Neurocalcin regulates nighttime sleep and arousal in Drosophila

Chen, Ko‐Fan; Lowe, Simon; Lamaze, Angélique; Krätschmer, Patrick; Jepson, James E.C.

doi:10.7554/elife.38114

Cited by 19 publications

(12 citation statements)

References 76 publications

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“…Because the activity of R5 neurons cycles, the light/clock-generated coding in these cells may have a multilayered structure that influences the circadian clock network and sleep-drive circuits. This theory is supported by a recent paper showing how light-input controls night sleep at the circuit level, independent of the clock (146). Thus, light information could be an important state variable in the relationship between circadian regulation of sleep and sleep homeostasis.…”

Section: The Roles Of Cry In Flies and Opsins In Mammalsmentioning

confidence: 68%

Light/Clock Influences Membrane Potential Dynamics to Regulate Sleep States

et al. 2021

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The circadian rhythm is a fundamental process that regulates the sleep–wake cycle. This rhythm is regulated by core clock genes that oscillate to create a physiological rhythm of circadian neuronal activity. However, we do not know much about the mechanism by which circadian inputs influence neurons involved in sleep–wake architecture. One possible mechanism involves the photoreceptor cryptochrome (CRY). In Drosophila, CRY is receptive to blue light and resets the circadian rhythm. CRY also influences membrane potential dynamics that regulate neural activity of circadian clock neurons in Drosophila, including the temporal structure in sequences of spikes, by interacting with subunits of the voltage-dependent potassium channel. Moreover, several core clock molecules interact with voltage-dependent/independent channels, channel-binding protein, and subunits of the electrogenic ion pump. These components cooperatively regulate mechanisms that translate circadian photoreception and the timing of clock genes into changes in membrane excitability, such as neural firing activity and polarization sensitivity. In clock neurons expressing CRY, these mechanisms also influence synaptic plasticity. In this review, we propose that membrane potential dynamics created by circadian photoreception and core clock molecules are critical for generating the set point of synaptic plasticity that depend on neural coding. In this way, membrane potential dynamics drive formation of baseline sleep architecture, light-driven arousal, and memory processing. We also discuss the machinery that coordinates membrane excitability in circadian networks found in Drosophila, and we compare this machinery to that found in mammalian systems. Based on this body of work, we propose future studies that can better delineate how neural codes impact molecular/cellular signaling and contribute to sleep, memory processing, and neurological disorders.

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Section: The Roles Of Cry In Flies and Opsins In Mammalsmentioning

confidence: 68%

Light/Clock Influences Membrane Potential Dynamics to Regulate Sleep States

et al. 2021

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“…After 2 days of acclimatisation, data were acquired from a 24 hr period on the third day (beginning at the onset of lights-on). A custom Microsoft Excel workbook ( Chen et al, 2019 ) was used to calculate total activity counts per fly in the day and night periods, and to calculate sleep minutes during the day period (continuous periods of fly inactivity lasting 5 min or longer were classified as sleep). Flies with more than 12 hr of continuous inactivity at the end of the experiment were excluded as potentially dead.…”

Section: Methodsmentioning

confidence: 99%

Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila

Atilano

Grönke

Niccoli

et al. 2021

eLife

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G4C2 repeat expansions within the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The repeats undergo repeat-associated non-ATG translation to generate toxic dipeptide repeat proteins. Here, we show that insulin/Igf signalling is reduced in fly models of C9orf72 repeat expansion using RNA-sequencing of adult brain. We further demonstrate that activation of insulin/Igf signalling can mitigate multiple neurodegenerative phenotypes in flies expressing either expanded G4C2 repeats or the toxic dipeptide repeat protein poly-GR. Levels of poly-GR are reduced when components of the insulin/Igf signalling pathway are genetically activated in the diseased flies, suggesting a mechanism of rescue. Modulating insulin signalling in mammalian cells also lowers poly-GR levels. Remarkably, systemic injection of insulin improves the survival of flies expressing G4C2 repeats. Overall, our data suggest that modulation of insulin/Igf signalling could be an effective therapeutic approach against C9orf72 ALS/FTD.

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“…After two days of acclimatization, data were obtained from a 24‐hr period on the third day (beginning at the onset of lights‐on). A custom Microsoft Excel workbook (Chen, Lowe, Lamaze, Krätschmer, & Jepson, 2019) was used to calculate total activity counts per fly in the day and night periods, as well as to define sleep (five or more continuous minutes with no activity) and calculate total sleep minutes and number of sleep bouts per fly in the day and night periods.…”

Section: Methodsmentioning

confidence: 99%

The neuronal receptor tyrosine kinase Alk is a target for longevity

et al. 2020

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Inhibition of signalling through several receptor tyrosine kinases (RTKs), including the insulin‐like growth factor receptor and its orthologues, extends healthy lifespan in organisms from diverse evolutionary taxa. This raises the possibility that other RTKs, including those already well studied for their roles in cancer and developmental biology, could be promising targets for extending healthy lifespan. Here, we focus on anaplastic lymphoma kinase (Alk), an RTK with established roles in nervous system development and in multiple cancers, but whose effects on aging remain unclear. We find that several means of reducing Alk signalling, including mutation of its ligand jelly belly (jeb), RNAi knock‐down of Alk, or expression of dominant‐negative Alk in adult neurons, can extend healthy lifespan in female, but not male, Drosophila. Moreover, reduced Alk signalling preserves neuromuscular function with age, promotes resistance to starvation and xenobiotic stress, and improves night sleep consolidation. We find further that inhibition of Alk signalling in adult neurons modulates the expression of several insulin‐like peptides, providing a potential mechanistic link between neuronal Alk signalling and organism‐wide insulin‐like signalling. Finally, we show that TAE‐684, a small molecule inhibitor of Alk, can extend healthy lifespan in Drosophila, suggesting that the repurposing of Alk inhibitors may be a promising direction for strategies to promote healthy aging.

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Neurocalcin regulates nighttime sleep and arousal in Drosophila

Cited by 19 publications

References 76 publications

Light/Clock Influences Membrane Potential Dynamics to Regulate Sleep States

Light/Clock Influences Membrane Potential Dynamics to Regulate Sleep States

Enhanced insulin signalling ameliorates C9orf72 hexanucleotide repeat expansion toxicity in Drosophila

The neuronal receptor tyrosine kinase Alk is a target for longevity

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