The Suprachiasmatic Nucleus at 50: Looking Back, Then Looking Forward

Ono, Daisuke; Weaver, David R.; Hastings, Michael H.; Honma, Ken-Ichi; Honma, Sato; Silver, Rae

doi:10.1177/07487304231225706

Cited by 16 publications

(3 citation statements)

References 311 publications

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“…Typically, a bioluminescent or fluorescent reporter is tagged to a TTFL component so that circadian parameters (period length, phase, and amplitude) can be recorded under constant conditions in cells, tissue slices, or whole animals 26 . In vivo experiments have further targeted TTFL components in specific neural cell types, most notably in the suprachiasmatic nucleus (SCN) of the hypothalamus 27 . The rationale for these approaches is based on the putative hierarchical assembly of the circadian system in mammals.…”

Section: Introductionmentioning

confidence: 99%

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Circadian clocks in human cerebral organoids

Rzechorzek,

Sutcliffe,

Mihut

et al. 2024

Preprint

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SummaryCircadian rhythms result from cell-intrinsic timing mechanisms that impact health and disease1,2. To date, however, neural circadian research has largely focused on the hypothalamic circuitry of nocturnal rodents3. Whether circadian rhythms exist in human brain cells is unknown. Here we showbona fidecircadian rhythms in human neurons, glia, cerebral organoids, and cerebral organoid slices (ALI-COs)4–8. Human neural circadian rhythms are synchronised by physiological timing cues such as glucocorticoids and daily temperature cycles, and these rhythms are temperature-compensated across the range of normal human brain temperatures9. Astrocyte rhythms are phase-advanced relative to other cultures and they modulate neuronal clock responses to temperature shift. Cerebral organoid rhythms are more robust at physiological brain temperatures; the relative amplitude of these rhythms increases over time in culture and their resetting capacity recapitulates key neurodevelopmental transitions in glucocorticoid signalling10–14. Remarkably, organoid post-transcriptional bioluminescent clock reporter rhythms are retained even when those of their putative transcriptional drivers are indiscernible15, and electrophysiology recordings confirm circadian rhythms in functional activity of monocultures, organoids, and ALI-COs. Around one third of the cerebral organoid proteome and phosphoproteome are circadian-rhythmic, with temporal consolidation of disease-relevant neural processes. Finally, we show that human brain organoid rhythms can be modulated and disrupted by commonly used brain-permeant drugs and mistimed cortisol exposure, respectively. Our results demonstrate that human brain cells and tissues develop their own circadian oscillations and that canonical mechanisms of the circadian clockwork may be inadequate to explain these rhythmic phenomena. 2D and 3D human neural cultures represent complementary and tractable models for exploring the emergence, disruption, and mechanics of the circadian neural clockwork, with important implications for chronobiology, brain function, and brain health.

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Section: Introductionmentioning

confidence: 99%

“…In rodents, the hypothalamic circuitry that coordinates cycles of rest and activity with those of day and night is well characterized 27 . Far fewer studies have explored circadian phenomena in other parts of the brain 30–33 , and fewer still have addressed them in naturally diurnal species.…”

Section: Introductionmentioning

confidence: 99%

Circadian clocks in human cerebral organoids

Rzechorzek,

Sutcliffe,

Mihut

et al. 2024

Preprint

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show abstract

“…The circadian clock controls many physiological functions in animals, including gene expression, stem cell proliferation, metabolism, neuronal activity, gut microbiota, mood, learning, and memory 1 . In mammals, the suprachiasmatic nucleus (SCN) in the hypothalamus serves as the master clock, orchestrating many peripheral clocks within different tissues 2–5 .…”

Section: Introductionmentioning

confidence: 99%

Discrete photoentrainment of mammalian central clock is regulated by bi-stable dynamic network in the suprachiasmatic nucleus

Yeh,

Jhan,

Chua

et al. 2024

Preprint

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The circadian clock, an evolutionarily conserved mechanism regulating the majority of physiological functions in many organisms, is synchronized with the environmental light-dark cycle through circadian photoentrainment. This process is mediated by light exposure at specific times, leading to a discrete phase shift including phase delays during early subjective night, phase advances during late subjective night, and no shift at midday, known as the dead zone. In mammals, such as mice, the intrinsically photosensitive retinal ganglion cells (ipRGCs) are crucial for conveying light information to the suprachiasmatic nucleus (SCN), the central clock consisting of approximately 20,000 neurons. While the intracellular signaling pathways that modulate clock gene expression post-light exposure are well-studied, the functional neuronal circuits responsible for the three discrete light responses are not well understood. Utilizing in vivo two-photon microscopy with gradient-index (GRIN) endoscopes, we have identified seven distinct light responses from SCN neurons. Our findings indicate that light responses from individual SCN neurons are mostly stochastic from trial to trial. However, at the population level, light response composition remains similar across trials, with only minor variations between circadian times, suggesting a dynamic populational coding for light input. Additionally, only a small subset of SCN neurons shows consistent light responses. Furthermore, by utilizing the targeted recombination in active populations (TRAP) system to label neurons that respond to light during early subjective night, we demonstrate that their activation can induce phase delays at any circadian time, effectively breaking the gate that produce photoentrainment dead zone typically observed at midday. Our results suggest the existence of at least two separate time-dependent functional circuits within the SCN. We propose a dynamic bi-stable network model for circadian photoentrainment in the mammalian central clock, where a shifting clock is driven by a dynamic functional circuit utilizing population coding to integrate information flow similar to proposed cortical computational network, rather than a simplistic, consistent linear circuit.

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The Art of Chilling Out: How Neurons Regulate Torpor

Ohba,

Yamaguchi

2024

BioEssays

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Endothermic animals expend significant energy to maintain high body temperatures, which offers adaptability to varying environmental conditions. However, this high metabolic rate requires increased food intake. In conditions of low environmental temperature and scarce food resources, some endothermic animals enter a hypometabolic state known as torpor to conserve energy. Torpor involves a marked reduction in body temperature, heart rate, respiratory rate, and locomotor activity, enabling energy conservation. Despite their biological significance and potential medical applications, the neuronal mechanisms regulating torpor still need to be fully understood. Recent studies have focused on fasting‐induced daily torpor in mice due to their suitability for advanced neuroscientific techniques. In this review, we highlight recent advances that extend our understanding of neuronal mechanisms regulating torpor. We also discuss unresolved issues in this research field and future directions.

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The Suprachiasmatic Nucleus at 50: Looking Back, Then Looking Forward

Cited by 16 publications

References 311 publications

Circadian clocks in human cerebral organoids

Circadian clocks in human cerebral organoids

Discrete photoentrainment of mammalian central clock is regulated by bi-stable dynamic network in the suprachiasmatic nucleus

The Art of Chilling Out: How Neurons Regulate Torpor

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