Dissecting and modeling photic and melanopsin effects to predict sleep disturbances induced by irregular light exposure in mice.

Artificial lighting, day-length changes, shift work, and transmeridian travel all lead to sleep-wake disturbances. The nychthemeral sleep-wake cycle (SWc) is known to be controlled by output from the central circadian clock in the suprachiasmatic nuclei (SCN), which is entrained to the light-dark cycle. Additionally, via intrinsically photosensitive retinal ganglion cells containing the photopigment melanopsin (Opn4), short-term light-dark alternations exert direct and acute influences on sleep and waking. However, the extent to which longer exposures typically experienced across the 24-h day exert such an effect has never been clarified or quantified, as disentangling sustained direct light effects (SDLE) from circadian effects is difficult. Recording sleep in mice lacking a circadian pacemaker, either through transgenesis (Syt10cre/creBmal1fl/- ) or SCN lesioning and/or melanopsin-based phototransduction (Opn4-/- ), we uncovered, contrary to prevailing assumptions, that the contribution of SDLE is as important as circadian-driven input in determining SWc amplitude. Specifically, SDLE were primarily mediated (>80%) through melanopsin, of which half were then relayed through the SCN, revealing an ancillary purpose for this structure, independent of its clock function in organizing SWc. Based on these findings, we designed a model to estimate the effect of atypical light-dark cycles on SWc. This model predicted SWc amplitude in mice exposed to simulated transequatorial or transmeridian paradigms. Taken together, we demonstrate this SDLE is a crucial mechanism influencing behavior on par with the circadian system. In a broader context, these findings mandate considering SDLE, in addition to circadian drive, for coping with health consequences of atypical light exposure in our society.

Pupillometry to differentiate idiopathic hypersomnia from narcolepsy type 1.

Idiopathic hypersomnia is poorly diagnosed in the absence of biomarkers to distinguish it from other central hypersomnia subtypes. Given that light plays a main role in the regulation of sleep and wake, we explored the retinal melanopsin-based pupil response in patients with idiopathic hypersomnia and narcolepsy type 1, and healthy subjects. Twenty-seven patients with narcolepsy type 1 (women 59%, 36 ± 11.5 years old), 36 patients with idiopathic hypersomnia (women 83%, 27.2 ± 7.2 years old) with long total sleep time (> 11/24 hr), and 43 controls (women 58%, 30.6 ± 9.3 years old) were included in this study. All underwent a pupillometry protocol to assess pupil diameter, and the relative post-illumination pupil response to assess melanopsin-driven pupil responses in the light non-visual input pathway. Differences between groups were assessed using logistic regressions adjusted on age and sex. We found that patients with narcolepsy type 1 had a smaller baseline pupil diameter as compared with idiopathic hypersomnia and controls (p < 0.05). In addition, both narcolepsy type 1 and idiopathic hypersomnia groups had a smaller relative post-illumination pupil response (respectively, 31.6 ± 13.9% and 33.2 ± 9.9%) as compared with controls (38.7 ± 9.7%), suggesting a reduced melanopsin-mediated pupil response in both types of central hypersomnia (p < 0.01). Both narcolepsy type 1 and idiopathic hypersomnia showed a smaller melanopsin-mediated pupil response, and narcolepsy type 1, unlike idiopathic hypersomnia, also displayed a smaller basal pupil diameter. Importantly, we found that the basal pupil size permitted to well discriminate idiopathic hypersomnia from narcolepsy type 1 with a specificity = 66.67% and a sensitivity = 72.22%. Pupillometry may aid to multi-feature differentiation of central hypersomnia subtypes.

Sleep Deprivation and Caffeine Treatment Potentiate Photic Resetting of the Master Circadian Clock in a Diurnal Rodent.

Circadian rhythms in nocturnal and diurnal mammals are primarily synchronized to local time by the light/dark cycle. However, nonphotic factors, such as behavioral arousal and metabolic cues, can also phase shift the master clock in the suprachiasmatic nuclei (SCNs) and/or reduce the synchronizing effects of light in nocturnal rodents. In diurnal rodents, the role of arousal or insufficient sleep in these functions is still poorly understood. In the present study, diurnal Sudanian grass rats, Arvicanthis ansorgei, were aroused at night by sleep deprivation (gentle handling) or caffeine treatment that both prevented sleep. Phase shifts of locomotor activity were analyzed in grass rats transferred from a light/dark cycle to constant darkness and aroused in early night or late night. Early night, but not late night, sleep deprivation induced a significant phase shift. Caffeine on its own induced no phase shifts. Both sleep deprivation and caffeine treatment potentiated light-induced phase delays and phase advances in response to a 30 min light pulse, respectively. Sleep deprivation in early night, but not late night, potentiated light-induced c-Fos expression in the ventral SCN. Caffeine treatment in midnight triggered c-Fos expression in dorsal SCN. Both sleep deprivation and caffeine treatment potentiated light-induced c-Fos expression in calbindin-containing cells of the ventral SCN in early and late night. These findings indicate that, in contrast to nocturnal rodents, behavioral arousal induced either by sleep deprivation or caffeine during the sleeping period potentiates light resetting of the master circadian clock in diurnal rodents, and activation of calbindin-containing suprachiasmatic cells may be involved in this effect.SIGNIFICANCE STATEMENT Arousing stimuli have the ability to regulate circadian rhythms in mammals. Behavioral arousal in the sleeping period phase shifts the master clock in the suprachiasmatic nuclei and/or slows down the photic entrainment in nocturnal animals. How these stimuli act in diurnal species remains to be established. Our study in a diurnal rodent, the Grass rat, indicates that sleep deprivation in the early rest period induces phase delays of circadian locomotor activity rhythm. Contrary to nocturnal rodents, both sleep deprivation and caffeine-induced arousal potentiate the photic entrainment in a diurnal rodent. Such enhanced light-induced circadian responses could be relevant for developing chronotherapeutic strategies.

Late enrichment maintains accurate recent and remote spatial memory only in aged rats that were unimpaired when middle aged.

Exposure of rodents to a stimulating environment has beneficial effects on some cognitive functions that are impaired during physiological aging, and especially spatial reference memory. The present study investigated whether environmental enrichment rescues these functions in already declining subjects and/or protects them from subsequent decline. Subgroups of 17-mo-old female rats with unimpaired versus impaired performance in a spatial reference memory task (Morris water maze) were housed until the age of 24 mo in standard or enriched environment. They were then trained in a second reference memory task, conducted in a different room than the first, and recent (1 d) and remote (10 d) memory were assessed. In unimpaired subgroups, spatial memory declined from 17 to 24 mo in rats housed in standard conditions; an enriched environment during this period allowed maintenance of accurate recent and remote spatial memory. At 24 mo, rats impaired at the age of 17 mo housed in enriched environment learned the task and displayed substantial recent memory, but their performance remained lower than that of unimpaired rats, showing that enrichment failed to rescue spatial memory in already cognitively declining rats. Controls indicated carryover effects of the first water maze training, especially in aged rats housed in standard condition, and confirmed the beneficial effect of enrichment on remote memory of aged rats even if they performed poorly than young adults housed for the same duration in standard or enriched condition.

Delaying circadian sleep phase under ultradian light cycle causes time-of-day-dependent alteration of cognition and mood.

Light exerts powerful and pervasive effects on physiology and behaviour. These effects can be indirect, through clock synchronization and phase adjustment of circadian rhythms, or direct, independent of the circadian process. Exposure to light at inappropriate times, as commonly experienced in today's society, leads to increased prevalence of circadian, sleep and mood disorders as well as cognitive impairments. In mice, exposure to an ultradian 3.5 h light/3.5 h dark cycle (T7) for several days has been shown to impair behaviour through direct, non-circadian, photic effects, a claim we challenge here. We first confirmed that T7 cycle induces a lengthening of the circadian period resulting in a day by day phase-delay of both activity and sleep rhythms. Spatial novelty preference test performed at different circadian time points in mice housed under T7 cycle demonstrated that cognitive deficit was restrained to the subjective night. Mice under the same condition also showed a modification of stress-induced despair-like behaviour in the forced swim test. Therefore, our data demonstrate that ultradian light cycles cause time-of-day-dependent alteration of cognition and mood through clock period lengthening delaying circadian sleep phase, and not through a direct photic influence. These results are of critical importance for the clinical applications of light therapy in the medical field and for today's society to establish lighting recommendations for shift work, schools, hospitals and homes.

Direct Effects of Light on Sleep under Ultradian Light-Dark Cycles Depend on Circadian Time and Pulses Duration.

Ultradian light-dark cycles in rodents are a precious tool to study the direct effects of repeated light exposures on sleep, in order to better understand the underlying mechanisms. This study aims to precisely evaluate the effects of light and dark exposures, according to circadian time, on sleep and waking distribution and quality, and to determine if these effects depend on the duration of light and dark pulses. To do this, mice were exposed to 24 h-long ultradian light-dark cycles with different durations of pulses: T2 cycle (1 h of light/1 h of dark) and T7 cycle (3.5 h of light/3.5 h of dark). Exposure to light not only promotes NREM and REM sleep and inhibits wake, but also drastically alters alertness and modifies sleep depth. These effects are modulated by circadian time, appearing especially during early subjective night, and their kinetics is highly dependent on the duration of pulses, suggesting that in the case of pulses of longer duration, the homeostatic process could overtake light direct influence for shaping sleep and waking distribution.

Slow Wave Sleep Deficits in the Flinders Sensitive Line Rodent Model of Depression: Effects of Medial Forebrain Bundle Deep-Brain Stimulation.

Major Depressive Disorder (MDD) is an affective disorder typically accompanied by sleep disturbances. Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) is an emerging intervention for treatment-resistant depression, but its effect on sleep has not been closely examined. Here we aimed to characterise sleep deficits in the Flinders sensitive line, an established rodent model of depression, and investigate the consequences of MFB stimulation on sleep-related phenotypes. Rats were implanted with bilateral stimulation electrodes in the MFB, surface electrodes to record electrocorticography and electromyography for sleep scoring and electrodes within the prelimbic cortex, nucleus accumbens (NAc) and dorsal hippocampus. Recordings of sleep and oscillatory activity were conducted prior to and following twenty-four hours of MFB stimulation. Behavioural anti-depressant effects were monitored using the forced swim test. Previously unreported abnormalities in the Flinders sensitive line rats were observed during slow wave sleep, including decreased circadian amplitude of its rhythm, a reduction in slow wave activity and elevated gamma band oscillations. Previously established rapid eye movement sleep deficits were replicated. MFB stimulation had anti-depressant effects on behavioural phenotype, but did not significantly impact sleep architecture; it suppressed elevated gamma activity during slow wave sleep in the electrocorticogram and prelimbic cortex signals. Diverse abnormalities in Flinders sensitive line rats emphasise slow wave sleep as a state of dysfunction in affective disorders. MFB stimulation is able to affect behaviour and sleep physiology without influencing sleep architecture. Gamma modulation may represent a component of antidepressant mechanism.

The melanopsin-mediated pupil response is reduced in idiopathic hypersomnia with long sleep time.

Idiopathic hypersomnia (IH), characterized by an excessive day-time sleepiness, a prolonged total sleep time on 24 h and/or a reduced sleep latency, affects 1 in 2000 individuals from the general population. However, IH remains underdiagnosed and inaccurately treated despite colossal social, professional and personal impacts. The pathogenesis of IH is poorly known, but recent works have suggested possible alterations of phototransduction. In this context, to identify biomarkers of IH, we studied the Post-Illumination Pupil Response (PIPR) using a specific pupillometry protocol reflecting the melanopsin-mediated pupil response in IH patients with prolonged total sleep time (TST > 660 min) and in healthy subjects. Twenty-eight patients with IH (women 86%, 25.4 year-old ± 4.9) and 29 controls (women 52%, 27.1 year-old ± 3.9) were included. After correction on baseline pupil diameter, the PIPR was compared between groups and correlated to sociodemographic and sleep parameters. We found that patients with IH had a lower relative PIPR compared to controls (32.6 ± 9.9% vs 38.5 ± 10.2%, p = 0.037) suggesting a reduced melanopsin response. In addition, the PIPR was not correlated to age, chronotype, TST, nor depressive symptoms. The melanopsin-specific PIPR may be an innovative trait marker of IH and the pupillometry might be a promising tool to better characterize hypersomnia.

Exposure to an enriched environment up to middle age allows preservation of spatial memory capabilities in old age.

In rats, some cognitive capabilities, like spatial learning and memory, are preserved from age-related decline by whole adult life enriched environment (EE) exposure. However, to which extent late EE contributes to such maintenance remains to be investigated. Here we assessed the impact of late housing condition (e.g., from the age of 18 months) on spatial learning and memory of aged rats (24 months) previously exposed or unexposed to EE from young adulthood. The results showed that late EE was not required for spatial memory maintenance in aged rats previously housed in EE. In contrast, late EE mitigates spatial memory deficit in aged rats previously unexposed to EE. These outcomes suggest that EE exposure up to middle age provides a "reserve"-like advantage which supports an enduring preservation of spatial capabilities in old age.