Cholecystokinin neurons in mouse suprachiasmatic nucleus regulate the robustness of circadian clock

Xie, Lucheng; Xiong, Yangyang; Ma, Danyi; Shi, Kaiwen; Chen, Jiu; Yang, Qiaoqiao; Yan, Jun

doi:10.1016/j.neuron.2023.04.016

Cited by 15 publications

(9 citation statements)

References 42 publications

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“…Behaviorally, we demonstrated that activation of CT 16-trapped neurons leads to phase delays across all time zones, supporting the idea of separable delay and advance circuitries within the SCN. Prior research indicated a partial PRC by activating VIP or CCK neurons 36,56 , hinting that a subset of these may correspond to our identified delay or advance cells.…”

Section: Discussionmentioning

confidence: 64%

“…For instance, optogenetic activation of VIP neurons can induce phase delay at early subjective night but does not produce the full PRC equivalent to the light pulse 37 . Conversely, activation of cholecystokinin (CCK) neurons within the SCN can only elicit phase advances during the late subjective night 56 . Thus, a time-gated functional network could be the underlying mechanism for the discrete properties of the PRC.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 64%

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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“…A number of these peptides play important roles in SCN light responses, light resetting, and entrainment. In particular, VIP released from light-excited retinorecipient SCN neurons transmits light input broadly in the SCN neural network [22,23] and neurons expressing CCK are critical for responses to long photoperiods and may activate VIP neurons specifically under long photoperiod [58]. We investigated 26 genes detected by DESeq2 that either make up the signaling axes themselves (peptides, receptors) or are involved in their modulation.…”

Section: Resultsmentioning

confidence: 99%

“…These include Dusp4 , Rasd1 and Gem which are each key modulators of the SCN light response [23,61,62]. In addition, there were changes in the expression of Prokr2 the widely expressed receptor for the critical PROK2 signaling network hub in the SCN [55], and in the expression of ( Cck), which is expressed in neurons critical for light-induced phase advances and entrainment to Long photoperiods [58].…”

Section: Discussionmentioning

confidence: 99%

Gene expression plasticity of the mammalian brain circadian clock in response to photoperiod

Cox,

Gianonni-Guzmán,

Cartailler

et al. 2024

Preprint

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Seasonal daylength, or circadian photoperiod, is a pervasive environmental signal that profoundly influences physiology and behavior. In mammals, the central circadian clock resides in the suprachiasmatic nuclei (SCN) of the hypothalamus and synchronizes, or entrains, physiology and behavior to the prevailing light cycle from retinal input. The process of entrainment induces considerable plasticity in the SCN, but the molecular mechanisms underlying SCN plasticity are incompletely understood. Entrainment to different photoperiods persistently alters the phase, waveform, period, and resetting properties of the SCN and its driven rhythms. To elucidate novel molecular mechanisms of photoperiod plasticity, we performed RNAseq on whole SCN dissected from mice raised in Long (LD 16:8) and Short (LD 8:16) photoperiods. Using differential rhythms analysis, we showed that fewer rhythmic genes were detected in Long photoperiod and that there was an overall phase advance of gene expression rhythms of 4-6 hours. However, a few genes showed significant phase delays, including GTP binding protein overexpressed in skeletal muscle (Gem), an SCN light responsive gene and light response modulator. Using differential expression analysis, we found significant expression changes in the clock-associated gene timeless circadian clock 1 (Timeless) and abundant changes in expression levels of SCN neural signaling genes related to light responses, neuropeptides, GABA, ion channels, and serotonin. Particularly striking were differences across photoperiods in the expression of the SCN neuropeptide signaling genes, prokineticin receptor 2 (Prokr2) and cholecystokinin (Cck), as well as convergent regulation of the expression of three SCN light response genes, dual specificity phosphatase 4 (Dusp4) and RAS, dexamethasone-induced 1 (Rasd1), andGem. Transcriptional modulation ofDusp4andRasd1,and phase regulation ofGem,are compelling candidate molecular mechanisms for photoperiod-induced plasticity in the SCN light response. Similarly, transcriptional modulation ofProkr2andCckmay critically support SCN neural network reconfiguration during photoperiodic entrainment. Our findings identify the SCN light response and neuropeptide signaling gene sets as rich substrates for elucidating novel mechanisms of photoperiod plasticity.

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“…Consistent with the DryR analysis, a lot of these 38 rhythmic genes showed earlier rise or fall of gene expression (i.e. phase-advanced), including the clock genes Per1 and Nr1d1; the dual-specificity phosphatases Dusp1 and 4; the thioredoxin interacting protein Txnip; the cold-induced RNA binding proteins Rbm3; the immediate-early gene Junb; the neuropeptides Cholecystokinin (Cck) and Prokineticin (Prok2) involved in the regulation of circadian locomotor activity [22][23][24] ; and acetylcholinesterase (Ache) (Fig. 2B).…”

Section: Methionine/choline Deficiency Reprograms the Scn Circadian T...mentioning

confidence: 99%

Dietary methionine/choline deficiency affects behavioural and molecular circadian rhythms

Saer,

Taylor,

Hayes

et al. 2024

Preprint

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The feeding/fasting cycles controlled by our circadian clock impose great daily metabolic and physiological changes, and yet investigations into the consequences of metabolic deficiencies, either dietary or genetic, have often ignored the time of day or the circadian time of the animals or subjects. In addition, these deficiencies may themselves disrupt our circadian clock, causing secondary metabolic, physiological and behavioural disorders. Dietary methionine/choline deficiency in rodents is a common model for human non-alcoholic steatohepatitis, but methionine and choline are nutrients essential for many other processes beyond fatty acid synthesis in the liver, including biological methylations and 1-carbon metabolism, regulation of translation notably via the mTOR pathway, phospholipid synthesis, polyamine pathway and glutathione synthesis. We have previously shown that circadian rhythms in many organisms are highly sensitive to deficiency or excesses of 1-carbon metabolites. Using a methionine/choline deficient diet in mice, we illustrate the nutrigenomic crosstalk between circadian rhythms and 1-carbon metabolism. We show not only that circadian locomotor activity behaviour is profoundly, rapidly and reversibly affected by methionine/choline deficiency, but also that the effects of methionine/choline deficiency on gene expression and 1-carbon metabolites are dependent on circadian time, illustrating the importance of considering circadian rhythms in metabolic studies. This study also highlights the impact of what we eat, or don't, on our behaviour and biological rhythms.

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Cholecystokinin neurons in mouse suprachiasmatic nucleus regulate the robustness of circadian clock

Cited by 15 publications

References 42 publications

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

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

Gene expression plasticity of the mammalian brain circadian clock in response to photoperiod

Dietary methionine/choline deficiency affects behavioural and molecular circadian rhythms

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