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Histamine Transmission Modulates the Phenotype of Murine Narcolepsy Caused by Orexin Neuron Deficiency.

Bastianini S, Silvani A, Berteotti C, Lo Martire V, Cohen G, Ohtsu H, Lin JS, Zoccoli G - PLoS ONE (2015)

Bottom Line: Thus, these narcolepsy signs are neither caused nor abrogated by the absence of histamine.Conversely, the lack of histamine produced obesity in HDC-KO and to a greater extent also in DM.Defects of histamine transmission may thus modulate the metabolic and respiratory phenotype of murine narcolepsy.

View Article: PubMed Central - PubMed

Affiliation: PRISM Laboratory, Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy.

ABSTRACT
Narcolepsy type 1 is associated with loss of orexin neurons, sleep-wake derangements, cataplexy, and a wide spectrum of alterations in other physiological functions, including energy balance, cardiovascular, and respiratory control. It is unclear which narcolepsy signs are directly related to the lack of orexin neurons or are instead modulated by dysfunction of other neurotransmitter systems physiologically controlled by orexin neurons, such as the histamine system. To address this question, we tested whether some of narcolepsy signs would be detected in mice lacking histamine signaling (HDC-KO). Moreover, we studied double-mutant mice lacking both histamine signaling and orexin neurons (DM) to evaluate whether the absence of histamine signaling would modulate narcolepsy symptoms produced by orexin deficiency. Mice were instrumented with electrodes for recording the electroencephalogram and electromyogram and a telemetric arterial pressure transducer. Sleep attacks fragmenting wakefulness, cataplexy, excess rapid-eye-movement sleep (R) during the activity period, and enhanced increase of arterial pressure during R, which are hallmarks of narcolepsy in mice, did not occur in HDC-KO, whereas they were observed in DM mice. Thus, these narcolepsy signs are neither caused nor abrogated by the absence of histamine. Conversely, the lack of histamine produced obesity in HDC-KO and to a greater extent also in DM. Moreover, the regularity of breath duration during R was significantly increased in either HDC-KO or DM relative to that in congenic wild-type mice. Defects of histamine transmission may thus modulate the metabolic and respiratory phenotype of murine narcolepsy.

No MeSH data available.


Related in: MedlinePlus

Sleep-related changes in breathing.(A) and (B), values of minute volume (VE) and breath duration (TTOT), respectively, during non-rapid-eye-movement sleep (N) and rapid-eye-movement sleep (R). In this and the other panels, data are means ± SEM in HDC-KO (n = 11 during N, n = 10 during R), DM (n = 7), and WT (n = 11). (C) Representative tracing (plethysmographic ventilator signal, VENT; electroencephalogram, EEG; electromyogram, EMG) during a transition from N to R in a DM mouse. The decrease in TTOT during R is evident from the occurrence of more closely spaced deflections of the VENT signal with individual breaths. The grey vertical bar shows the transition point between states. (D) Short-term (SD1) and long-term (SD2) variability of TTOT. (E) Representative Poincaré plot during N in a DM mouse, in which abscissa and ordinate of each point indicate TTOT of successive breaths. SD1 and SD2 correspond to the standard deviations around axes (black segments) oriented with or orthogonal to the line of identity of the Poincaré plot, respectively. SD1 and SD2 are computed excluding extreme values of TTOT (black points). The red lines mark the threshold for apnea detection (i.e., three times the average TTOT value). (F) and (G), representative tracings during N in a DM mouse showing augmented breaths (sighs) either isolated (F) or followed by breathing pauses (apneas; G, arrows). (H) and (I), frequency of occurrence of sighs and apneas during N and R, respectively. *, †, and ‡, P < 0.05, WT vs. DM, WT vs. HDC-KO, and HDC-KO vs. DM, respectively (t-tests). In panel H, the symbol (†) indicates a statistical tendency for the difference between HDC-KO and WT (P = 0.051, ANOVA; HDC-KO vs. WT, P = 0.017, t-test).
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pone.0140520.g005: Sleep-related changes in breathing.(A) and (B), values of minute volume (VE) and breath duration (TTOT), respectively, during non-rapid-eye-movement sleep (N) and rapid-eye-movement sleep (R). In this and the other panels, data are means ± SEM in HDC-KO (n = 11 during N, n = 10 during R), DM (n = 7), and WT (n = 11). (C) Representative tracing (plethysmographic ventilator signal, VENT; electroencephalogram, EEG; electromyogram, EMG) during a transition from N to R in a DM mouse. The decrease in TTOT during R is evident from the occurrence of more closely spaced deflections of the VENT signal with individual breaths. The grey vertical bar shows the transition point between states. (D) Short-term (SD1) and long-term (SD2) variability of TTOT. (E) Representative Poincaré plot during N in a DM mouse, in which abscissa and ordinate of each point indicate TTOT of successive breaths. SD1 and SD2 correspond to the standard deviations around axes (black segments) oriented with or orthogonal to the line of identity of the Poincaré plot, respectively. SD1 and SD2 are computed excluding extreme values of TTOT (black points). The red lines mark the threshold for apnea detection (i.e., three times the average TTOT value). (F) and (G), representative tracings during N in a DM mouse showing augmented breaths (sighs) either isolated (F) or followed by breathing pauses (apneas; G, arrows). (H) and (I), frequency of occurrence of sighs and apneas during N and R, respectively. *, †, and ‡, P < 0.05, WT vs. DM, WT vs. HDC-KO, and HDC-KO vs. DM, respectively (t-tests). In panel H, the symbol (†) indicates a statistical tendency for the difference between HDC-KO and WT (P = 0.051, ANOVA; HDC-KO vs. WT, P = 0.017, t-test).

Mentions: Neither mean minute volume nor mean breath duration during sleep differed significantly between HDC-KO and WT. Conversely, DM had significantly greater minute volume during R than WT. There was a statistical tendency (P = 0.054) for this difference to be significant also between DM and HDC-KO (Fig 5A). This occurred because of a significant reduction in breath duration during R in DM compared with either HDC-KO or WT (Fig 5B and 5C), whereas tidal volume did not differ (S3 Fig). HDC-KO had significantly lower short-term and long-term variability of breath duration during R and significantly lower long-term variability of breath duration during N than WT. Similar differences occurred during R in DM compared with WT (Fig 5D and 5E). Augmented breaths (sighs) during N were significantly more frequent in DM than either in HDC-KO or WT, whereas their occurrence rate did not differ significantly between HDC-KO and WT. The apnea index in N tended to be lower in HDC-KO than in WT (P = 0.051, ANOVA; HDC-KO vs. WT, P = 0.017, t-test), whereas it did not differ significantly between DM and WT. HDC-KO, DM, and WT did not differ significantly in terms of sighs and apneas in R (Fig 5H and 5I).


Histamine Transmission Modulates the Phenotype of Murine Narcolepsy Caused by Orexin Neuron Deficiency.

Bastianini S, Silvani A, Berteotti C, Lo Martire V, Cohen G, Ohtsu H, Lin JS, Zoccoli G - PLoS ONE (2015)

Sleep-related changes in breathing.(A) and (B), values of minute volume (VE) and breath duration (TTOT), respectively, during non-rapid-eye-movement sleep (N) and rapid-eye-movement sleep (R). In this and the other panels, data are means ± SEM in HDC-KO (n = 11 during N, n = 10 during R), DM (n = 7), and WT (n = 11). (C) Representative tracing (plethysmographic ventilator signal, VENT; electroencephalogram, EEG; electromyogram, EMG) during a transition from N to R in a DM mouse. The decrease in TTOT during R is evident from the occurrence of more closely spaced deflections of the VENT signal with individual breaths. The grey vertical bar shows the transition point between states. (D) Short-term (SD1) and long-term (SD2) variability of TTOT. (E) Representative Poincaré plot during N in a DM mouse, in which abscissa and ordinate of each point indicate TTOT of successive breaths. SD1 and SD2 correspond to the standard deviations around axes (black segments) oriented with or orthogonal to the line of identity of the Poincaré plot, respectively. SD1 and SD2 are computed excluding extreme values of TTOT (black points). The red lines mark the threshold for apnea detection (i.e., three times the average TTOT value). (F) and (G), representative tracings during N in a DM mouse showing augmented breaths (sighs) either isolated (F) or followed by breathing pauses (apneas; G, arrows). (H) and (I), frequency of occurrence of sighs and apneas during N and R, respectively. *, †, and ‡, P < 0.05, WT vs. DM, WT vs. HDC-KO, and HDC-KO vs. DM, respectively (t-tests). In panel H, the symbol (†) indicates a statistical tendency for the difference between HDC-KO and WT (P = 0.051, ANOVA; HDC-KO vs. WT, P = 0.017, t-test).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4608736&req=5

pone.0140520.g005: Sleep-related changes in breathing.(A) and (B), values of minute volume (VE) and breath duration (TTOT), respectively, during non-rapid-eye-movement sleep (N) and rapid-eye-movement sleep (R). In this and the other panels, data are means ± SEM in HDC-KO (n = 11 during N, n = 10 during R), DM (n = 7), and WT (n = 11). (C) Representative tracing (plethysmographic ventilator signal, VENT; electroencephalogram, EEG; electromyogram, EMG) during a transition from N to R in a DM mouse. The decrease in TTOT during R is evident from the occurrence of more closely spaced deflections of the VENT signal with individual breaths. The grey vertical bar shows the transition point between states. (D) Short-term (SD1) and long-term (SD2) variability of TTOT. (E) Representative Poincaré plot during N in a DM mouse, in which abscissa and ordinate of each point indicate TTOT of successive breaths. SD1 and SD2 correspond to the standard deviations around axes (black segments) oriented with or orthogonal to the line of identity of the Poincaré plot, respectively. SD1 and SD2 are computed excluding extreme values of TTOT (black points). The red lines mark the threshold for apnea detection (i.e., three times the average TTOT value). (F) and (G), representative tracings during N in a DM mouse showing augmented breaths (sighs) either isolated (F) or followed by breathing pauses (apneas; G, arrows). (H) and (I), frequency of occurrence of sighs and apneas during N and R, respectively. *, †, and ‡, P < 0.05, WT vs. DM, WT vs. HDC-KO, and HDC-KO vs. DM, respectively (t-tests). In panel H, the symbol (†) indicates a statistical tendency for the difference between HDC-KO and WT (P = 0.051, ANOVA; HDC-KO vs. WT, P = 0.017, t-test).
Mentions: Neither mean minute volume nor mean breath duration during sleep differed significantly between HDC-KO and WT. Conversely, DM had significantly greater minute volume during R than WT. There was a statistical tendency (P = 0.054) for this difference to be significant also between DM and HDC-KO (Fig 5A). This occurred because of a significant reduction in breath duration during R in DM compared with either HDC-KO or WT (Fig 5B and 5C), whereas tidal volume did not differ (S3 Fig). HDC-KO had significantly lower short-term and long-term variability of breath duration during R and significantly lower long-term variability of breath duration during N than WT. Similar differences occurred during R in DM compared with WT (Fig 5D and 5E). Augmented breaths (sighs) during N were significantly more frequent in DM than either in HDC-KO or WT, whereas their occurrence rate did not differ significantly between HDC-KO and WT. The apnea index in N tended to be lower in HDC-KO than in WT (P = 0.051, ANOVA; HDC-KO vs. WT, P = 0.017, t-test), whereas it did not differ significantly between DM and WT. HDC-KO, DM, and WT did not differ significantly in terms of sighs and apneas in R (Fig 5H and 5I).

Bottom Line: Thus, these narcolepsy signs are neither caused nor abrogated by the absence of histamine.Conversely, the lack of histamine produced obesity in HDC-KO and to a greater extent also in DM.Defects of histamine transmission may thus modulate the metabolic and respiratory phenotype of murine narcolepsy.

View Article: PubMed Central - PubMed

Affiliation: PRISM Laboratory, Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy.

ABSTRACT
Narcolepsy type 1 is associated with loss of orexin neurons, sleep-wake derangements, cataplexy, and a wide spectrum of alterations in other physiological functions, including energy balance, cardiovascular, and respiratory control. It is unclear which narcolepsy signs are directly related to the lack of orexin neurons or are instead modulated by dysfunction of other neurotransmitter systems physiologically controlled by orexin neurons, such as the histamine system. To address this question, we tested whether some of narcolepsy signs would be detected in mice lacking histamine signaling (HDC-KO). Moreover, we studied double-mutant mice lacking both histamine signaling and orexin neurons (DM) to evaluate whether the absence of histamine signaling would modulate narcolepsy symptoms produced by orexin deficiency. Mice were instrumented with electrodes for recording the electroencephalogram and electromyogram and a telemetric arterial pressure transducer. Sleep attacks fragmenting wakefulness, cataplexy, excess rapid-eye-movement sleep (R) during the activity period, and enhanced increase of arterial pressure during R, which are hallmarks of narcolepsy in mice, did not occur in HDC-KO, whereas they were observed in DM mice. Thus, these narcolepsy signs are neither caused nor abrogated by the absence of histamine. Conversely, the lack of histamine produced obesity in HDC-KO and to a greater extent also in DM. Moreover, the regularity of breath duration during R was significantly increased in either HDC-KO or DM relative to that in congenic wild-type mice. Defects of histamine transmission may thus modulate the metabolic and respiratory phenotype of murine narcolepsy.

No MeSH data available.


Related in: MedlinePlus