synchronization between rhythms (although still present) in peripheral tissue with that of the SCN master clock [132], suggesting a functional diversity of Bmal1 in different cell types.

In Vgat-Cre mice, with GABAergic-specific Bmal1 knockout leads to behavioral manifestations of circadian rhythm disorders [128, 133]. In mice with striatum-specific knockdown of Bmal1 in neutrophilic multigrade spiny neurons, mice displayed normal circadian rhythms but voluntary alcohol intake are altered with anxiolytic and antidepressant responses [134, 135]. Moreover, Bmal1 knockdown in DG neurons of the hippocampus resulted in increased susceptibility to epileptic symptoms induced by trichothecene [136]. Furthermore, Bmal1 knockout in adrenocorticotropin-releasing hormone (CRH) neurons of the hypothalamic paraventricular nucleus, which has monosynaptic efferent from SCN neurons, induced alterations in the rhythms of neuronal calcium activity as well as corticosterone release. However, in mice with Bmal1 knockout in CRH neurons across all brain regions, circadian rhythm and sleep electroencephalograms remains intact [137].

In addition to targeting neurons, several studies have examined the effects of Bmal1 deficiency in other cell populations. In astrocytes, Bmal1 knockout using the glial Glu and aspartate transporter (Glast-Cre) results in molecular clock impairment in the hypothalamus, and alters circadian motor behavior, cognition and lifespan, affecting metabolic balance and glucose homeostasis. Increased Glu and GABA levels were also observed in hypothalamic of mice with astrocyte hyperplasia. However, modulation of GABAA receptor signaling can fully restore Glu levels, and delay glial hyperplasia and metabolic disorders, ultimately extending lifespan. Suggested that GABA signaling may also regulate neuronal clock activity, potentially promoting metabolic dysfunction and cellular senescence [48, 138]. SCN-specific knockdown of astrocytic Bmal1, by using the aldehyde dehydrogenase 1 family member L1 (Aldh1L1)-Cre label astrocytes was shown to prolong the circadian cycle of clock gene expression in SCN, suggesting that astrocytes in the SCN, like SCN neurons, can regulate daily rhythms of gene expression in the SCN and animal behavior [70]. Global, astrocyte-specific knockout of Bmal1 can promote astrocyte activation [119]. However, Bmal1 knockout in astrocytes does not affect Aβ plaque burden, dystrophic neurites, or microglial activation in AD model mice [119], thus supporting a relationship between Bmal1-mediated astrogliosis and AD.

In addition to master clock brain regions, NAc-specific knockdown of Bmal1 (i.e., in brain regions related to the reward system) resulted in changes of daytime exploratory drive behaviors, glutamatergic signaling to adjacent medium spiny neurons, and metabolism-related functions (such as lactate and glutathione concentrations), suggesting that Bmal1 also have effects on the reward system [139]. As AVP has been identified as critical for SCN output, Bmal1 knockout in AVP-Cre mice did not result in dysrhythmias but instead led to prolonged activity cycles, suggesting an impaired synchronization between SCN neurons [140]. The absence of Bmal1 in microglia can also lead to varying degrees of memory impairment, although phagocytosis of these cells is increased [141]. Bmal1 deficiency in Purkinje cells leads to dysmotility and autistic-like behavior, accompanied by deranged inhibitory/excitatory synaptic transmission and reduced spontaneous firing rates [10]. Together, Bmal1 can function as a biological clock regulator, but its dysfunction can trigger other neurological disorders, both in neurons and glial cells.

In conclusion, evidence from model mice with conditional ablation of Bmal1 in different brain regions or cell types demonstrates its wide range of physiological roles involving biological clock rhythms, behavior, and even metabolic homeostasis. However, despite this wealth of available evidence, our perspective remains limited regarding the neurological related functions of Bmal1, which may be resolved with further investigation of its cell-specific functions. These local or cell type specialized functions also increase the difficulty and complexity of Bmal1 research, and it remains unclear whether there are other regulatory effects independent of biological clock rhythms. Further division of related studies based on brain region or different cellular subpopulations will help to better define the regulatory role of the Bmal1 gene in neurological diseases.

Conclusion

This review delineates the role of Bmal1 in neural function. Currently, studies in a variety of animal models suggests that Bmal1 might contribute to the development of neurological disorders, providing a non-trivial body of evidence supporting that changes in Bmal1 gene-related loci or Bmal1 expression itself may be associated with various neurological disorders. However, considerable work is still needed to comprehensively depict the mechanisms by which Bmal1 could mediate the development of neurological disorders. According to our current understanding, Bmal1 shares a complex relationship with SCN neuronal activity, and its role in circadian oscillatory coupling involves not only different cell types in the SCN, such as neurons and astrocytes, but also several important molecular signals, including GABA, Glu, VIP, and others. In the synchronization and maintenance of rhythm or neural circuitry, these factors function as part of a sophisticated network. Thus, Bmal1 obviously does not function in isolation, and is central to this wide network controlling overall neuronal activity, coupling between neurons, and positive feedback-based synchronization of rhythmic oscillations in the transcription of other biological clock genes.

Availability of data and materials

All data are included in the manuscript.

Abbreviations

TTFL:

Transcription/translation feedback loop

SCN:

Suprachiasmatic nucleus

mTOR:

Mammalian target of rapamycin

VIP:

Vasoactive intestinal polypeptide

AVP:

Arginine Vasopressin

GABA:

γ-Aminobutyric acid

SFR:

Spontaneous firing rate

GABA-A:

γ-Aminobutyric acid receptor

cAMP:

Cyclic adenosine monophosphate

MAPKs:

Mitogen-activated protein kinases

PKC:

Protein kinase C

RACK 1:

Receptor for activated C kinase-1

PV:

Parvalbumin

Glu:

Glutamate

ATP:

Adenosine Triphosphate

ASP:

Aspartic Acid

Gly:

Glycine

NMDAR:

N-Methyl-d-aspartic acid receptor

PKA:

Protein kinase

scRNA-seq:

Single-cell RNA sequencing

PFC:

Prefrontal cortex

AD:

Alzheimer's disease

PD:

Parkinson's disease

SNP:

Single nucleotide polymorphism

mTORC1:

Mammalian target of rapamycin complex 1

DA:

Dopamine

Syt10:

Synaptotagmin10

CaMKII:

Calmodulin-dependent protein kinase II

CRH:

Adrenocorticotropin-releasing hormone

Aldh1L1:

Aldehyde dehydrogenase 1 family member L1

GRP:

Gastrin Releasing Peptide

ASP:

Aspartic Acid

Gly:

Glycine

VPAC2:

Vasoactive Intestinal Peptide Receptor 2

VGCC:

Voltage-Gated Calcium Channel

GAT:

GABA transporter

fcOIS:

Optical intrinsic signal functional connectivity imaging

PSG:

Polysomnographic recording

ICV:

Intracerebroventricular

EEG:

Electroencephalogram

EMG:

Electromyogram

NAc:

Nucleus accumbens

EPSC:

Excitatory postsynaptic currents

MSNs:

Moderately spiny neurons

POMC:

Pro-opiomelanocortin

PVN:

Paraventricular nucleus

References

  1. Koike N, Yoo SH, Huang HC, Kumar V, Lee C, Kim TK, Takahashi JS. Transcriptional architecture and chromatin landscape of the core circadian clock in mammals. Science. 2012;338(6105):349–54.

    Article  CAS  Google Scholar 

  2. Dunlap JC. Molecular bases for circadian clocks. Cell. 1999;96(2):271–90.

    Article  CAS  Google Scholar 

  3. Kato T. Molecular genetics of bipolar disorder and depression. Psychiat Clin Neuros. 2007;61(1):3–19.

    Article  CAS  Google Scholar 

  4. Cai Y, Liu S, Sothern RB, Xu S, Chan P. Expression of clock genes Per1 and Bmal1 in total leukocytes in health and Parkinson’s disease. Eur J Neurol. 2010;17(4):550–4.

    Article  CAS  Google Scholar 

  5. Petrasek T, Vojtechova I, Lobellova V, Popelikova A, Janikova M, Brozka H, Houdek P, Sladek M, Sumova A, Kristofikova Z, et al. The McGill transgenic rat model of Alzheimer’s disease displays cognitive and motor impairments, changes in anxiety and social behavior, and altered circadian activity. Front Aging Neurosci. 2018;10:250.

    Article  Google Scholar 

  6. Cooper JM, Halter KA, Prosser RA. Circadian rhythm and sleep-wake systems share the dynamic extracellular synaptic milieu. Neurobiol Sleep Circadian Rhythms. 2018;5:15–36.

    Article  Google Scholar 

  7. Stranahan AM. Chronobiological approaches to Alzheimer’s disease. Curr Alzheimer Res. 2012;9(1):93–8.

    Article  CAS  Google Scholar 

  8. Akladious A, Azzam S, Hu Y, Feng P. Bmal1 knockdown suppresses wake and increases immobility without altering orexin A, corticotrophin-releasing hormone, or glutamate decarboxylase. Cns Neurosci Ther. 2018;24(6):549–63.

    Article  CAS  Google Scholar 

  9. Hasegawa S, Fukushima H, Hosoda H, Serita T, Ishikawa R, Rokukawa T, Kawahara-Miki R, Zhang Y, Ohta M, Okada S, et al. Hippocampal clock regulates memory retrieval via Dopamine and PKA-induced GluA1 phosphorylation. Nat Commun. 2019;10(1):5766.

    Article  CAS  Google Scholar 

  10. Liu D, Nanclares C, Simbriger K, Fang K, Lorsung E, Le N, Amorim IS, Chalkiadaki K, Pathak SS, Li J, et al. Autistic-like behavior and cerebellar dysfunction in Bmal1 mutant mice ameliorated by mTORC1 inhibition. Mol Psychiatr. 2022. https://doi.org/10.1038/s41380-022-01499-6.

    Article  Google Scholar 

  11. Curtis AM, Cheng Y, Kapoor S, Reilly D, Price TS, Fitzgerald GA. Circadian variation of blood pressure and the vascular response to asynchronous stress. P Natl Acad Sci USA. 2007;104(9):3450–5.

    Article  CAS  Google Scholar 

  12. Bunger MK, Wilsbacher LD, Moran SM, Clendenin C, Radcliffe LA, Hogenesch JB, Simon MC, Takahashi JS, Bradfield CA. Mop3 is an essential component of the master circadian pacemaker in mammals. Cell. 2000;103(7):1009–17.

    Article  CAS  Google Scholar 

  13. Welsh DK, Logothetis DE, Meister M, Reppert SM. Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing rhythms. Neuron. 1995;14(4):697–706.

    Article  CAS  Google Scholar 

  14. Colwell CS. Linking neural activity and molecular oscillations in the SCN. Nat Rev Neurosci. 2011;12(10):553–69.

    Article  CAS  Google Scholar 

  15. Ray S, Valekunja UK, Stangherlin A, Howell SA, Snijders AP, Damodaran G, Reddy AB. Circadian rhythms in the absence of the clock gene Bmal1. Science. 2020;367(6479):800–6.

    Article  CAS  Google Scholar 

  16. Kondratov RV, Kondratova AA, Gorbacheva VY, Vykhovanets OV, Antoch MP. Early aging and age-related pathologies in mice deficient in BMAL1, the core componentof the circadian clock. Gene Dev. 2006;20(14):1868–73.

    Article  CAS  Google Scholar 

  17. McDearmon EL, Patel KN, Ko CH, Walisser JA, Schook AC, Chong JL, Wilsbacher LD, Song EJ, Hong HK, Bradfield CA, et al. Dissecting the functions of the mammalian clock protein BMAL1 by tissue-specific rescue in mice. Science. 2006;314(5803):1304–8.

    Article  CAS  Google Scholar 

  18. Bunger MK, Walisser JA, Sullivan R, Manley PA, Moran SM, Kalscheur VL, Colman RJ, Bradfield CA. Progressive arthropathy in mice with a targeted disruption of the Mop3/Bmal-1 locus. Genesis. 2005;41(3):122–32.

    Article  CAS  Google Scholar 

  19. Benitah SA, Welz PS. Circadian regulation of adult stem cell homeostasis and aging. Cell Stem Cell. 2020;26(6):817–31.

    Article  CAS  Google Scholar 

  20. Khapre RV, Kondratova AA, Patel S, Dubrovsky Y, Wrobel M, Antoch MP, Kondratov RV. BMAL1-dependent regulation of the mTOR signaling pathway delays aging. Aging. 2014;6(1):48–57.

    Article  CAS  Google Scholar 

  21. Ramsey KM, Yoshino J, Brace CS, Abrassart D, Kobayashi Y, Marcheva B, Hong HK, Chong JL, Buhr ED, Lee C, et al. Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science. 2009;324(5927):651–4.

    Article  CAS  Google Scholar 

  22. Liang C, Ke Q, Liu Z, Ren J, Zhang W, Hu J, Wang Z, Chen H, Xia K, Lai X, et al. BMAL1 moonlighting as a gatekeeper for LINE1 repression and cellular senescence in primates. Nucleic Acids Res. 2022. https://doi.org/10.1038/s41380-022-01499-6.

    Article  Google Scholar 

  23. Jiang Y, Li S, Xu W, Ying J, Qu Y, Jiang X, Zhang A, Yue Y, Zhou R, Ruan T, et al. Critical roles of the circadian transcription factor BMAL1 in reproductive endocrinology and fertility. Front EndocrinoL. 2022;13: 818272.

    Article  Google Scholar 

  24. Ratajczak CK, Boehle KL, Muglia LJ. Impaired steroidogenesis and implantation failure in Bmal1-/- mice. Endocrinology. 2009;150(4):1879–85.

    Article  CAS  Google Scholar 

  25. Schoeller EL, Clark DD, Dey S, Cao NV, Semaan SJ, Chao LW, Kauffman AS, Stowers L, Mellon PL. Bmal1 is required for normal reproductive behaviors in male mice. Endocrinology. 2016;157(12):4914–29.

    Article  CAS  Google Scholar 

  26. Early JO, Menon D, Wyse CA, Cervantes-Silva MP, Zaslona Z, Carroll RG, Palsson-McDermott EM, Angiari S, Ryan DG, Corcoran SE, et al. Circadian clock protein BMAL1 regulates IL-1beta in macrophages via NRF2. P Natl Acad Sci USA. 2018;115(36):E8460–8.

    Article  CAS  Google Scholar 

  27. Hong H, Cheung YM, Cao X, Wu Y, Li C, Tian XY. REV-ERBalpha agonist SR9009 suppresses IL-1beta production in macrophages through BMAL1-dependent inhibition of inflammasome. Biochem Pharmacol. 2021;192: 114701.

    Article  CAS  Google Scholar 

  28. Timmons GA, Carroll RG, O’Siorain JR, Cervantes-Silva MP, Fagan LE, Cox SL, Palsson-McDermott E, Finlay DK, Vincent EE, Jones N, et al. The circadian clock protein BMAL1 acts as a metabolic sensor in macrophages to control the production of pro IL-1beta. Front Immunol. 2021;12: 700431.

    Article  CAS  Google Scholar 

  29. Curtis AM, Bellet MM, Sassone-Corsi P, O’Neill LA. Circadian clock proteins and immunity. Immunity. 2014;40(2):178–86.

    Article  CAS  Google Scholar 

  30. Pan X, Hussain MM. Bmal1 regulates production of larger lipoproteins by modulating cAMP-responsive element-binding protein H and apolipoprotein AIV. Hepatology. 2022;76(1):78–93.

    Article  CAS  Google Scholar 

  31. Marcheva B, Ramsey KM, Buhr ED, Kobayashi Y, Su H, Ko CH, Ivanova G, Omura C, Mo S, Vitaterna MH, et al. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature. 2010;466(7306):627–31.

    Article  CAS  Google Scholar 

  32. Rudic RD, McNamara P, Curtis AM, Boston RC, Panda S, Hogenesch JB, Fitzgerald GA. BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. Plos Biol. 2004;2(11): e377.

    Article  Google Scholar 

  33. Greco CM, Koronowski KB, Smith JG, Shi J, Kunderfranco P, Carriero R, Chen S, Samad M, Welz PS, Zinna VM, et al. Integration of feeding behavior by the liver circadian clock reveals network dependency of metabolic rhythms. Sci Adv. 2021;7(39): i7828.

    Article  Google Scholar 

  34. Gabriel BM, Altintas A, Smith J, Sardon-Puig L, Zhang X, Basse AL, Laker RC, Gao H, Liu Z, Dollet L, et al. Disrupted circadian oscillations in type 2 diabetes are linked to altered rhythmic mitochondrial metabolism in skeletal muscle. Sci Adv. 2021;7(43): i9654.

    Article  Google Scholar 

  35. Moreno-Smith M, Milazzo G, Tao L, Fekry B, Zhu B, Mohammad MA, Di Giacomo S, Borkar R, Reddy K, Capasso M, et al. Restoration of the molecular clock is tumor suppressive in neuroblastoma. Nat Commun. 2021;12(1):4006.

    Article  CAS  Google Scholar 

  36. Tang Q, Cheng B, Xie M, Chen Y, Zhao J, Zhou X, Chen L. Circadian clock gene Bmal1 inhibits tumorigenesis and increases paclitaxel sensitivity in tongue squamous cell carcinoma. Cancer Res. 2017;77(2):532–44.

    Article  CAS  Google Scholar 

  37. Kettner NM, Voicu H, Finegold MJ, Coarfa C, Sreekumar A, Putluri N, Katchy CA, Lee C, Moore DD, Fu L. Circadian homeostasis of liver metabolism suppresses hepatocarcinogenesis. Cancer Cell. 2016;30(6):909–24.

    Article  CAS  Google Scholar 

  38. Papagiannakopoulos T, Bauer MR, Davidson SM, Heimann M, Subbaraj L, Bhutkar A, Bartlebaugh J, Vander HM, Jacks T. Circadian rhythm disruption promotes lung tumorigenesis. Cell Metab. 2016;24(2):324–31.

    Article  CAS  Google Scholar 

  39. Puram RV, Kowalczyk MS, de Boer CG, Schneider RK, Miller PG, McConkey M, Tothova Z, Tejero H, Heckl D, Jaras M, et al. Core circadian clock genes regulate leukemia stem cells in AML. Cell. 2016;165(2):303–16.

    Article  CAS  Google Scholar 

  40. Janich P, Pascual G, Merlos-Suarez A, Batlle E, Ripperger J, Albrecht U, Cheng HY, Obrietan K, Di Croce L, Benitah SA. The circadian molecular clock creates epidermal stem cell heterogeneity. Nature. 2011;480(7376):209–14.

    Article  CAS  Google Scholar 

  41. Kinouchi K, Sassone-Corsi P. Metabolic rivalry: circadian homeostasis and tumorigenesis. Nat Rev Cancer. 2020;20(11):645–61.

    Article  CAS  Google Scholar 

  42. Qiu P, Jiang J, Liu Z, Cai Y, Huang T, Wang Y, Liu Q, Nie Y, Liu F, Cheng J, et al. BMAL1 knockout macaque monkeys display reduced sleep and psychiatric disorders. Natl Sci Rev. 2019;6(1):87–100.

    Article  CAS  Google Scholar 

  43. Antle MC, Silver R. Orchestrating time: arrangements of the brain circadian clock. Trends Neurosci. 2005;28(3):145–51.

    Article  CAS  Google Scholar 

  44. Park J, Zhu H, O’Sullivan S, Ogunnaike BA, Weaver DR, Schwaber JS, Vadigepalli R. Single-cell transcriptional analysis reveals novel neuronal phenotypes and interaction networks involved in the central circadian clock. Front Neurosci-Switz. 2016;10:481.

    Google Scholar 

  45. Freeman GJ, Krock RM, Aton SJ, Thaben P, Herzog ED. GABA networks destabilize genetic oscillations in the circadian pacemaker. Neuron. 2013;78(5):799–806.

    Article  CAS  Google Scholar 

  46. Moore RY, Speh JC. GABA is the principal neurotransmitter of the circadian system. Neurosci Lett. 1993;150(1):112–6.

    Article  CAS  Google Scholar 

  47. Belenky MA, Yarom Y, Pickard GE. Heterogeneous expression of gamma-aminobutyric acid and gamma-aminobutyric acid-associated receptors and transporters in the rat suprachiasmatic nucleus. J Comp Neurol. 2008;506(4):708–32.

    Article  CAS  Google Scholar 

  48. Barca-Mayo O, Pons-Espinal M, Follert P, Armirotti A, Berdondini L, De Pietri TD. Astrocyte deletion of Bmal1 alters daily locomotor activity and cognitive functions via GABA signalling. Nat Commun. 2017;8:14336.

    Article  CAS  Google Scholar 

  49. Hastings MH, Maywood ES, Brancaccio M. Generation of circadian rhythms in the suprachiasmatic nucleus. Nat Rev Neurosci. 2018;19(8):453–69.

    Article  CAS  Google Scholar 

  50. Green DJ, Gillette R. Circadian rhythm of firing rate recorded from single cells in the rat suprachiasmatic brain slice. Brain Res. 1982;245(1):198–200.

    Article  CAS  Google Scholar 

  51. de Jeu M, Hermes M, Pennartz C. Circadian modulation of membrane properties in slices of rat suprachiasmatic nucleus. NeuroReport. 1998;9(16):3725–9.

    Article  Google Scholar 

  52. Groos G, Hendriks J. Circadian rhythms in electrical discharge of rat suprachiasmatic neurones recorded in vitro. Neurosci Lett. 1982;34(3):283–8.

    Article  CAS  Google Scholar 

  53. Kuhlman SJ, McMahon DG. Rhythmic regulation of membrane potential and potassium current persists in SCN neurons in the absence of environmental input. Eur J Neurosci. 2004;20(4):1113–7.

    Article  Google Scholar 

  54. Pennartz CM, de Jeu MT, Bos NP, Schaap J, Geurtsen AM. Diurnal modulation of pacemaker potentials and calcium current in the mammalian circadian clock. Nature. 2002;416(6878):286–90.

    Article  CAS  Google Scholar 

  55. Kononenko NI, Kuehl-Kovarik MC, Partin KM, Dudek FE. Circadian difference in firing rate of isolated rat suprachiasmatic nucleus neurons. Neurosci Lett. 2008;436(3):314–6.

    Article  CAS  Google Scholar 

  56. Flourakis M, Kula-Eversole E, Hutchison AL, Han TH, Aranda K, Moose DL, White KP, Dinner AR, Lear BC, Ren D, et al. A conserved bicycle model for circadian clock control of membrane excitability. Cell. 2015;162(4):836–48.

    Article  CAS  Google Scholar 

  57. Whitt JP, Montgomery JR, Meredith AL. BK channel inactivation gates daytime excitability in the circadian clock. Nat Commun. 2016;7:10837.

    Article  CAS  Google Scholar 

  58. Hermanstyne TO, Granados-Fuentes D, Mellor RL, Herzog ED, Nerbonne JM. Acute knockdown of Kv4.1 regulates repetitive firing rates and clock gene expression in the suprachiasmatic nucleus and daily rhythms in locomotor behavior. eNeuro. 2017. https://doi.org/10.1523/ENEURO.0377-16.2017.

    Article  Google Scholar 

  59. Granados-Fuentes D, Hermanstyne TO, Carrasquillo Y, Nerbonne JM, Herzog ED. IA channels encoded by Kv1.4 and Kv4.2 regulate circadian period of PER2 expression in the suprachiasmatic nucleus. J Biol Rhythm. 2015;30(5):396–407.

    Article  CAS  Google Scholar 

  60. Myung J, Hong S, DeWoskin D, De Schutter E, Forger DB, Takumi T. GABA-mediated repulsive coupling between circadian clock neurons in the SCN encodes seasonal time. P Natl Acad Sci USA. 2015;112(29):E3920–9.

    Article  CAS  Google Scholar 

  61. Nitabach MN, Holmes TC, Blau J. Membranes, ions, and clocks: testing the Njus-Sulzman-Hastings model of the circadian oscillator. Method Enzymol. 2005;393:682–93.

    Article  CAS  Google Scholar 

  62. Ikeda M, Sugiyama T, Wallace CS, Gompf HS, Yoshioka T, Miyawaki A, Allen CN. Circadian dynamics of cytosolic and nuclear Ca2+ in single suprachiasmatic nucleus neurons. Neuron. 2003;38(2):253–63.

    Article  CAS  Google Scholar 

  63. Lundkvist GB, Kwak Y, Davis EK, Tei H, Block GD. A calcium flux is required for circadian rhythm generation in mammalian pacemaker neurons. J Neurosci. 2005;25(33):7682–6.

    Article  CAS  Google Scholar 

  64. Kon N, Yoshikawa T, Honma S, Yamagata Y, Yoshitane H, Shimizu K, Sugiyama Y, Hara C, Kameshita I, Honma K, et al. CaMKII is essential for the cellular clock and coupling between morning and evening behavioral rhythms. Gene Dev. 2014;28(10):1101–10.

    Article  CAS  Google Scholar 

  65. O’Neill JS, Maywood ES, Chesham JE, Takahashi JS, Hastings MH. cAMP-dependent signaling as a core component of the mammalian circadian pacemaker. Science. 2008;320(5878):949–53.

    Article  CAS  Google Scholar 

  66. Ferreyra GA, Golombek DA. Cyclic AMP and protein kinase A rhythmicity in the mammalian suprachiasmatic nuclei. Brain Res. 2000;858(1):33–9.

    Article  CAS  Google Scholar 

  67. Hastings MH, Maywood ES, O’Neill JS. Cellular circadian pacemaking and the role of cytosolic rhythms. Curr Biol. 2008;18(17):R805–15.

    Article  CAS  Google Scholar 

  68. Robles MS, Boyault C, Knutti D, Padmanabhan K, Weitz CJ. Identification of RACK1 and protein kinase Calpha as integral components of the mammalian circadian clock. Science. 2010;327(5964):463–6.

    Article  CAS  Google Scholar 

  69. Kobayashi Y, Ye Z, Hensch TK. Clock genes control cortical critical period timing. Neuron. 2015;86(1):264–75.

    Article  CAS  Google Scholar 

  70. Tso CF, Simon T, Greenlaw AC, Puri T, Mieda M, Herzog ED. Astrocytes regulate daily rhythms in the suprachiasmatic nucleus and behavior. Curr Biol. 2017;27(7):1055–61.

    Article  CAS  Google Scholar 

  71. Brancaccio M, Patton AP, Chesham JE, Maywood ES, Hastings MH. Astrocytes control circadian timekeeping in the suprachiasmatic nucleus via glutamatergic signaling. Neuron. 2017;93(6):1420–35.

    Article  CAS  Google Scholar 

  72. Ali A, Schwarz-Herzke B, Rollenhagen A, Anstotz M, Holub M, Lubke J, Rose CR, Schnittler HJ, von Gall C. Bmal1-deficiency affects glial synaptic coverage of the hippocampal mossy fiber synapse and the actin cytoskeleton in astrocytes. Glia. 2020;68(5):947–62.

    Article  Google Scholar 

  73. Yamaguchi S, Isejima H, Matsuo T, Okura R, Yagita K, Kobayashi M, Okamura H. Synchronization of cellular clocks in the suprachiasmatic nucleus. Science. 2003;302(5649):1408–12.

    Article  CAS  Google Scholar 

  74. Silver R, LeSauter J, Tresco PA, Lehman MN. A diffusible coupling signal from the transplanted suprachiasmatic nucleus controlling circadian locomotor rhythms. Nature. 1996;382(6594):810–3.

    Article  CAS  Google Scholar 

  75. Maywood ES, Chesham JE, O’Brien JA, Hastings MH. A diversity of paracrine signals sustains molecular circadian cycling in suprachiasmatic nucleus circuits. P Natl Acad Sci USA. 2011;108(34):14306–11.

    Article  CAS  Google Scholar 

  76. Colwell CS. Rhythmic coupling among cells in the suprachiasmatic nucleus. J Neurobiol. 2000;43(4):379–88.

    Article  CAS  Google Scholar 

  77. Webb AB, Angelo N, Huettner JE, Herzog ED. Intrinsic, nondeterministic circadian rhythm generation in identified mammalian neurons. P Natl Acad Sci USA. 2009;106(38):16493–8.

    Article  CAS  Google Scholar 

  78. Welsh DK, Takahashi JS, Kay SA. Suprachiasmatic nucleus: cell autonomy and network properties. Annu Rev Physiol. 2010;72:551–77.

    Article  CAS  Google Scholar 

  79. Moldavan M, Cravetchi O, Williams M, Irwin RP, Aicher SA, Allen CN. Localization and expression of GABA transporters in the suprachiasmatic nucleus. Eur J Neurosci. 2015;42(12):3018–32.

    Article  Google Scholar 

  80. Marpegan L, Swanstrom AE, Chung K, Simon T, Haydon PG, Khan SK, Liu AC, Herzog ED, Beaule C. Circadian regulation of ATP release in astrocytes. J Neurosci. 2011;31(23):8342–50.

    Article  CAS  Google Scholar 

  81. Burkeen JF, Womac AD, Earnest DJ, Zoran MJ. Mitochondrial calcium signaling mediates rhythmic extracellular ATP accumulation in suprachiasmatic nucleus astrocytes. J NEUROSCI. 2011;31(23):8432–40.

    Article  CAS  Google Scholar 

  82. Schwarz Y, Zhao N, Kirchhoff F, Bruns D. Astrocytes control synaptic strength by two distinct v-SNARE-dependent release pathways. Nat Neurosci. 2017;20(11):1529–39.

    Article  CAS  Google Scholar 

  83. Shinohara K, Honma S, Katsuno Y, Abe H, Honma K. Circadian release of amino acids in the suprachiasmatic nucleus in vitro. NeuroReport. 1998;9(1):137–40.

    Article  CAS  Google Scholar 

  84. Castaneda TR, de Prado BM, Prieto D, Mora F. Circadian rhythms of dopamine, glutamate and GABA in the striatum and nucleus accumbens of the awake rat: modulation by light. J Pineal Res. 2004;36(3):177–85.

    Article  CAS  Google Scholar 

  85. Ding JM, Chen D, Weber ET, Faiman LE, Rea MA, Gillette MU. Resetting the biological clock: mediation of nocturnal circadian shifts by glutamate and NO. Science. 1994;266(5191):1713–7.

    Article  CAS  Google Scholar 

  86. Mintz EM, Albers HE. Microinjection of NMDA into the SCN region mimics the phase shifting effect of light in hamsters. Brain Res. 1997;758(1–2):245–9.

    Article  CAS  Google Scholar 

  87. van den Pol AN, Finkbeiner SM, Cornell-Bell AH. Calcium excitability and oscillations in suprachiasmatic nucleus neurons and glia in vitro. J Neurosci. 1992;12(7):2648–64.

    Article  Google Scholar 

  88. Chi-Castaneda D, Waliszewski SM, Zepeda RC, Hernandez-Kelly LC, Caba M, Ortega A. Glutamate-dependent BMAL1 regulation in cultured bergmann glia cells. Neurochem Res. 2015;40(5):961–70.

    Article  CAS  Google Scholar 

  89. Hastings MH, Brancaccio M, Maywood ES. Circadian pacemaking in cells and circuits of the suprachiasmatic nucleus. J Neuroendocrinol. 2014;26(1):2–10.

    Article  CAS  Google Scholar 

  90. Albus H, Vansteensel MJ, Michel S, Block GD, Meijer JH. A GABAergic mechanism is necessary for coupling dissociable ventral and dorsal regional oscillators within the circadian clock. Curr Biol. 2005;15(10):886–93.

    Article  CAS  Google Scholar 

  91. Allen Brain MAP. https://portal.brain-map.org/. Accessed 17 Aug 2022

  92. Li F, Huang QY, Liu SJ, Guo Z, Xiong XX, Gui L, Shu HJ, Huang SM, Tan G, Liu YY. The role of Bmal1 in neuronal radial migration and axonal projection of the embryonic mouse cerebral cortex. Yi Chuan. 2019;41(6):524–33.

    Google Scholar 

  93. Morioka N, Sugimoto T, Sato K, Okazaki S, Saeki M, Hisaoka-Nakashima K, Nakata Y. The induction of Per1 expression by the combined treatment with glutamate, 5-hydroxytriptamine and dopamine initiates a ripple effect on Bmal1 and Cry1 mRNA expression via the ERK signaling pathway in cultured rat spinal astrocytes. Neurochem Int. 2015;90:9–19.

    Article  CAS  Google Scholar 

  94. Saunders A, Macosko EZ, Wysoker A, Goldman M, Krienen FM, de Rivera H, Bien E, Baum M, Bortolin L, Wang S, et al. Molecular diversity and specializations among the cells of the adult mouse brain. Cell. 2018;174(4):1015–30.

    Article  CAS  Google Scholar 

  95. Frederick A, Goldsmith J, de Zavalia N, Amir S. Mapping the co-localization of the circadian proteins PER2 and BMAL1 with enkephalin and substance P throughout the rodent forebrain. PLoS ONE. 2017;12(4): e176279.

    Article  Google Scholar 

  96. Li JZ, Bunney BG, Meng F, Hagenauer MH, Walsh DM, Vawter MP, Evans SJ, Choudary PV, Cartagena P, Barchas JD, et al. Circadian patterns of gene expression in the human brain and disruption in major depressive disorder. P Natl Acad Sci USA. 2013;110(24):9950–5.

    Article  CAS  Google Scholar 

  97. Cermakian N, Lamont EW, Boudreau P, Boivin DB. Circadian clock gene expression in brain regions of Alzheimer ’s disease patients and control subjects. J Biol Rhythm. 2011;26(2):160–70.

    Article  Google Scholar 

  98. Wu YH, Fischer DF, Kalsbeek A, Garidou-Boof ML, van der Vliet J, van Heijningen C, Liu RY, Zhou JN, Swaab DF. Pineal clock gene oscillation is disturbed in Alzheimer’s disease, due to functional disconnection from the “master clock.” FASEB J. 2006;20(11):1874–6.

    Article  CAS  Google Scholar 

  99. Yang S, Van Dongen HP, Wang K, Berrettini W, Bucan M. Assessment of circadian function in fibroblasts of patients with bipolar disorder. Mol Psychiatr. 2009;14(2):143–55.

    Article  CAS  Google Scholar 

  100. Partonen T, Treutlein J, Alpman A, Frank J, Johansson C, Depner M, Aron L, Rietschel M, Wellek S, Soronen P, et al. Three circadian clock genes Per2, Arntl, and Npas2 contribute to winter depression. Ann Med. 2007;39(3):229–38.

    Article  CAS  Google Scholar 

  101. Chen Q, Huang CQ, Hu XY, Li SB, Zhang XM. Functional CLOCK gene rs1554483 G/C polymorphism is associated with susceptibility to Alzheimer’s disease in the Chinese population. J Int Med Res. 2013;41(2):340–6.

    Article  CAS  Google Scholar 

  102. Chen HF, Huang CQ, You C, Wang ZR, Si-qing H. Polymorphism of CLOCK gene rs 4580704 C > G is associated with susceptibility of Alzheimer’s disease in a Chinese population. Arch Med Res. 2013;44(3):203–7.

    Article  CAS  Google Scholar 

  103. Anttila V, Bulik-Sullivan B, Finucane HK, Walters RK, Bras J, Duncan L, Escott-Price V. Analysis of shared heritability in common disorders of the brain. Science. 2018;360(6395):eaap8757.

    Article  Google Scholar 

  104. Consortium BDAS. Genomic dissection of bipolar disorder and schizophrenia, including 28 subphenotypes. Cell. 2018;173(7):1705–15.

    Article  Google Scholar 

  105. Nievergelt CM, Kripke DF, Barrett TB, Burg E, Remick RA, Sadovnick AD, McElroy SL, Keck PJ, Schork NJ, Kelsoe JR. Suggestive evidence for association of the circadian genes PERIOD3 and ARNTL with bipolar disorder. Am J Med Genet B. 2006;141B(3):234–41.

    Article  CAS  Google Scholar 

  106. Mansour HA, Wood J, Logue T, Chowdari KV, Dayal M, Kupfer DJ, Monk TH, Devlin B, Nimgaonkar VL. Association study of eight circadian genes with bipolar I disorder, schizoaffective disorder and schizophrenia. Genes Brain Behav. 2006;5(2):150–7.

    Article  CAS  Google Scholar 

  107. Bengesser SA, Reininghaus EZ, Lackner N, Birner A, Fellendorf FT, Platzer M, Kainzbauer N, Tropper B, Hormanseder C, Queissner R, et al. Is the molecular clock ticking differently in bipolar disorder? Methylation analysis of the clock gene ARNTL. World J Biol Psychia. 2018;19(sup2):S21–9.

    Article  Google Scholar 

  108. Cronin P, McCarthy MJ, Lim A, Salmon DP, Galasko D, Masliah E, De Jager PL, Bennett DA, Desplats P. Circadian alterations during early stages of Alzheimer’s disease are associated with aberrant cycles of DNA methylation in BMAL1. Alzheimers Dement. 2017;13(6):689–700.

    Article  Google Scholar 

  109. Bunney BG, Bunney WE. Mechanisms of rapid antidepressant effects of sleep deprivation therapy: clock genes and circadian rhythms. Biol Psychiat. 2013;73(12):1164–71.

    Article  CAS  Google Scholar 

  110. Mendlewicz J. Disruption of the circadian timing systems: molecular mechanisms in mood disorders. CNS Drugs. 2009;23(Suppl 2):15–26.

    Article  CAS  Google Scholar 

  111. Yin L, Wang J, Klein PS, Lazar MA. Nuclear receptor Rev-erbalpha is a critical lithium-sensitive component of the circadian clock. Science. 2006;311(5763):1002–5.

    Article  CAS  Google Scholar 

  112. Singla R, Mishra A, Lin H, Lorsung E, Le N, Tin S, Jin VX, Cao R. Haploinsufficiency of a Circadian Clock Gene Bmal1 (Arntl or Mop3) causes brain-wide mTOR hyperactivation and autism-like behavioral phenotypes in mice. Int J Mol Sci. 2022;23(11):6317.

    Article  CAS  Google Scholar 

  113. Christiansen SL, Bouzinova EV, Fahrenkrug J, Wiborg O. Altered expression pattern of clock genes in a rat model of depression. Int J Neuropsychoph. 2016;19(11):pyw061.

    Article  Google Scholar 

  114. Marti AR, Patil S, Mrdalj J, Meerlo P, Skrede S, Pallesen S, Pedersen TT, Bramham CR, Gronli J. No escaping the rat race: simulated night shift work alters the time-of-day variation in BMAL1 translational activity in the prefrontal cortex. Front Neural Circuit. 2017;11:70.

    Article  Google Scholar 

  115. Chen X, Hu Q, Zhang K, Teng H, Li M, Li D, Wang J, Du Q, Zhao M. The clock-controlled chemokine contributes to neuroinflammation-induced depression. FASEB J. 2020;34(6):8357–66.

    Article  CAS  Google Scholar 

  116. Yujnovsky I, Hirayama J, Doi M, Borrelli E, Sassone-Corsi P. Signaling mediated by the dopamine D2 receptor potentiates circadian regulation by CLOCK:BMAL1. P Natl Acad Sci USA. 2006;103(16):6386–91.

    Article  CAS  Google Scholar 

  117. Guo D, Zhang S, Sun H, Xu X, Hao Z, Mu C, Xu X, Wang G, Ren H. Tyrosine hydroxylase down-regulation after loss of Abelson helper integration site 1 (AHI1) promotes depression via the circadian clock pathway in mice. J Biol Chem. 2018;293(14):5090–101.

    Article  CAS  Google Scholar 

  118. Liu WW, Wei SZ, Huang GD, Liu LB, Gu C, Shen Y, Wang XH, Xia ST, Xie AM, Hu LF, et al. BMAL1 regulation of microglia-mediated neuroinflammation in MPTP-induced Parkinson’s disease mouse model. FASEB J. 2020;34(5):6570–81.

    Article  CAS  Google Scholar 

  119. McKee CA, Lee J, Cai Y, Saito T, Saido T, Musiek ES. Astrocytes deficient in circadian clock gene Bmal1 show enhanced activation responses to amyloid-beta pathology without changing plaque burden. Sci Rep-UK. 2022;12(1):1796.

    Article  CAS  Google Scholar 

  120. Musiek ES, Lim MM, Yang G, Bauer AQ, Qi L, Lee Y, Roh JH, Ortiz-Gonzalez X, Dearborn JT, Culver JP, et al. Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration. J Clin Invest. 2013;123(12):5389–400.

    Article  CAS  Google Scholar 

  121. Yoo ID, Park MW, Cha HW, Yoon S, Boonpraman N, Yi SS, Moon JS. Elevated CLOCK and BMAL1 contribute to the impairment of aerobic glycolysis from astrocytes in Alzheimer’s disease. Int J Mol Sci. 2020;21(21):7862.

    Article  CAS  Google Scholar 

  122. Satou R, Sugihara N, Ishizuka Y, Matsukubo T, Onishi Y. DNA methylation of the BMAL1 promoter. Biochem Bioph Res Co. 2013;440(3):449–53.

    Article  CAS  Google Scholar 

  123. Taniguchi H, Fernandez AF, Setien F, Ropero S, Ballestar E, Villanueva A, Yamamoto H, Imai K, Shinomura Y, Esteller M. Epigenetic inactivation of the circadian clock gene BMAL1 in hematologic malignancies. Cancer Res. 2009;69(21):8447–54.

    Article  CAS  Google Scholar 

  124. Song H, Moon M, Choe HK, Han DH, Jang C, Kim A, Cho S, Kim K, Mook-Jung I. Abeta-induced degradation of BMAL1 and CBP leads to circadian rhythm disruption in Alzheimer’s disease. Mol Neurodegener. 2015;10:13.

    Article  Google Scholar 

  125. Sharma A, Sethi G, Tambuwala MM, Aljabali A, Chellappan DK, Dua K, Goyal R. Circadian rhythm disruption and Alzheimer’s disease: the dynamics of a vicious cycle. Curr Neuropharmacol. 2021;19(2):248–64.

    Article  CAS  Google Scholar 

  126. Kondratova AA, Dubrovsky YV, Antoch MP, Kondratov RV. Circadian clock proteins control adaptation to novel environment and memory formation. Aging. 2010;2(5):285–97.

    Article  CAS  Google Scholar 

  127. Landgraf D, Long JE, Proulx CD, Barandas R, Malinow R, Welsh DK. Genetic disruption of circadian rhythms in the suprachiasmatic nucleus causes helplessness, behavioral despair, and anxiety-like behavior in mice. Biol Psychiat. 2016;80(11):827–35.

    Article  Google Scholar 

  128. Husse J, Zhou X, Shostak A, Oster H, Eichele G. Synaptotagmin10-Cre, a driver to disrupt clock genes in the SCN. J Biol Rhythm. 2011;26(5):379–89.

    Article  CAS  Google Scholar 

  129. Lee IT, Chang AS, Manandhar M, Shan Y, Fan J, Izumo M, Ikeda Y, Motoike T, Dixon S, Seinfeld JE, et al. Neuromedin s-producing neurons act as essential pacemakers in the suprachiasmatic nucleus to couple clock neurons and dictate circadian rhythms. Neuron. 2015;85(5):1086–102.

    Article  CAS  Google Scholar 

  130. Price K, Obrietan K. Modulation of learning and memory by the genetic disruption of circadian oscillator populations. Physiol Behav. 2018;194:387–93.

    Article  Google Scholar 

  131. Snider KH, Dziema H, Aten S, Loeser J, Norona FE, Hoyt K, Obrietan K. Modulation of learning and memory by the targeted deletion of the circadian clock gene Bmal1 in forebrain circuits. Behav Brain Res. 2016;308:222–35.

    Article  CAS  Google Scholar 

  132. Izumo M, Pejchal M, Schook AC, Lange RP, Walisser JA, Sato TR, Wang X, Bradfield CA, Takahashi JS. Differential effects of light and feeding on circadian organization of peripheral clocks in a forebrain Bmal1 mutant. Elife. 2014;3: e04617.

    Article  Google Scholar 

  133. Weaver DR, van der Vinne V, Giannaris EL, Vajtay TJ, Holloway KL, Anaclet C. functionally complete excision of conditional alleles in the mouse suprachiasmatic nucleus by vgat-ires-cre. J Biol Rhythm. 2018;33(2):179–91.

    Article  CAS  Google Scholar 

  134. de Zavalia N, Schoettner K, Goldsmith JA, Solis P, Ferraro S, Parent G, Amir S. Bmal1 in the striatum influences alcohol intake in a sexually dimorphic manner. Commun Biol. 2021;4(1):1227.

    Article  Google Scholar 

  135. Schoettner K, Alonso M, Button M, Goldfarb C, Herrera J, Quteishat N, Meyer C, Bergdahl A, Amir S. Characterization of affective behaviors and motor functions in mice with a striatal-specific deletion of Bmal1 and Per2. Front Physiol. 2022;13: 922080.

    Article  Google Scholar 

  136. Wu H, Liu Y, Liu L, Meng Q, Du C, Li K, Dong S, Zhang Y, Li H, Zhang H. Decreased expression of the clock gene Bmal1 is involved in the pathogenesis of temporal lobe epilepsy. Mol Brain. 2021;14(1):113.

    Article  CAS  Google Scholar 

  137. Hung CJ, Yamanaka A, Ono D. Conditional knockout of Bmal1 in corticotropin-releasing factor neurons does not alter sleep-wake rhythm in mice. Front Neurosci-Switz. 2021;15: 808754.

    Article  Google Scholar 

  138. Barca-Mayo O, Boender AJ, Armirotti A, De Pietri TD. Deletion of astrocytic BMAL1 results in metabolic imbalance and shorter lifespan in mice. Glia. 2020;68(6):1131–47.

    Article  Google Scholar 

  139. Becker-Krail DD, Ketchesin KD, Burns JN, Zong W, Hildebrand MA, DePoy LM, Vadnie CA, Tseng GC, Logan RW, Huang YH, et al. Astrocyte molecular clock function in the nucleus accumbens is important for reward-related behavior. Biol Psychiat. 2022;92(1):68–80.

    Article  CAS  Google Scholar 

  140. Mieda M, Ono D, Hasegawa E, Okamoto H, Honma K, Honma S, Sakurai T. Cellular clocks in AVP neurons of the SCN are critical for interneuronal coupling regulating circadian behavior rhythm. Neuron. 2015;85(5):1103–16.

    Article  CAS  Google Scholar 

  141. Wang XL, Kooijman S, Gao Y, Tzeplaeff L, Cosquer B, Milanova I, Wolff S, Korpel N, Champy MF, Petit-Demouliere B, et al. Microglia-specific knock-down of Bmal1 improves memory and protects mice from high fat diet-induced obesity. Mol Psychiatr. 2021;26(11):6336–49.

    Article  CAS  Google Scholar 

  142. DropViz. http://dropviz.org/. Accessed 17 Aug 2022

  143. Wang XL, Wolff S, Korpel N, Milanova I, Sandu C, Rensen P, Kooijman S, Cassel JC, Kalsbeek A, Boutillier AL, et al. Deficiency of the circadian clock gene Bmal1 reduces microglial immunometabolism. Front Immunol. 2020;11: 586399.

    Article  CAS  Google Scholar 

  144. Jones JR, Chaturvedi S, Granados-Fuentes D, Herzog ED. Circadian neurons in the paraventricular nucleus entrain and sustain daily rhythms in glucocorticoids. Nat Commun. 2021;12(1):5763.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This work was supported, in part, by National Natural Science Fund of China (81973948), National Key R&D Program of China (2019YFC1712105), Innovation Team Program of Guangdong Provincial Department of education (2018KCXTD006), Science and Technology Program of Guangdong (2018B030334001), Project funded by China Postdoctoral Science Foundation (2021M702045), College Students' Innovative Entrepreneurial Training Plan Program (X202110572179, X202110572167), Special Fund for Science and Technology Innovation cultivation of Guangdong University students (pdjh2020a0129), National Training Program of Innovation and Entrepreneurship for College Students (202010572009).

Author information

Authors and Affiliations

  1. Research Institute of Acupuncture and Moxibustion, Shandong University of Traditional Chinese Medicine, Jinan, China

    Yuanjia Zheng, Feixue Wang, Jinglan Yan, Taiyi Wang, Yucen Xia, Lin Yao, Meng Zhang & Yongjun Chen

  2. South China Research Center for Acupuncture and Moxibustion, Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, China

    Yuanjia Zheng, Lingyun Pan, Kelin Deng, Yuqi Zheng, Xiaoye Xia, Hongjie Chen, Jie Lin, Zhenwei Ding, Kaitong Zhang & Yongjun Chen

  3. Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, Guangzhou, China

    Yongjun Chen

  4. The Second Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China

    Zhikai Su

Authors
  1. Yuanjia Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lingyun Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Feixue Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jinglan Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Taiyi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yucen Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lin Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kelin Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yuqi Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xiaoye Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zhikai Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hongjie Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jie Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Zhenwei Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Kaitong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Meng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Yongjun Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YC, YuaZ and MZ conceived and designed project. YuaZ, KD, YuqZ, XX, ZS, HC prepared the reference. YuaZ, JL, ZD, KZ prepared the figures. YC, YuaZ, LP, FW, JY wrote the manuscript. MZ, YX, Lin Yao helped revise the manuscript. All authors performed data analyses, and interpretations. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Meng Zhang or Yongjun Chen.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

With the submission of this manuscript we would like to undertake that all authors of this paper have read and approved the final version submitted.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zheng, Y., Pan, L., Wang, F. et al. Neural function of Bmal1: an overview. Cell Biosci 13, 1 (2023). https://doi.org/10.1186/s13578-022-00947-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13578-022-00947-8

Keywords

Cell & Bioscience

ISSN: 2045-3701

Contact us