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Our laboratory aims to elucidate the operating principles of the neural network in the suprachiasmatic nucleus (SCN), which functions as the central circadian clock in mammals. In addition, we seek to achieve an integrated understanding of how the central circadian clock regulates brain functions as well as systemic homeostasis and homeodynamics. Ultimately, we aim to extend our findings toward clarifying the pathophysiology of diseases caused by circadian clock dysfunction and developing novel disease models.
Our laboratory aims to elucidate the operating principles of the neural network in the suprachiasmatic nucleus (SCN), which functions as the central circadian clock in mammals. In addition, we seek to achieve an integrated understanding of how the central circadian clock regulates brain functions as well as systemic homeostasis and homeodynamics. Ultimately, we aim to extend our findings toward clarifying the pathophysiology of diseases caused by circadian clock dysfunction and developing novel disease models.
Background
Background
Most organisms on Earth exhibit approximately 24-hour rhythms in biological activities, known as circadian rhythms. In mammals, including humans, not only sleep and behavior but also numerous physiological processes—such as hormone secretion and autonomic nervous system activity—follow circadian patterns.
Most organisms on Earth exhibit approximately 24-hour rhythms in biological activities, known as circadian rhythms. In mammals, including humans, not only sleep and behavior but also numerous physiological processes—such as hormone secretion and autonomic nervous system activity—follow circadian patterns.
These rhythms are controlled by the suprachiasmatic nucleus (SCN) in the hypothalamus. The SCN serves as the master clock of the body, determining broad behavioral patterns such as the timing of daily activity. Circadian rhythms enable organisms to anticipate the day–night cycle caused by Earth’s rotation and to optimize internal physiology and behavior accordingly (Figure 1).
These rhythms are controlled by the suprachiasmatic nucleus (SCN) in the hypothalamus. The SCN serves as the master clock of the body, determining broad behavioral patterns such as the timing of daily activity. Circadian rhythms enable organisms to anticipate the day–night cycle caused by Earth’s rotation and to optimize internal physiology and behavior accordingly (Figure 1).
When internal circadian time becomes misaligned with external time, various problems arise. Jet lag is a typical example. Chronic circadian disruption, such as that caused by shift work, increases the risk of sleep disorders, mood disorders, cancer, and metabolic syndrome. Therefore, understanding the mechanisms of the circadian clock and developing methods (e.g., pharmacological interventions) to properly regulate its function are of great importance in modern society, where daily rhythms are easily disrupted.
When internal circadian time becomes misaligned with external time, various problems arise. Jet lag is a typical example. Chronic circadian disruption, such as that caused by shift work, increases the risk of sleep disorders, mood disorders, cancer, and metabolic syndrome. Therefore, understanding the mechanisms of the circadian clock and developing methods (e.g., pharmacological interventions) to properly regulate its function are of great importance in modern society, where daily rhythms are easily disrupted.
Figure 1：The suprachiasmatic nucleus (SCN): the brain’s central circadian clock
Figure 1：The suprachiasmatic nucleus (SCN): the brain’s central circadian clock
The time-of-day information generated by the suprachiasmatic nucleus is transmitted throughout the body and regulates a wide range of physiological functions. The slight mismatch between the intrinsic period of the central circadian clock (approximately 24 hours) and Earth’s 24-hour rotation cycle is corrected by environmental light signals. Light information is conveyed to the suprachiasmatic nucleus via the retina, where it resets the central circadian clock each day.
（１）Neural Network Mechanisms of the Central Circadian Clock
（１）Neural Network Mechanisms of the Central Circadian Clock
The discovery of clock genes revealed that cells possess an approximately 24-hour molecular oscillator known as the transcription–translation feedback loop (TTFL). This intracellular clock exists in nearly all cells of the body.
The discovery of clock genes revealed that cells possess an approximately 24-hour molecular oscillator known as the transcription–translation feedback loop (TTFL). This intracellular clock exists in nearly all cells of the body.
However, individual cellular clocks are not highly precise; their intrinsic periods vary by several hours between cells. Despite this variability, organisms maintain an accurate ~24-hour rhythm at the whole-body level. This high precision is generated by the central clock in the SCN, which synchronizes peripheral cellular clocks and maintains coherent circadian rhythms throughout the organism.
However, individual cellular clocks are not highly precise; their intrinsic periods vary by several hours between cells. Despite this variability, organisms maintain an accurate ~24-hour rhythm at the whole-body level. This high precision is generated by the central clock in the SCN, which synchronizes peripheral cellular clocks and maintains coherent circadian rhythms throughout the organism.
The function of the central clock cannot be explained solely by intracellular clock genes. Instead, interactions within the SCN neuronal network are essential. Although this has long been suspected, the detailed operating principles of this network remained unclear.
The function of the central clock cannot be explained solely by intracellular clock genes. Instead, interactions within the SCN neuronal network are essential. Although this has long been suspected, the detailed operating principles of this network remained unclear.
The SCN consists of approximately 20,000 neurons. These neurons are not homogeneous but comprise multiple distinct cell types. While each neuron possesses a cell-autonomous clock, stable and robust circadian oscillation at the network level requires coordinated interactions among these neurons.
The SCN consists of approximately 20,000 neurons. These neurons are not homogeneous but comprise multiple distinct cell types. While each neuron possesses a cell-autonomous clock, stable and robust circadian oscillation at the network level requires coordinated interactions among these neurons.
Using cell-type-specific genetic manipulation and neuronal activity control within the SCN, combined with detailed behavioral and physiological analyses, we have demonstrated that arginine vasopressin (AVP)-producing neurons function as critical clock neurons that stabilize network rhythms and determine circadian period (Mieda et al., Neuron 2015; Mieda et al., Current Biology 2016; Maejima et al., PNAS 2021; Tsuno et al., PLoS Biol 2023).
Using cell-type-specific genetic manipulation and neuronal activity control within the SCN, combined with detailed behavioral and physiological analyses, we have demonstrated that arginine vasopressin (AVP)-producing neurons function as critical clock neurons that stabilize network rhythms and determine circadian period (Mieda et al., Neuron 2015; Mieda et al., Current Biology 2016; Maejima et al., PNAS 2021; Tsuno et al., PLoS Biol 2023).
Vasoactive intestinal polypeptide (VIP), another neuropeptide expressed in the SCN, is also known to be essential for circadian rhythm generation. Recently, we integrated our findings on AVP neurons as core clock cells with previous findings from other groups identifying VIP as a synchronizing factor within the SCN. Based on this integration, we proposed a fundamental mechanism by which the SCN generates robust circadian rhythms (Wang et al, Nat Commun 2026).
Vasoactive intestinal polypeptide (VIP), another neuropeptide expressed in the SCN, is also known to be essential for circadian rhythm generation. Recently, we integrated our findings on AVP neurons as core clock cells with previous findings from other groups identifying VIP as a synchronizing factor within the SCN. Based on this integration, we proposed a fundamental mechanism by which the SCN generates robust circadian rhythms (Wang et al, Nat Commun 2026).
1. AVP neurons act as core clock cells generating circadian rhythms. Their intrinsic period is slightly short (~22.5 hours), and their oscillation amplitude is relatively small.
1. AVP neurons act as core clock cells generating circadian rhythms. Their intrinsic period is slightly short (~22.5 hours), and their oscillation amplitude is relatively small.
2. VIP neurons become active in synchrony with the AVP rhythm and release VIP.
2. VIP neurons become active in synchrony with the AVP rhythm and release VIP.
3. Released VIP acts on AVP neurons, delaying their rhythm, lengthening the period to approximately 24 hours, and increasing oscillation amplitude.
3. Released VIP acts on AVP neurons, delaying their rhythm, lengthening the period to approximately 24 hours, and increasing oscillation amplitude.
Through this feedback-type neuronal network, the SCN generates stable and robust circadian rhythms. This mechanism resembles pushing a child on a swing at the appropriate timing—amplifying the oscillation and slightly lengthening the period.
Through this feedback-type neuronal network, the SCN generates stable and robust circadian rhythms. This mechanism resembles pushing a child on a swing at the appropriate timing—amplifying the oscillation and slightly lengthening the period.
We named this mechanism the SNFL (SCN Neuronal Feedback Loop), in analogy to the intracellular TTFL (transcription–translation feedback loop).
We named this mechanism the SNFL (SCN Neuronal Feedback Loop), in analogy to the intracellular TTFL (transcription–translation feedback loop).
When the circadian period deviates substantially from 24 hours, adaptation to the external day–night cycle becomes difficult. For example, a so-called “evening chronotype” (night owl tendency) may be partly explained by a longer intrinsic period of the central clock. In jet lag, the clock’s phase is misaligned with the external environment. Age-related sleep fragmentation may reflect reduced circadian amplitude. Precisely understanding how period, phase, and amplitude are controlled will provide the foundation for developing improved interventions for circadian-related health disorders.
When the circadian period deviates substantially from 24 hours, adaptation to the external day–night cycle becomes difficult. For example, a so-called “evening chronotype” (night owl tendency) may be partly explained by a longer intrinsic period of the central clock. In jet lag, the clock’s phase is misaligned with the external environment. Age-related sleep fragmentation may reflect reduced circadian amplitude. Precisely understanding how period, phase, and amplitude are controlled will provide the foundation for developing improved interventions for circadian-related health disorders.
Figure 2：Neuronal feedback loop of the suprachiasmatic nucleus generates robust circadian rhythms
Figure 2：Neuronal feedback loop of the suprachiasmatic nucleus generates robust circadian rhythms
The suprachiasmatic nucleus (SCN), the central circadian clock, consists of a neural network of approximately 20,000 neurons. Each neuron contains an intracellular molecular clock mechanism driven by clock genes, known as the transcription–translation feedback loop (TTFL). While the TTFL is necessary for the SCN to function as the central clock, it is not sufficient. In addition to the intracellular mechanism, reciprocal interactions between vasopressin (AVP)-producing neurons and vasoactive intestinal polypeptide (VIP)-producing neurons—via a bidirectional feedback circuit termed the SCN Neuronal Feedback Loop (SNFL)—generate a robust and stable ~24-hour circadian rhythm (Wang et al, Nat Commun 2026).
（２）Brain–Organ Network Centered on the Central Circadian Clock
（２）Brain–Organ Network Centered on the Central Circadian Clock
The circadian rhythms generated by the central clock regulate numerous physiological functions. However, the precise pathways and mechanisms through which these regulations occur remain largely unknown. Even in the case of sleep, the specific neural circuits mediating SCN-driven control are surprisingly incompletely understood.
The circadian rhythms generated by the central clock regulate numerous physiological functions. However, the precise pathways and mechanisms through which these regulations occur remain largely unknown. Even in the case of sleep, the specific neural circuits mediating SCN-driven control are surprisingly incompletely understood.
The most important entraining factor for the central clock is environmental light. Because the endogenous circadian period slightly deviates from 24 hours, daily adjustment is necessary. Light information from the retina is transmitted directly to the SCN via the retinohypothalamic tract, fine-tuning clock phase each day. In contrast, physiologically significant non-photic regulatory mechanisms of the central clock remain poorly characterized.
The most important entraining factor for the central clock is environmental light. Because the endogenous circadian period slightly deviates from 24 hours, daily adjustment is necessary. Light information from the retina is transmitted directly to the SCN via the retinohypothalamic tract, fine-tuning clock phase each day. In contrast, physiologically significant non-photic regulatory mechanisms of the central clock remain poorly characterized.
Using optogenetics, chemogenetics, neuron-type-specific activity manipulation, recombinant viral vector-based circuit tracing, and gene expression profiling, we aim to elucidate how the central circadian clock regulates diverse brain functions and peripheral organ systems. We are also working to identify novel brain functions regulated by the central clock and to discover new mechanisms that regulate the central clock itself.
Using optogenetics, chemogenetics, neuron-type-specific activity manipulation, recombinant viral vector-based circuit tracing, and gene expression profiling, we aim to elucidate how the central circadian clock regulates diverse brain functions and peripheral organ systems. We are also working to identify novel brain functions regulated by the central clock and to discover new mechanisms that regulate the central clock itself.
（３）Circadian Disruption and Disease
（３）Circadian Disruption and Disease
By experimentally perturbing the central circadian clock, we investigate how abnormalities arise in sleep, behavior, and systemic physiology. Furthermore, we aim to develop new technologies that enable precise and flexible manipulation of the central clock, ultimately paving the way for therapeutic strategies targeting circadian dysfunction.
By experimentally perturbing the central circadian clock, we investigate how abnormalities arise in sleep, behavior, and systemic physiology. Furthermore, we aim to develop new technologies that enable precise and flexible manipulation of the central clock, ultimately paving the way for therapeutic strategies targeting circadian dysfunction.
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