Abnormal response of melanin-concentrating hormone deficient mice to fasting: hyperactivity and rapid eye movement sleep suppression - PubMed (original) (raw)

Abnormal response of melanin-concentrating hormone deficient mice to fasting: hyperactivity and rapid eye movement sleep suppression

J T Willie et al. Neuroscience. 2008.

Abstract

Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that has been implicated in energy homeostasis. Pharmacological studies with MCH and its receptor antagonists have suggested additional behavioral roles for the neuropeptide in the control of mood and vigilance states. These suggestions have been supported by a report of modified sleep in the MCH-1 receptor knockout mouse. Here we found that MCH knockout (MCH(-)(/)(-)) mice slept less during both the light and dark phases under baseline conditions. In response to fasting, MCH(-)(/)(-) mice exhibited marked hyperactivity, accelerated weight loss and an exaggerated decrease in rapid eye movement (REM) sleep. Following a 6-h period of sleep deprivation, however, the sleep rebound in MCH(-)(/)(-) mice was normal. Thus MCH(-)(/)(-) mice adapt poorly to fasting, and their loss of bodyweight under this condition is associated with behavioral hyperactivity and abnormal expression of REM sleep. These results support a role for MCH in vigilance state regulation in response to changes in energy homeostasis and may relate to a recent report of initial clinical trials with a novel MCH-1 receptor antagonist. When combined with caloric restriction, the treatment of healthy, obese subjects with this compound resulted in some subjects experiencing vivid dreams and sleep disturbances.

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Figures

Figure 1

Figure 1. MCH deficiency promotes wakefulness

(A) Mean wakefulness times for each genotype displayed on an hourly basis (min/h ± SEM) during 24 h of ad libitum feeding. (B) The total times awake over 24 h (min/24 h) under these conditions. _MCH_−/− mice spent more time awake during the dark phase and over 24 h. A significant difference between wild-type and _MCH_−/− mice is indicated by an asterisk.

Figure 2

Figure 2. MCH deficiency induces marked hyperactivity when food is unavailable

(A) Mean hourly distance traveled in the open field (103 cm/h ± SEM) displayed for each genotype during 24 h of ad libitum feeding, followed by 24 h of fasting. Note the pattern of the increase in activity of the _MCH_−/− mice during fasting: hyperactivity occurs during an initial phase at the onset of fasting and this is followed by a second phase towards the end of the subsequent light phase. (B) The mean total distance traveled in the open field (103 cm/24 h ± SEM) during ad libitum feeding and fasting, integrated over 24 h for each genotype. A significant difference between wild-type and _MCH_−/− mice is indicated by an asterisk. For clarity of display, significant differences on the hourly plot during the 24 h of fasting are not shown (all hourly values are significantly different except hours 20:00, 10:00, 11:00, 12:00).

Figure 3

Figure 3. MCH deficiency decreases REM sleep during fasting

Time spent in NREM sleep (A) and REM sleep (B), on an hourly basis (min/h ± SEM) and the total times in these states over 24 h (min/24 h), displayed for each genotype during 24 h of ad libitum feeding, followed by 24 h fasting. Although _MCH_−/− mice respond similarly to wild-type mice during fasting with a reduction NREM sleep, the effect on REM sleep is disproportionately greater in _MCH_−/− mice. See text and table for details. A significant difference between wild-type and _MCH_−/− mice is indicated by an asterisk.

Figure 4

Figure 4. Increase of REM sleep latency in fasting _MCH_−/− mice

The reduction in REM sleep time in _MCH_−/− mice during fasting reflects both an excessive reduction in the number of episodes of REM sleep combined with a failure to increase the mean episode duration. (A) Histograms of the distributions of REM sleep latencies for both genotypes, comparing both ad libitum feeding and fasting conditions. These distributions are different only during fasting, reflecting the shift to long latencies (≥20 min) in _MCH_−/− mice. Under ad libitum feeding, although the overall distributions are not different, a deficit in the occurrence of shorter REM sleep latencies (i.e., ≤ 3 min) is apparent in the _MCH_−/− mice. (B) The mean REM sleep episode duration (min + SEM) displaying the increase in this parameter in wild-type mice during fasting in contrast with the lack of change in the _MCH_−/− mice. A significant difference between wild-type and _MCH_−/− mice is indicated by an asterisk.

Figure 5

Figure 5. Accelerated loss of bodyweight in fasting _MCH_−/− mice

(A) During a 24 h period in the open field with ad libitum access to chow, _MCH_−/− and wild-type mice consumed similar amounts of food (g/24 h/g bodyweight + SEM) (B) During a subsequent 24 h period in the open field without access to food, _MCH_−/− mice lost more weight (cf. Figure 2) (C) _MCH_−/− mice exhibited reduced adiposity as determined NMR body mass analysis under baseline conditions. A significant difference between wild-type and _MCH_−/− mice is indicated by an asterisk.

Figure 6

Figure 6. The sleep homeostat in _MCH_−/− mice is normal

Mice were deprived of sleep by gentle handling for the second 6 h of the light phase, marked by the horizontal bar. (A) The mean hourly times spent awake (min/h ± SEM) in the two genotypes during the subsequent 36 h of recovery sleep time, beginning at the onset of the dark phase (cf. Figure 1). (B) The 12-h NREM and REM sleep times (min/12 h + SEM), during the recovery phase are not different.

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