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Genetic deletion of MT1 melatonin receptors alters spontaneous behavioral rhythms in male and female C57BL/6 mice.

ABSTRACT: Behaviors vary over the 24h light/dark cycle and these temporal patterns reflect in part modulation by circadian neural circuits and hormones, such as melatonin. The goal of this study was to investigate the involvement of MT1 melatonin receptors in behavioral regulation by comparing male and female C57 wild type (WT) mice with C57 mice with genetic deletion of the MT1 receptor (MT1KO). A comprehensive array of fifteen distinct spontaneous behaviors was recorded continuously in the homecage over multiple days using the HomeCageScan system. Behaviors assessed were activity-like (i.e. come down, hang, jump, walk), exploration-like (i.e. dig, groom, rear up, sniff, stretch), resting-like (i.e. awake, remain low, rest, twitch) and ingestion-like (i.e. drink, eat). Phenotypic array and temporal distribution analysis revealed distinct behavioral rhythms that differed between WT and MT1KO mice. The rhythms were consistent from day to day in males and varied with the estrous cycle in females. We also studied the role of MT1 receptors on depressive and anxiety-like behaviors. Genetic deletion of MT1 receptors increased immobility time in the forced swim test and decreased the number of marbles buried in the marble burying test in both male and female C57 mice. We conclude that MT1 melatonin receptors are involved in neural pathways modulating diurnal rhythms of spontaneous behavior in the homecage as well as pathways regulating depressive and anxiolytic-like behaviors.

SUBMITTER: Adamah-Biassi EB

PROVIDER: S-EPMC4698802 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Project description:BackgroundAluminum (Al) is considered to be a neurotoxic metal, and excessive exposure to Al has been reported to be a potential risk factor for neurodegenerative diseases. Al ammonium sulfate is one of the Al compounds that is widely used as a food additive. However, the effects of the oral administration of Al ammonium sulfate on physical development and behavior remain to be examined.MethodsIn this study, we investigated the effects of the administration of Al ammonium sulfate 12-water dissolved in drinking water (0.075 mg/mL) beginning in adolescence on various types of behavior in adult female C57BL/6J mice through a battery of behavioral tests (low-dose experiment; Experiment 1). We further examined the behavioral effects of the oral administration of a higher dose of the Al compound in drinking water (1 mg/mL) beginning in the prenatal period on behavior in adult male and female mice (high-dose experiment; Experiment 2).ResultsIn the low-dose experiment, in which females' oral intake of Al was estimated to be 0.97 mg Al/kg/d as adults, Al-treated females exhibited an increase in total arm entries in the elevated plus maze test, an initial decrease and subsequent increase in immobility in the forced swim test, and reduced freezing in the fear conditioning test approximately 1 month after the conditioning session compared with vehicle-treated females (uncorrected P < .05). However, the behavioral differences did not reach a statistically significant level after correction for multiple testing. In the high-dose experiment, in which animals' oral intakes were estimated to be about ten times higher than those in the low-dose experiment, behavioral differences found in the low-dose experiment were not observed in high-dose Al-treated mice, suggesting that the results of the low-dose experiment might be false positives. Additionally, although high-dose Al-treated females exhibited increased social contacts with unfamiliar conspecifics and impaired reference memory performance, and high-dose Al-treated mice exhibited decreases in prepulse inhibition and in correct responses in the working memory task (uncorrected P < .05), the differences in any of the behavioral measures did not reach the significance level after correction for multiple testing.ConclusionOur results show that long-term oral exposure to Al ammonium sulfate at the doses used in this study may have the potential to induce some behavioral changes in C57BL/6J mice. However, the behavioral effects of Al were small and statistically weak, as indicated by the fact that the results failed to reach the study-wide significance level. Thus, further study will be needed to replicate the results and reevaluate the behavioral outcomes of oral intake of Al ammonium sulfate.

Project description:Study objectiveWe have previously established that CAST/EiJ (CAST) mice differ from normal mice, such as C57BL/6J (B6), in the timing of wheel-running onset relative to light/dark cycles. These mice provide an animal model for studies of the genetic and neurobiological basis for circadian phase misalignment in humans. Neither differences in endogenous circadian period nor the shape of the photic phase response curve explain the difference in the timing of activity onset between CAST and B6 mice, suggesting a mechanism downstream of the circadian clock. Here, we further test the hypothesis that the two strains differ with respect to circadian oscillations at the molecular level.DesignSleep/wake cycles were examined and rhythms of Period1 (Per1) and Period2 (Per2) expression were measured in the cerebral cortex, suprachiasmatic nucleus (SCN), and other hypothalamic regions.SettingBasic sleep and molecular research laboratory.Patients or participantsMale mice of the B6 and CAST inbred strains.InterventionsNone.Measurements and resultsSleep/wake cycles were advanced by approximately 4 h in CAST mice relative to B6 mice. This was paralleled by phase-advanced rhythms of Per1 and Per2 expression, as measured byin situ hybridization, in the cerebral cortex of CAST relative to B6. By contrast, the timing of circadian oscillations and the photic induction ofPer1 and Per2 expression in the SCN were unaffected by strain.ConclusionThe advanced phase of wheel running and sleep/wake cycles in CAST mice relative to B6 mice is apparently not associated with differences in molecular oscillations in the SCN clock itself, but most likely in mechanisms downstream of the SCN clock. CAST mice may therefore provide a model system to investigate circadian downstream mechanisms underlying unusual patterns of entrainment to the ambient photoperiod.CitationJiang P; Franklin KM; Duncan MJ; O'Hara BF; Wisor JP. Distinct phase relationships between suprachiasmatic molecular rhythms, cerebral cortex molecular rhythms, and behavioral rhythms in early runner (CAST/EiJ) and nocturnal (C57BL/6J) mice. SLEEP 2012;35(10):1385-1394.

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Genetic deletion of MT1 melatonin receptors alters spontaneous behavioral rhythms in male and female C57BL/6 mice.

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