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Homeostasis in C. elegans sleep is characterized by two behaviorally and genetically distinct mechanisms.

Nagy S, Tramm N, Sanders J, Iwanir S, Shirley IA, Levine E, Biron D - Elife (2014)

Bottom Line: This response to strong stimuli required the function of the DAF-16/FOXO transcription factor in neurons, but not that of NPR-1.Conversely, response to weak stimuli did not require the function of DAF-16/FOXO.These findings suggest that routine homeostatic stabilization of sleep may be distinct from homeostatic compensation following a strong disturbance.

View Article: PubMed Central - PubMed

Affiliation: Institute for Biophysical Dynamics, University of Chicago, Chicago, United States.

ABSTRACT
Biological homeostasis invokes modulatory responses aimed at stabilizing internal conditions. Using tunable photo- and mechano-stimulation, we identified two distinct categories of homeostatic responses during the sleep-like state of Caenorhabditis elegans (lethargus). In the presence of weak or no stimuli, extended motion caused a subsequent extension of quiescence. The neuropeptide Y receptor homolog, NPR-1, and an inhibitory neuropeptide known to activate it, FLP-18, were required for this process. In the presence of strong stimuli, the correlations between motion and quiescence were disrupted for several minutes but homeostasis manifested as an overall elevation of the time spent in quiescence. This response to strong stimuli required the function of the DAF-16/FOXO transcription factor in neurons, but not that of NPR-1. Conversely, response to weak stimuli did not require the function of DAF-16/FOXO. These findings suggest that routine homeostatic stabilization of sleep may be distinct from homeostatic compensation following a strong disturbance.

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Homeostatic responses to strong stimuli, but not micro-homeostasis, require DAF-16.(A) Left: the fraction of quiescence of wild-type animals and daf-16 mutants during L4leth (shaded area). Plots depict mean ± s.e.m, the numbers of animals assayed are denoted in parentheses. Right: pairwise bout correlations shown with a plot of binned bouts (see Figure 2A for details). Pairwise correlations were reduced in the mutant, although less so than in npr-1 mutants (p < 0.05). All correlations are given with 95% confidence intervals and error bars depict ±s.e.m. The number of bouts in each case is denoted in parentheses. (B) A posture-based analysis of responses of L4int and L4leth daf-16 mutants to strong stimuli (15 s, 1 kHz vibrations): the fraction of forward locomotion, backward locomotion, dwelling, and quiescence before, during, and after the stimulus. (C) Left: frame subtraction based analyses of responses of L4leth daf-16 mutants to weak stimuli (15 s, 20 mW/cm2, blue light). Inset: the response of daf-16 mutants during L4leth on a semi-log scale. Middle: the fraction of quiescence during 1 min intervals centered at the times of the peak and trough of the L4leth responses, as well as for their respective pre-stimulus baselines. All stimuli were initiated at t = 0. N = 50–60 animals. Plots and bars depict mean ± s.e.m, asterisks denote p < 0.001. Right: a posture-based analysis of bout dynamics of daf-16 mutants following a weak stimulus. Plots depict mean ± s.e.m, smoothed using a 30 s running window average. N = 12 animals. The compensatory enhancement of quiescence bouts shortly after the stimulus, as assayed by both methods, was similar to wild-type. (D) The mean baseline fractions of quiescence of daf-16 mutants in undisturbed animals and in the presence of weak and strong stimuli. In contrast to wild-type, baseline quiescence fraction was indistinguishable between the different conditions. Expression of daf-16 in neurons, but not in body-wall muscles, restored the homeostatic response of daf-16 mutants to strong mechanical stimuli. Error bar depicts ±s.e.m. The number of stimuli assayed is noted in parentheses for each condition.DOI:http://dx.doi.org/10.7554/eLife.04380.018
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fig8: Homeostatic responses to strong stimuli, but not micro-homeostasis, require DAF-16.(A) Left: the fraction of quiescence of wild-type animals and daf-16 mutants during L4leth (shaded area). Plots depict mean ± s.e.m, the numbers of animals assayed are denoted in parentheses. Right: pairwise bout correlations shown with a plot of binned bouts (see Figure 2A for details). Pairwise correlations were reduced in the mutant, although less so than in npr-1 mutants (p < 0.05). All correlations are given with 95% confidence intervals and error bars depict ±s.e.m. The number of bouts in each case is denoted in parentheses. (B) A posture-based analysis of responses of L4int and L4leth daf-16 mutants to strong stimuli (15 s, 1 kHz vibrations): the fraction of forward locomotion, backward locomotion, dwelling, and quiescence before, during, and after the stimulus. (C) Left: frame subtraction based analyses of responses of L4leth daf-16 mutants to weak stimuli (15 s, 20 mW/cm2, blue light). Inset: the response of daf-16 mutants during L4leth on a semi-log scale. Middle: the fraction of quiescence during 1 min intervals centered at the times of the peak and trough of the L4leth responses, as well as for their respective pre-stimulus baselines. All stimuli were initiated at t = 0. N = 50–60 animals. Plots and bars depict mean ± s.e.m, asterisks denote p < 0.001. Right: a posture-based analysis of bout dynamics of daf-16 mutants following a weak stimulus. Plots depict mean ± s.e.m, smoothed using a 30 s running window average. N = 12 animals. The compensatory enhancement of quiescence bouts shortly after the stimulus, as assayed by both methods, was similar to wild-type. (D) The mean baseline fractions of quiescence of daf-16 mutants in undisturbed animals and in the presence of weak and strong stimuli. In contrast to wild-type, baseline quiescence fraction was indistinguishable between the different conditions. Expression of daf-16 in neurons, but not in body-wall muscles, restored the homeostatic response of daf-16 mutants to strong mechanical stimuli. Error bar depicts ±s.e.m. The number of stimuli assayed is noted in parentheses for each condition.DOI:http://dx.doi.org/10.7554/eLife.04380.018

Mentions: Prolonged and stressful deprivation of quiescence during lethargus causes the translocation of DAF-16, a FOXO transcription factor that activates stress responses, into the nucleus. Moreover, daf-16 mutants were shown to be defective in their behavioral response to prolonged deprivation (Lin et al., 1997; Henderson and Johnson, 2001; Driver et al., 2013). Although micro-homeostasis responses occur on a timescale that is too short to be regulated by changes in transcription, repeated weak stimuli may still be stressful. To test the roles of DAF-16 in regulating homeostasis during lethargus, we assayed daf-16(mu86) (Libina et al., 2003) mutants under no-, weak-, and strong-stimulus conditions. These mutants were similar to wild-type in their total fraction of quiescence, their initial responses to weak stimuli and subsequent compensation, their responses outside of lethargus to weak and to strong stimuli, and their initial responses during lethargus to strong stimuli. When not disturbed, the quiescence bouts of daf-16 mutants were shorter than wild-type (data not shown) and their pairwise correlations between subsequent bouts were smaller, but not abolished (Figure 8A–C). A second mutant allele, daf-16(mgDf50) (Ogg et al., 1997), exhibited similar behavior under unstimulated conditions (data not shown). Thus, micro-homeostasis during C. elegans lethargus was mostly independent of DAF-16/FOXO signaling.10.7554/eLife.04380.018Figure 8.Homeostatic responses to strong stimuli, but not micro-homeostasis, require DAF-16.


Homeostasis in C. elegans sleep is characterized by two behaviorally and genetically distinct mechanisms.

Nagy S, Tramm N, Sanders J, Iwanir S, Shirley IA, Levine E, Biron D - Elife (2014)

Homeostatic responses to strong stimuli, but not micro-homeostasis, require DAF-16.(A) Left: the fraction of quiescence of wild-type animals and daf-16 mutants during L4leth (shaded area). Plots depict mean ± s.e.m, the numbers of animals assayed are denoted in parentheses. Right: pairwise bout correlations shown with a plot of binned bouts (see Figure 2A for details). Pairwise correlations were reduced in the mutant, although less so than in npr-1 mutants (p < 0.05). All correlations are given with 95% confidence intervals and error bars depict ±s.e.m. The number of bouts in each case is denoted in parentheses. (B) A posture-based analysis of responses of L4int and L4leth daf-16 mutants to strong stimuli (15 s, 1 kHz vibrations): the fraction of forward locomotion, backward locomotion, dwelling, and quiescence before, during, and after the stimulus. (C) Left: frame subtraction based analyses of responses of L4leth daf-16 mutants to weak stimuli (15 s, 20 mW/cm2, blue light). Inset: the response of daf-16 mutants during L4leth on a semi-log scale. Middle: the fraction of quiescence during 1 min intervals centered at the times of the peak and trough of the L4leth responses, as well as for their respective pre-stimulus baselines. All stimuli were initiated at t = 0. N = 50–60 animals. Plots and bars depict mean ± s.e.m, asterisks denote p < 0.001. Right: a posture-based analysis of bout dynamics of daf-16 mutants following a weak stimulus. Plots depict mean ± s.e.m, smoothed using a 30 s running window average. N = 12 animals. The compensatory enhancement of quiescence bouts shortly after the stimulus, as assayed by both methods, was similar to wild-type. (D) The mean baseline fractions of quiescence of daf-16 mutants in undisturbed animals and in the presence of weak and strong stimuli. In contrast to wild-type, baseline quiescence fraction was indistinguishable between the different conditions. Expression of daf-16 in neurons, but not in body-wall muscles, restored the homeostatic response of daf-16 mutants to strong mechanical stimuli. Error bar depicts ±s.e.m. The number of stimuli assayed is noted in parentheses for each condition.DOI:http://dx.doi.org/10.7554/eLife.04380.018
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fig8: Homeostatic responses to strong stimuli, but not micro-homeostasis, require DAF-16.(A) Left: the fraction of quiescence of wild-type animals and daf-16 mutants during L4leth (shaded area). Plots depict mean ± s.e.m, the numbers of animals assayed are denoted in parentheses. Right: pairwise bout correlations shown with a plot of binned bouts (see Figure 2A for details). Pairwise correlations were reduced in the mutant, although less so than in npr-1 mutants (p < 0.05). All correlations are given with 95% confidence intervals and error bars depict ±s.e.m. The number of bouts in each case is denoted in parentheses. (B) A posture-based analysis of responses of L4int and L4leth daf-16 mutants to strong stimuli (15 s, 1 kHz vibrations): the fraction of forward locomotion, backward locomotion, dwelling, and quiescence before, during, and after the stimulus. (C) Left: frame subtraction based analyses of responses of L4leth daf-16 mutants to weak stimuli (15 s, 20 mW/cm2, blue light). Inset: the response of daf-16 mutants during L4leth on a semi-log scale. Middle: the fraction of quiescence during 1 min intervals centered at the times of the peak and trough of the L4leth responses, as well as for their respective pre-stimulus baselines. All stimuli were initiated at t = 0. N = 50–60 animals. Plots and bars depict mean ± s.e.m, asterisks denote p < 0.001. Right: a posture-based analysis of bout dynamics of daf-16 mutants following a weak stimulus. Plots depict mean ± s.e.m, smoothed using a 30 s running window average. N = 12 animals. The compensatory enhancement of quiescence bouts shortly after the stimulus, as assayed by both methods, was similar to wild-type. (D) The mean baseline fractions of quiescence of daf-16 mutants in undisturbed animals and in the presence of weak and strong stimuli. In contrast to wild-type, baseline quiescence fraction was indistinguishable between the different conditions. Expression of daf-16 in neurons, but not in body-wall muscles, restored the homeostatic response of daf-16 mutants to strong mechanical stimuli. Error bar depicts ±s.e.m. The number of stimuli assayed is noted in parentheses for each condition.DOI:http://dx.doi.org/10.7554/eLife.04380.018
Mentions: Prolonged and stressful deprivation of quiescence during lethargus causes the translocation of DAF-16, a FOXO transcription factor that activates stress responses, into the nucleus. Moreover, daf-16 mutants were shown to be defective in their behavioral response to prolonged deprivation (Lin et al., 1997; Henderson and Johnson, 2001; Driver et al., 2013). Although micro-homeostasis responses occur on a timescale that is too short to be regulated by changes in transcription, repeated weak stimuli may still be stressful. To test the roles of DAF-16 in regulating homeostasis during lethargus, we assayed daf-16(mu86) (Libina et al., 2003) mutants under no-, weak-, and strong-stimulus conditions. These mutants were similar to wild-type in their total fraction of quiescence, their initial responses to weak stimuli and subsequent compensation, their responses outside of lethargus to weak and to strong stimuli, and their initial responses during lethargus to strong stimuli. When not disturbed, the quiescence bouts of daf-16 mutants were shorter than wild-type (data not shown) and their pairwise correlations between subsequent bouts were smaller, but not abolished (Figure 8A–C). A second mutant allele, daf-16(mgDf50) (Ogg et al., 1997), exhibited similar behavior under unstimulated conditions (data not shown). Thus, micro-homeostasis during C. elegans lethargus was mostly independent of DAF-16/FOXO signaling.10.7554/eLife.04380.018Figure 8.Homeostatic responses to strong stimuli, but not micro-homeostasis, require DAF-16.

Bottom Line: This response to strong stimuli required the function of the DAF-16/FOXO transcription factor in neurons, but not that of NPR-1.Conversely, response to weak stimuli did not require the function of DAF-16/FOXO.These findings suggest that routine homeostatic stabilization of sleep may be distinct from homeostatic compensation following a strong disturbance.

View Article: PubMed Central - PubMed

Affiliation: Institute for Biophysical Dynamics, University of Chicago, Chicago, United States.

ABSTRACT
Biological homeostasis invokes modulatory responses aimed at stabilizing internal conditions. Using tunable photo- and mechano-stimulation, we identified two distinct categories of homeostatic responses during the sleep-like state of Caenorhabditis elegans (lethargus). In the presence of weak or no stimuli, extended motion caused a subsequent extension of quiescence. The neuropeptide Y receptor homolog, NPR-1, and an inhibitory neuropeptide known to activate it, FLP-18, were required for this process. In the presence of strong stimuli, the correlations between motion and quiescence were disrupted for several minutes but homeostasis manifested as an overall elevation of the time spent in quiescence. This response to strong stimuli required the function of the DAF-16/FOXO transcription factor in neurons, but not that of NPR-1. Conversely, response to weak stimuli did not require the function of DAF-16/FOXO. These findings suggest that routine homeostatic stabilization of sleep may be distinct from homeostatic compensation following a strong disturbance.

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