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Aging is a major risk factor for cognitive deficits, impaired locomotion, and gait disorders. Although oxidative stress and circadian disruption are involved in both normal aging and the pathogenesis of age-associated diseases, just a very few studies explore the consequences of aging on circadian rhythms in the cerebellum. Here, we investigated age-dependent changes in the circadian organization of the molecular clock, antioxidant defenses and synaptic plasticity-related factors, in the rat cerebellum, and discussed the impact of that altered temporal organization on the cognitive function of this brain area. Particularly, we examined the circadian patterns of Brain and muscle ARNT-like 1 (BMAL1) protein levels, Glutathione peroxidase 4 (GPx4) gene expression, GPx and Catalase (CAT) enzymes activity, reduced glutathione (GSH) levels, and the Brain-derived neurotrophic factor (Bdnf) and its Tyrosine kinase receptor B (TrkB) circadian expression. Endogenously-driven circadian rhythms of BMAL1, GPx4, CAT, GSH, and Bdnf/TrkB factors, were observed in the young rat cerebellum. The rhythms' acrophases show a circadian organization that might be crucial for the daily cerebellar-dependent cognitive functions. Notably, aging disrupted circadian rhythms and the temporal organization of BMAL1, antioxidant defenses, and cognitive Bdnf/TrkB gene expression. Increased oxidative stress and disruption of clock-controlled rhythms during aging, might precede and cause the loss of circadian organization in the aged cerebellum. We expect our results highlight circadian rhythms of the studied factors as new targets for the treatment of age-dependent cerebellar disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Light is detected in the eye by three classes of photoreceptors (rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs)) that are each optimized for a specific function and express a particular light-detecting photopigment. The significant role of short-wavelength light and ipRGCs in improving alertness has been well-established; however, few reviews have been undertaken to assess the other wavelengths' effects regarding timing and intensity. This study aims to evaluate the impact of different narrowband light wavelengths on subjective and objective alertness among the 36 studies included in this systematic review, 17 of which were meta-analyzed. Short-wavelength light (∼460-480 nm) significantly improves subjective alertness, cognitive function, and neurological brain activities at night, even for a sustained period (∼6h) (for λmax: 470/475 nm, 0.4 < |Hedges's g| < 0.6, p < 0.05), but except early morning, it almost does not show this effect during the day when melatonin level is lowest. Long-wavelength light (∼600-640 nm) has little effect at night, but significantly increases several measures of alertness at lower irradiance during the daytime (∼1h), particularly when there is homeostatic sleep drive (for λmax: ∼630 nm, 0.5 < |Hedges's g| < 0.8, p < 0.05). The results further suggest that melanopic illuminance may not always be sufficient to measure the alerting effect of light., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)

The localization and function of synaptotagmin (syt)17 in the suprachiasmatic nucleus (SCN) of the brain, which is the master circadian oscillator, were investigated. The Syt17 mRNA-containing neurons were mainly situated in the shell region while SYT17 immunoreactive cell bodies and neural fibers were detected in the core and shell of the SCN and the subparaventricular zone (SPZ). Further, electron microscopy analysis revealed SYT17 in the rough endoplasmic reticulum (rER), Golgi apparatus (G), and large and small vesicles of neurons. Syt17 mRNA expression in the SCN showed a circadian rhythm, and light exposure at night suppressed its expression. In addition, the free running period of locomotor activity rhythm was shortened in Syt17-deletion mutant mice. These findings suggest that SYT17 is involved in the regulation of circadian rhythms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Pronounced environmental changes between the day and night led to evolution of specialised mechanisms organising their daily physiology, named circadian clocks. Currently, it has become clear that the master clock in the suprachiasmatic nuclei of the hypothalamus is not an exclusive brain site to generate daily rhythms. Indeed, several brain areas, including the subcortical visual system have been recently shown to change their neuronal activity across the daily cycle. Here we focus our investigation on the olivary pretectal nucleus (OPN) - a retinorecipient structure primarily involved in the pupillary light reflex. Using the multi-electrode array technology ex vivo we provide evidence for OPN neurons to elevate their firing during the behaviourally quiescent light phase. Additionally, we report the robust responsivity to orexin A via the identified OX 2 receptor in this pretectal centre, with higher responsiveness noted during the night. Interestingly, we likewise report a daily variation in the response to PAC1 receptor activation, with implications for the convergence of orexinergic and visual input on the same OPN neurons. Altogether, our report is first to suggest a daily modulation of the OPN activity via intrinsic and extrinsic mechanisms, organising its temporal physiology., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Alzheimer disease (AD) is the most frequent form of dementia in the elderly. It is characterized by the deterioration of memory and learning. The histopathological hallmarks of AD include the presence of extracellular deposits of amyloid beta peptide, intracellular neurofibrillary tangles, neuron and synapse loss, in the brain, including the hippocampus. Accumulation of Aβ peptide causes an increase in intracellular reactive oxygen species (ROS) and free radicals associated to a deficient antioxidant defense system. Besides oxidative stress and cognitive deficit, AD patients show alterations in their circadian rhythms. The objective of this work was to investigate the effects of an intracerebroventricular injection of amyloid beta peptide Aβ(1-42) aggregates on temporal patterns of protein oxidation, antioxidant enzymes and clock factors in the rat hippocampus. Four-month-old male Holtzman rats divided into the groups control (CO) and Aβ-injected (Aβ), were maintained under 12 h-light12h-dark conditions and received water and food ad-libitum. Hippocampus samples were isolated every 6 h during a 24 h period. Our results showed daily patterns of protein carbonyls, catalase (CAT) and glutathione peroxidase (GPx) expression and activity, as well as Rorα and Rev-erbß mRNA, in the rat hippocampus. Interestingly, an intracerebroventricular injection of Aβ aggregates modified daily oscillation of protein carbonyls levels, phase-shifted daily rhythms of clock genes and had a differential effect on the daily expression and activity of CAT and GPx. Thus, Aβ aggregates might affect clock-mediated transcriptional regulation of antioxidant enzymes, by affecting the formation of BMAL1:CLOCK heterodimer, probably, as a consequence of the alteration of the redox state observed in rats injected with Aβ., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Sleep is involved in metabolic system, mental health and cognitive functions. Evidence shows that sleep deprivation (SD) negatively affects mental health and impairs cognitive functions, including learning and memory. Furthermore, the metabotropic glutamate receptor subtype 5 (mGluR5) is a metabolic biomarker, which is affected by various conditions, including stress, sleep deprivation, and cognitive and psychiatric disorders. In this research, we investigated the effect of SD and reverse circadian (RC), and two models of napping (continuous and non-continuous) combined with SD or RC on fear-conditioning memory, anxiety-like behavior and mGluR5 fluctuations in the amygdala. 64 male Wistar rats were used in this study. The water box apparatus was used to induce SD/RC for 48 h, and fear-conditioning memory apparatus was used to assess fear memory. The results showed, fear-conditioning memory was impaired following SD and RC, especially in contextual stage. However, anxiety-like behavior was increased. Furthermore, mGluR5 was increased in the left amygdala more than the right amygdala. Additionally, continuous napping significantly improved fear-conditioning memory, especially freezing behavior. In conclusion, following SD and RC, fear-conditioning memory in contextual stage is more vulnerable than in auditory stage. Furthermore, increase in anxiety-like behavior is related to increase in the activity of left amygdala and mGluR5 receptors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The suprachiasmatic nucleus (SCN) is the center of the mammalian circadian system. Environmental photic signals shifts the phase of the circadian rhythm in the SCN except during the dead zone, when the photic signal is gated somewhere on the way from the retina to the neurons in the SCN. Here we examined the phase of the dead zone after an abrupt delay of the LD cycles for several days by observing the mc-Fos induction in the SCN by light pulses. After an abrupt shift of the LD cycles, the dead zone showed a slow phase shift, about two hours per day, which was well corresponded with the slow phase shift of the rest-activity cycles. In our previous study we demonstrated that, after an abrupt shift of the LD cycles, the SCN showed transient endogenous desynchronization between shell and core regions that showed a slow and a rapid shift of the circadian rhythms, respectively. Therefore, the present findings on the phase shift of the dead zone after the LD cycles shift suggest that the phase of the dead zone is under the control of the timing signals from the shell region of the SCN., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Dopamine is primarily produced in the substantia nigra (SN) and the ventral tegmentum area (VTA) in the brain. It plays a well-established role in the motor control, reward, mood regulation and addiction behaviour. Dopamine release has been shown to be regulated by the circadian clock and hence, plays a regulatory role in the sleep-wake cycle. Clinically, dopaminergic agents have been widely used to modulate alertness. The following review offers a demonstration of the heterogeneous dopamine system in the brain and the various studies investigating the circadian rhythmicity of the dopamine system and its regulation of sleep-wake behaviour. Additionally, it suggests a potential link between the circadian clock and the sleep-wake cycle in mood regulation through the dopaminergic system., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Light influences the daily patterning of activity by both synchronizing internal clocks to environmental light-dark cycles and acutely modulating arousal states, a process known as masking. Masking responses are completely reversed in diurnal and nocturnal species. In nocturnal rodents, masking is mediated through a subset of intrinsically photosensitive retinal ganglion cells (ipRGCs) whose projections are similar in diurnal and nocturnal rodents. This raises the possibility that differences in responsivity to signals that these cells release might underlie chronotype differences in masking. We explored one aspect of this hypothesis by examining the distribution of excitatory and inhibitory neuronal populations in many ipRGC target areas of a diurnal species (Nile grass rat) and a nocturnal one (Norway rat). We discovered that while many of these regions were very similar in these two species, there were striking differences in the ventral lateral geniculate nucleus (vLGN; higher density of glutamate cells in Norway rats) and in the lateral habenula (LHb; GABAeric cells present in grass rats, but not Norway rats). These patterns raise the possibility that the vLGN and LHb contribute to differences in masking and/or circadian regulation of diurnal and nocturnal species., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The neuropeptide orexin/hypocretin regulates a wide range of behaviors and physiology through its receptors OX1R and OX2R, or HCRTR-1 and HCRTR-2. Although the distributions of these receptors have been established in nocturnal rodents, their distributions in the brain of diurnal species have not been studied. In the present study, we examined spatial patterns of OX1R and OX2R mRNA expression in diurnal Nile grass rats (Arvicanthis niloticus) by in situ hybridization and compared them with those in nocturnal mice (Mus musculus). Both receptors showed similar spatial patterns between species in most brain regions. However, species-specific expression was found in several regions that are mainly implicated in regulation of sleep/wakefulness, emotion and cognition. OX1R expression was detected in the caudate putamen and ventral tuberomammillary nucleus only in grass rats, while it was detected in the bed nucleus of the stria terminalis, medial division, posteromedial part only in mice. The distribution of OX2R mRNA was mostly consistent between the two species, although it was more widely expressed in the ventral tuberomammillary nucleus in grass rats compared to mice. These results suggest that neuronal pathways of the orexin system differ between chronotypes, and these differences could underlie the distinct profiles in behaviors and physiology between diurnal and nocturnal species., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The importance of circadian function in the aetiology, progression and treatment of Parkinson's disease is a topic of increasing interest to the scientific and clinical community. While clinical studies on this theme are relatively new and limited in number there are many preclinical studies which explore possible circadian involvement in Parkinson's disease and speculate as to the mechanism by which clinical benefit can be derived by manipulating the circadian system. The present review explores the sequelae of circadian related studies from a historical perspective and reveals mechanisms that may be involved in the aetiology and progression of the disease. A systematic review of these studies also sets the stage for understanding the basic neuroscientific approaches which have been applied and provides new direction from which circadian function can be explored., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Shiftworkers are exposed to several adverse health conditions, one being eating at night. Food consumption at an unnatural time-of-day is thought to be one of the main factors responsible for the increased risk of developing metabolic diseases, such as obesity and diabetes mellitus. The underlying mechanism is considered to include disruption of the circadian organization of physiology, leading to disruption of metabolism. When food is consumed at night, the hypothalamus, a brain region central to homeostasis, receives contradicting input from the central clock and the systemic circulation. This study investigated how timing of feeding affects hypothalamic function by studying, in different hypothalamic nuclei, expression of clock genes and key neuropeptide genes involved in energy metabolism, including orexin, melanin-concentrating hormone (MCH) and neuropeptide Y. Animals with food available ad libitum showed diurnal variation in the expression of clock genes Per1 and Per2 in the perifornical area and arcuate nucleus. Clock gene rhythms were lost in both nuclei when food was restricted to the light (i.e., sleep) period. Neuropeptide genes did not display significant daily variation in either feeding groups, except for orexin-receptor 1 in ad libitum animals. Analysis of genes involved in glutamatergic and GABAergic signaling did not reveal diurnal variation in expression, nor effects of feeding time. In conclusion, feeding at the 'wrong' time-of-day not only induces desynchronization between brain and body clocks but also within the hypothalamus, which may contribute further to the underlying pathology of metabolic dysregulation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Survivors of hypoxic-ischemic brain damage (HIBD), besides impairment of psychomotor development, often develop circadian rhythm disorders, although the underlying mechanisms are largely unknown. Here, we first verified that mRNA and protein expression of pineal aralkylamine N-acetyltransferase (Aanat), a key regulator for melatonin (MT) synthesis, along with MT, were severely impaired after HIBD. In addition, we demonstrated that neonatal HIBD disrupted the circadian rhythmicity of locomotor activities in juvenile rats. Based on bioinformatics analysis of a high throughput screening of miRNA expression changes after HIBD (Ding et al., 2015), we identified one microRNA, miR-325-3p, as a potential candidate responsible for the down regulation of Aanat after HIBD. Luciferase reporter assays demonstrated a specific interaction between miR-325-3p and Aanat mRNA 3'-UTR. miR-325-3p blocked norepinephrine (NE) induced Aanat activation in cultured pinealocytes. In addition, miR-325-3p inhibition partially rescued Aanat induction by NE, which was significantly reduced under oxygen glucose deprivation. By elucidating the role of pineal miR-325-3p on Aanat expression upon injury, our study provides new insights into the pathophysiological mechanisms of circadian dysfunction and potential therapeutic targets after HIBD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The accumulation of amyloid-β (Aβ) peptides in the brain of Alzheimer disease patients is associated to cognitive deficit, increased oxidative stress, and alterations in the circadian rhythms. Brain-derived neurotrophic factor (BDNF) and Neurogranin (RC3), play an important role in the synaptic plasticity underlying memory and learning. Previously, we observed BDNF and RC3 expression follow a daily rhythmic pattern in the hippocampus of young rats. The objective of this study was to investigate the effects of an intracerebroventricular (i.c.v) injection of aggregated Aβ peptide (1-42) on temporal patterns of ApoE protein, Bdnf and Rc3 mRNA, lipid peroxidation (LPO) and reduced glutathione (GSH) levels, in the rat hippocampus. We observed an i.c.v. injection of Aβ aggregates phase shifts daily BDNF and RC3 expression as well as LPO and decreased the mesor of GSH rhythms. ApoE protein levels vary rhythmically throughout the day. ApoE levels increase at ZT 03:39±00:22 in the hippocampus of control rats and at ZT 06:30±00:28 in the treated animals. Thus, elevated levels of Aβ aggregates, characteristic of AD, altered temporal patterns of cognition related-factors, probably, as a consequence of changes in the daily variation of ApoE-mediated Aβ aggregates clearance as well as in the 24h rhythms of the cellular redox state., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aging brain undergoes several changes leading to a decline in cognitive functions. Memory and learning-related genes such as Creb, Bdnf and its receptor TrkB, are expressed in different brain regions including prefrontal cortex. Those genes' proteins regulate a wide range of functions such as synaptic plasticity and long-term potentiation. In this work, our objectives were: 1) to investigate whether Creb1, Bdnf and TrkB genes display endogenous circadian expression rhythms, in the prefrontal cortex of rats maintained under constant darkness conditions; 2) to study the synchronization of those temporal patterns to the local cellular clock and 3) to evaluate the aging consequences on both cognition-related genes and activating clock transcription factor, BMAL1, rhythms. A bioinformatics analysis revealed clock-responsive (E-box) sites in regulatory regions of Creb1, Bdnf and TrkB genes. Additionally, cAMP response elements (CRE) were found in Bdnf and TrkB promoters. We observed those key cognition-related factors expression oscillates in the rat prefrontal cortex. Creb1 and TrkB mRNAs display a circadian rhythm with their highest levels occurring at the second half of the 24h period. Interestingly, the cosinor analysis revealed a 12-h rhythm of Bdnf transcript levels, with peaks occurring at the second half of the subjective day and night, respectively. As expected, the BMAL1 rhythm's acrophase precedes Creb1 and first Bdnf expression peaks. Noteworthy, Creb1, Bdnf and TrkB expression rhythms are lost in the prefrontal cortex of aged rats, probably, as consequence of the loss of BMAL1 protein circadian rhythm and altered function of the local cellular clock., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Serotonin plays an important role in the central regulation of circadian clock function. Serotonin levels are generally higher in the brain during periods of high activity, and these periods are in turn heavily regulated by the circadian clock located in the suprachiasmatic nucleus. However, the role of serotonin as a regulator of circadian rhythms elsewhere in the brain has not been extensively examined. In this study, we examined circadian rhythms of clock gene expression in the cerebellum in mice lacking the Pet-1 transcription factor, which results in a developed brain that is deficient in serotonin neurons. If serotonin helps to synchronize rhythms in brain regions other than the suprachiasmatic nucleus, we would expect to see differences in clock gene expression in these serotonin deficient mice. We found minor differences in the expression of Per1 and Per2 in the knockout mice as compared to wild type, but these differences were small and of questionable functional importance. We also measured the response of cerebellar clocks to injections of the serotonin agonist 8-OH-DPAT during the early part of the night. No effect on clock genes was observed, though the immediate-early gene Fos showed increased expression in wild type mice but not the knockouts. These results suggest that serotonin is not an important mediator of circadian rhythms in the cerebellum in a way that parallels its regulation of the circadian clock in the suprachiasmatic nucleus., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A major challenge in the field of circadian rhythms is to understand the neural mechanisms controlling the oppositely phased temporal organization of physiology and behaviour between night- and day-active animals. Most identified components of the master clock in the suprachiasmatic nuclei (SCN), called circadian genes, display similar oscillations according to the time of day, independent of the temporal niche. This has led to the predominant view that the switch between night- and day-active animals occurs downstream of the master clock, likely also involving differential feedback of behavioral cues onto the SCN. The Barbary striped grass mouse, Lemniscomys barbarus is known as a day-active Muridae. Here we show that this rodent, when housed in constant darkness, displays a temporal rhythmicity of metabolism matching its diurnal behaviour (i.e., high levels of plasma leptin and hepatic glycogen during subjective midday and dusk, respectively). Regarding clockwork in their SCN, these mice show peaks in the mRNA profiles of the circadian gene Period1 (Per1) and the clock-controlled gene Vasopressin (Avp), which occur during the middle and late subjective day, respectively, in accordance with many observations in both diurnal and nocturnal species. Strikingly, expression of the circadian gene Clock in the SCN of the Barbary striped grass mouse was not constitutive as in nocturnal rodents, but it was rhythmic. As this is also the case for the other diurnal species investigated in the literature (sheep, marmoset, and quail), a hypothesis is that the transcriptional control of Clock within the SCN participates in the mechanisms underlying diurnality and nocturnality., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Animals maintained under conditions of food-availability restricted to a specific period of the day show molecular and physiological circadian rhythms and increase their locomotor activity 2-3h prior to the next scheduled feeding, called food anticipatory activity (FAA). Although the anatomical substrates and underlying mechanisms of the food-entrainable oscillator are not well understood, experimental evidence indicates that it involves multiple structures and systems. Using rabbit pups entrained to circadian nursing as a natural model of food restriction, we hypothesized that the anterior piriform cortex (APCx) and the olfactory tubercle (OTu) are activated during nursing-associated FAA. Two groups of litters were entrained to one of two different nursing times. At postnatal day 7, when litters showed clear FAA, pups from each litter were euthanized at nursing time, or 1, 2, 4, 8, 12, 16 or 20h later. Neural metabolic activities of the APCx, OTu, olfactory bulb (OB) and suprachiasmatic nucleus (SCN) were assessed by cytochrome oxidase histochemistry. Additionally, two fasted groups were nurse-deprived for two cycles before being euthanized at postnatal day 9. In nursed pups, metabolic activity of APCx, OTu and OB increased during FAA and after feeding, independently of the geographical time. Metabolic activity in SCN was not affected by nursing schedule. Given that APCx and OTu are in a key network position to integrate temporal odor signals with body energetic state, brain arousal and reward mechanisms, we suggest that these structures could be an important part of the conditioned oscillatory mechanism that leads to food entrainment., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The synchronization of circadian rhythms in sleep, endocrine and metabolic functions with the environmental light cycle is essential for health, and dysfunction of this synchrony is thought to play a part in the development of many neurological disorders. There is a demonstrable need to develop new therapeutics for the treatment of neurological disorders such as depression and schizophrenia, and oxytocin is currently being investigated for this purpose. There are no published reports describing activity of oxytocin receptor ligands on mammalian circadian rhythms and that, then, is the purpose of this study. Non-peptide oxytocin receptor ligands that cross the blood brain barrier were systemically injected in hamsters to determine their ability to modulate light-induced phase advances and delays of circadian wheel running rhythms. The oxytocin receptor agonist WAY267464 (10 mg/kg) inhibited light induced phase advances of wheel running rhythms by 55%, but had no effect on light-induced phase delays. In contrast, the oxytocin receptor antagonist WAY162720 (10 mg/kg) inhibited light-induced phase delays by nearly 75%, but had no effect on light-induced phase advances. Additionally, WAY162720 was able to antagonize the inhibitory effects of WAY267464 on light-induced phase advances. These results are consistent for a role of oxytocin in the phase-delaying effects of light on circadian activity rhythms early in the night. Therefore, oxytocin may prove to be useful in developing therapeutics for the treatment of mood disorders with a concomitant dysfunction in circadian rhythms. Investigators should also be cognizant that oxytocin ligands may negatively affect circadian rhythms during clinical trials for other conditions., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Stress is an important risk factor for mood disorders. Stress also stimulates the secretion of glucocorticoids, which have been found to influence mood. To determine the role of forebrain glucocorticoid receptors (GR) in behavioral responses to chronic stress, the present experiments compared behavioral effects of repeated social defeat in mice with forebrain GR deletion and in floxed GR littermate controls. Repeated defeat produced alterations in forced swim and tail suspension immobility in floxed GR mice that did not occur in mice with forebrain GR deletion. Defeat-induced changes in immobility in floxed GR mice were prevented by chronic antidepressant treatment, indicating that these behaviors were dysphoria-related. In contrast, although mice with forebrain GR deletion exhibited antidepressant-induced decreases in tail suspension immobility in the absence of stress, this response did not occur in mice with forebrain GR deletion after defeat. There were no marked differences in plasma corticosterone between genotypes, suggesting that behavioral differences depended on forebrain GR rather than on abnormal glucocorticoid secretion. Defeat-induced gene expression of the neuronal activity marker c-fos in the ventral hippocampus, paraventricular thalamus and lateral septum correlated with genotype-related differences in behavioral effects of defeat, whereas c-fos induction in the nucleus accumbens and central and basolateral amygdala correlated with genotype-related differences in behavioral responses to antidepressant treatment. The dependence of both negative (dysphoria-related) and positive (antidepressant-induced) behaviors on forebrain GR is consistent with the contradictory effects of glucocorticoids on mood, and implicates these or other forebrain regions in these effects., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Cognition is modulated by circadian rhythms, in both nocturnal and diurnal species. Rhythms of clock gene expression occur in brain regions that are outside the master circadian oscillator of the suprachiasmatic nucleus and that control cognitive functions, perhaps by regulating the expression neural-plasticity genes such as brain derived neurotrophic factor (BDNF) and its high affinity receptor, tyrosine kinase B (TrkB). In the diurnal grass rat (Arvicanthis niloticus), the hippocampus shows rhythms of clock genes that are 180° out of phase with those of nocturnal rodents. Here, we examined the hypothesis that this reversal extends to the optimal phase for learning a hippocampal-dependent task and to the phase of hippocampal rhythms in BDNF/TrkB expression. We used the Morris water maze (MWM) to test for time of day differences in reference memory and monitored daily patterns of hippocampal BDNF/TrkB expression in grass rats. Grass rats showed superior long-term retention of the MWM, when the training and testing occurred during the day as compared to the night, at a time when nocturnal laboratory rats show superior retention; acquisition of the MWM was not affected by time of day. BDNF/TrkB expression was rhythmic in the hippocampus of grass rats, and the phase of the rhythms was reversed compared to that of nocturnal rodents. Our findings provide correlational evidence for the claim that the circadian regulation of cognition may involve rhythms of BDNF/TrkB expression in the hippocampus and that their phase may contribute to species differences in the optimal phase for learning., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Studies of rats and voles suggest that distinct pathways emanating from the anterior hypothalamic-retrochiasmatic area and the mediobasal hypothalamic arcuate nucleus independently generate ultradian rhythms (URs) in hormone secretion and behavior. We evaluated the hypothesis that destruction of arcuate nucleus (ARC) neurons, in concert with dampening of suprachiasmatic nucleus (SCN) circadian rhythmicity, would compromize the generation of ultradian rhythms (URs) of locomotor activity. Siberian hamsters retain-->of both sexes treated neonatally with monosodium glutamate (MSG) that destroys ARC neurons were subjected in adulthood to a circadian disrupting phase-shift protocol (DPS) that produces SCN arrhythmia. MSG treatments induced hypogonadism and obesity, retain-->and markedly reduced the size of the optic chiasm and optic nerves. MSG-treated hamsters exhibited normal entrainment to the light-dark cycle, but MSG treatretain-->ment counteracted the circadian arrhythmicity induced by the DPS protocol: only 6% of retain-->MSG-treated hamsters exhibited circadian arrhythmia, whereas 50% of control hamsters were circadian disrupted. In MSG-treated hamsters that retained circadian rhythmicity after DPS treatment, quantitative parameters of URs appeared normal, but in the two MSG-treated hamsters that became circadian arrhythmic after DPS, both dark-phase and light-phase URs were abolished. Although preliminary, these data are consistent with reports in voles suggesting that the combined disruption of SCN and ARC function impairs the expression of behavioral URs. The data also suggest that light thresholds for entrainment of circadian rhythms may be lower than those required to disrupt circadian organization., (Copyright © 2013 Elsevier B.V. All rights reserved.)

In mammals Orexin-A and -B are neuropeptides involved in the hypothalamic regulation of diverse physiological functions including food intake and the sleep-wake cycle. This generalisation was investigated in meat-(broiler) and layer-type juvenile domestic chickens by immunocytochemical localisation of orexin A/B in the hypothalamus, and by measurements of hypothalamic hypocretin mRNA which encodes for orexin A/B after chronic food restriction, and during the sleep-wake cycle. Orexin immunoreactive fibres were observed throughout the hypothalamus with cell bodies in and around the paraventricular nucleus. No differences were observed in the pattern of immunoreactivity using anti- human orexin-A, or -B antisera. The amount of hypothalamic hypocretin mRNA in food -restricted broilers was higher than in broilers fed ad libitum, but the same as in layer- type hens fed ad libitum. Hypothalamic hypocretin mRNA was increased (P<0.01) in 12-week-old broilers fed 25% of their ad libitum intake between 6-12 weeks of age. No difference in hypothalamic hypocretin mRNA was seen in 12-week-old layer- type hens when they were awake (1-2h after lights on) or sleeping (1-2h after lights off). It is concluded that in the chicken, we could not find evidence that hypothalamic orexin plays a role in the sleep-wake cycle and it may be involved in aspects of energy balance., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Deletion of the core clock gene, Bmal1, ablates circadian rhythms and accelerates aging, leading to cognitive deficits and tissue atrophy (e.g., skeletal muscle) (Kondratov et al., 2006, Kondratova et al., 2010). Although normal aging has been shown to attenuate Bmal1 expression in the master circadian pacemaker in the suprachiasmatic nucleus (SCN), relatively little is known about age-related changes in Bmal1 expression in other tissues, where Bmal1 may have multiple functions. This study tested the hypothesis that aging reduces Bmal1 expression in extra-SCN oscillators including brain substrates for memory and in skeletal muscle. Brains and gastrocnemius muscles were collected from young (3-5 months) and old hamsters (17-21 months) euthanized at four times of day. Bmal1 mRNA expression was determined by conducting in situ hybridization on brain sections or real-time PCR on muscle samples. The results showed age-related attenuation of Bmal1 expression in many brain regions, and included loss of diurnal rhythms in the hippocampal CA2 and CA3 subfields, but no change in muscle. In situ hybridization for Per2 mRNA was also conducted and showed age-related reduction of diurnal rhythm amplitude selectively in the hippocampal CA1 and DG subfields. In conclusion, aging has tissue-dependent effects on Bmal1 expression in extra-SCN oscillators. These finding on normal aging will provide a reference for comparing potential changes in Bmal1 and Per2 expression in age-related pathologies. In conjunction with previous reports, the results suggest the possibility that attenuation of clock gene expression in some brain regions (the hippocampus, cingulate cortex and SCN) may contribute to age-related cognitive deficits., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Circadian rhythms in behavior and physiology change substantially as female mammals undergo the transition from a non-pregnant to a pregnant state. Here, we examined the possibility that site-specific changes in brain regions known to regulate the sleep/wake cycle and body temperature might reflect altered rhythms in these overt functions. Specifically, we compared daily patterns of immunoreactive FOS in early pregnant and diestrous rats in the medial septum (MS), vertical and horizontal diagonal bands of Broca (VDB and HDB), perifornical lateral hypothalamus (LH), and ventrolateral, medial, and median preoptic areas (VLPO, MPA, and MnPO, respectively). In the pregnant animals, FOS expression was reduced and the daily rhythms of expression were lost or attenuated in the MS, VDB, and LH, areas known to support wakefulness, and in the MPA, a brain region that may coordinate sleep/wake patterns with temperature changes. However, despite the well-documented differences in sleep patterns between diestrous and pregnant rats, reproductive state did not affect FOS expression in the VLPO or MnPO, two brain regions in which FOS expression usually correlates with sleep. These data indicate that plasticity in sleep/wake patterns during early pregnancy may be driven by a reduction in wakefulness-promotion by the brain, rather than by an increase in sleep drive., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Central administration of thyrotropin releasing hormone (TRH) reduces anxiety; amygdalar TRH expression is inversely proportional to the anxious behavior displayed in the elevated plus maze performed during the dark phase (EPM-D). To better understand the role of TRH in amygdala function, we evaluated the expression of TRH and the elements involved in its transmission in various stressful paradigms and how they associated with behavior. Wistar male rats were exposed to restraint (RES), EPM, or the open field test (OFT) and sacrificed 0-60 min afterwards; OFT, RES and EPM were performed during the light (L), and OFT during the dark phase. Restraint increased amygdalar levels of proCRH mRNA, without change in proTRH. All paradigms augmented corticosterone release, highest after OFT-L that also enhanced proCRH mRNA levels and decreased those of proTRH. OFT-D activated the TRH system. Levels of anxiety or locomotion were similar in animals tested in light or dark phases but their association with biochemical parameters differed. ProTRH expression and TRH release correlated positively with decreased anxiety in EPM-L and in OFT-D. No association with anxiety was detected in OFT-L where proCRH and proTRH expression correlated with locomotion supporting their involvement in arousal. The responses of TRH amygdalar systems appeared modulated by the extent of the stress response and by the circadian conditions. Increased proTRH expression of animals exposed to OFT-D was specifically observed in the cortical nucleus of the amygdala, area involved in processing fear stimuli; these TRH neurons may thus be part of a circuit with anxiolytic properties., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Corticosterone influences emotion and cognition via actions in a diversity of corticolimbic structures, including the amygdala. Since extracellular levels of corticosterone in brain have rarely been studied, we characterized a specific and sensitive enzymatic immunoassay for microdialysis quantification of corticosterone in the basolateral amygdaloid complex of freely-moving rats. Corticosterone levels showed marked diurnal variation with an evening (dark phase) peak and stable, low levels during the day (light phase). The "anxiogenic agents", FG7142 (20 mg/kg) and yohimbine (10 mg/kg), and an environmental stressor, 15-min forced-swim, induced marked and sustained (1-3 h) increases in dialysis levels of corticosterone in basolateral amygdaloid complex. They likewise increased dialysis levels of dopamine and noradrenaline, but not serotonin and GABA. As compared to basal corticosterone levels of ~200-300 pg/ml, the elevation provoked by forced-swim was ca. 20-fold and this increase was abolished by adrenalectomy. Interestingly, stress-induced rises of corticosterone levels in basolateral amygdaloid complex were abrogated by combined but not separate administration of the corticotrophin releasing factor(1) (CRF(1)) receptor antagonist, CP154,526, and the vasopressin(1b) (V(1b)) receptor antagonist, SSR149,415. Underpinning their specificity, they did not block forced-swim-induced elevations in dopamine and noradrenaline. In conclusion, extracellular levels of corticosterone in the basolateral amygdaloid complex display marked diurnal variation. Further, they are markedly elevated by acute stressors, the effects of which are mediated (in contrast to concomitant elevations in levels of monoamines) by co-joint recruitment of CRF(1) and V(1b) receptors., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Here we used a within-subject design to evaluate hypothalamic-pituitary-adrenal (HPA) activity following replacement of low and high physiological levels of testosterone (T) to adult, gonadally-suppressed, male rhesus macaques, and replacement with sex-specific low and high physiological doses of dihydrotestosterone (DHT) in the same adult males as well as in adult, gonadally-suppressed, female rhesus macaques. As indexes of HPA axis activation following T and DHT replacement, serum levels of cortisol (CORT) were measured before and following dexamethasone (DEX) inhibition, and corticotrophin-releasing factor (CRF) induced activation. Female monkeys were assessed for differences in response associated with dominant (DOM) and subordinate (SUB) social status. Data show that the high physiological dose of DHT significantly decreased basal CORT in both male and female monkeys irrespective of social status, but reduced CRF-stimulated CORT only in males. SUB female monkeys showed a trend towards increased CRF-stimulated CORT release under high-dose DHT replacement compared to DOM females or males given the same treatment, indicating that androgens likely have no influence on reducing HPA activation under chronic psychosocial stress in females. The normal circadian rhythm of CORT release was absent in placebo-replaced SUB and DOM females and was restored with low-dose DHT replacement. These results indicate that DHT significantly reduces CRF-stimulated CORT release only in male monkeys, and plays a role in maintaining circadian changes in CORT release in female monkeys., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The results from various studies have indicated possible functional relationships between crayfish electroretinogram (ERG) rhythmic amplitude changes and the serotonergic pathways projecting from the central brain through the optic neuropils to the eye, but to date, this functional interaction has not been proven. Here, in a set of experiments using an isolated eyestalk-brain preparation, we investigated whether there is a circadian input from the brain to retina that regulates this rhythm. We sought to determine whether the protocerebral bridge (PB) stimulation affects the ERG amplitude in accordance with the zeitgeber time (ZT) and whether 5-HT modulates the associate input. Our results showed that photic stimulation of retina produced changes in both the amplitude and the frequency of spontaneous electrical activity in the protocerebral neuropils. In addition, electrical stimulation of the medial protocerebrum, particularly the PB, produced statistically significant changes in the ERG that depended on both the time of day and the level of serotonin. This suggests that pathways between retina and PB seem to be serotonergic., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Testosterone has been the focus of several investigations and review studies in males, but few have addressed its effects on sleep and sexual function, despite evidence of its androgenic effects on circadian activity in both sexes. Studies have been conducted to understand how sleeping increases (and how waking decreases) testosterone levels and how this rhythm can be related to sexual function. This review addresses the inter-relationships among testosterone, sexual function and sleep, including sleep-disordered breathing in both sexes, specifically its effects related to sleep deprivation. In addition, hormonal changes in testosterone that occur in the gonadal and adrenal axis with obstructive sleep apnea and other conditions of chronic sleep deprivation, and which consequently affect sexual life, have also been explored. Nevertheless, hormone-associated sleep disruptions occur across a lifetime, particularly in women. The association between endogenous testosterone and sex, sleep and sleep disturbances is discussed, including the results of clinical trials as well as animal model studies. Evidence of possible pathophysiological mechanisms underlying this relationship is also described. Unraveling the associations of sex steroid hormone concentrations with sleep and sexual function may have clinical implications, as sleep loss reduces testosterone levels in males, and low sex steroid hormone concentrations have been associated with sexual dysfunction., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Modulation of TASK-3 (Kcnk9) potassium channels affect neurotransmitter release in thalamocortical centers and other sleep-related nuclei having the capacity to regulate arousal cycles and REM sleep changes associated with mood disorders and antidepressant action. Circumstantial evidence from this and previous studies suggest the potential for TASK-3 to be a novel antidepressant therapeutic target; TASK-3 knock-out mice display augmented circadian amplitude and exhibit sleep architecture characterized by suppressed REM activity. Detailed analysis of locomotor activity indicates that the amplitudes of activity bout duration and bout number are augmented in TASK-3 mutants well beyond that seen in wildtypes, findings substantiated by amplitude increases in body temperature and EEG recordings of sleep stage bouts. Polysomnographic analysis of TASK-3 mutants reveals increases in nocturnal active wake and suppressed REM sleep time while increased slow wave sleep typifies the inactive phase, findings that have implications for the cognitive impact of reduced TASK-3 activity. In direct measures of their resistance to despair behavior, TASK-3 knock-outs displayed significant decreases in immobility relative to wildtype controls in both tail suspension and forced swim tests. Treatment of wildtype animals with the antidepressant Fluoxetine markedly reduced REM sleep, while leaving active wake and slow wave sleep relatively intact. Remarkably, these effects were absent in TASK-3 mutants indicating that TASK-3 is either directly involved in the mechanism of this drug's action, or participates in parallel pathways that achieve the same effect. Together, these results support the TASK-3 channel to act as a therapeutic target for antidepressant action., (Copyright © 2011. Published by Elsevier B.V.)

Many clinical studies have shown that circadian rhythm abnormalities are strongly associated with major depression. The master clock of the circadian system in mammals is located in the suprachiasmatic nucleus (SCN) within the anterior hypothalamus, where Per1 and Per2 are essential core components of circadian rhythm oscillation. Chronic unpredictable stress (CUS) is a reliable animal model of depression with good face, predictive, and constructive validity. In the present study, we investigated the effects of CUS on the circadian expression of PER1 and PER2 in the SCN. We found that CUS led to depressive-like behavior and reduced the amplitude of PER2 oscillation in the SCN, which were blocked by 3 weeks of desipramine (DMI) treatment. 2 weeks after termination of CUS, the decreased peak of PER2 expression returned to control levels, whereas depressive-like behavior remained unchanged. Our findings suggest that the dampened amplitude of PER2 expression in the SCN may participate in the development of depressive-like behavior induced by CUS but is unlikely involved in the long-lasting effects of CUS on depressive-like behavior., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The Wistar Audiogenic Rat (WAR) strain is a genetic model of sound-induced reflex epilepsy which was selected starting from audiogenic seizures susceptible Wistar rats. Wistar resistant rats were used as WAR's control in this study. In the acute situation, audiogenic seizures (AS) in WARs mimic tonic-clonic seizures and, in the chronic protocol, mimic temporal lobe epilepsy. AS have been shown to evoke neuroendocrine responses; however, the hypothalamic-pituitary-adrenal activity in the WAR has not been established. The aim of this study was to evaluate the hypothalamic-pituitary-adrenal axis (HPA) responses to exogenous ACTH stimulation (8 ng/rat), fifteen minute restraint stress and circadian variation (8 am and 8 pm) under rest conditions in these animals through plasma measurements of ACTH and corticosterone concentrations. We also measured the body weight from birth to the 9th week of life and determined adrenal gland weight. We found that WARs are smaller than Wistar and presented a higher adrenal gland weight with a higher level of corticosterone release after intravenous ACTH injection. They also showed altered HPA axis circadian rhythms and responses to restraint stress. Our data indicate that, despite the lower body weight, WARs have increased adrenal gland weight associated with enhanced pituitary and adrenal responsiveness after HPA axis stimulation. Thus, we propose WARs as a model to study stress-epilepsy interactions and epilepsy-neuropsychiatry comorbidities., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Phosphodiesterase10A (PDE10A) is a dual specific cyclic nucleotide phosphodiesterase that is specifically enriched in striatum and which has gained attention as a therapeutic target for psychiatric disorders. The present study shows that PDE10A is also highly expressed in retinal neurons including photoreceptors. The levels of PDE10A transcript and protein display daily rhythms which could be seen in preparations of the whole retina. Corresponding changes in PDE10A mRNA were seen in photoreceptors isolated using laser microdissection. This suggests that the expressional control of the photoreceptor Pde10a gene contributes to the observed cyclicity in the amount of retinal PDE10A. The daily rhythmicity in the retinal PDE10A mRNA amount is retained under constant darkness but can be blocked by constant light or modulated by the lighting regime. It therefore appears to be driven by the endogenous retinal clock system which itself is entrained by light. The findings presented place PDE10A in the context of the visual system and suggest a role of PDE10A in the adaptation of cyclic nucleotide signaling to daily changes in light intensity in retinal neurons including photoreceptors., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Temporal perception is fundamental to environmental adaptation in humans and other animals. To deal with timing and time perception, organisms have developed multiple systems that are active over a broad range of order of magnitude, the most important being circadian timing, interval timing and millisecond timing. The circadian pacemaker is located in the suprachiasmatic nuclei (SCN) of the hypothalamus, and is driven by a self-sustaining oscillator with a period close to 24h. Time estimation in the second-to-minutes range--known as interval timing--involves the interaction of the basal ganglia and the prefrontal cortex. In this work we tested the hypothesis that interval timing in mice is sensitive to circadian modulations. Animals were trained following the peak-interval (PI) procedure. Results show significant differences in the estimation of 24-second intervals at different times of day, with a higher accuracy in the group trained at night, which were maintained under constant dark (DD) conditions. Interval timing was also studied in animals under constant light (LL) conditions, which abolish circadian rhythmicity. Mice under LL conditions were unable to acquire temporal control in the peak interval procedure. Moreover, short time estimation in animals subjected to circadian desynchronizations (modeling jet lag-like situations) was also affected. Taken together, our results indicate that short-time estimation is modulated by the circadian clock., (Copyright © 2010 Elsevier B.V. All rights reserved.)

5-HT(7) receptors in the dorsal raphe nucleus (DRN) influence circadian rhythms, sleep, and serotonin release. Because interactions between 5-HT(7) receptors and glutamatergic and GABAergic neurons have been demonstrated previously, the current studies tested the hypothesis that GABAergic and/or glutamatergic neurons mediate phase shifts induced by activation of DRN 5-HT(7) receptors. Hamsters were fitted with guide cannulae aimed at the DRN, housed in cages with running wheels, and exposed to 14h light (L):10h dark (D). In Experiment 1, hamsters received DRN pretreatment with muscimol (87.6 pmol) or vehicle before DRN 8-OH-DPAT (6 pmol) microinjections at ZT6. After exposure to constant darkness (10 days), phase shifts were calculated and animals were re-exposed to 14L:10D. The procedure was repeated to give each animal the alternate pretreatment. In Experiment 2, hamsters received DRN pretreatment with NMDA (20 pmol) or vehicle before 8-OH-DPAT at ZT 6. Other experiments tested the effects of single DRN microinjections of muscimol, bicuculline (136 pmol), NMDA, MK-801 (10 pmol) or vehicle. Phase shifts (mean ± S.E.M., h) in muscimol/8-OH-DPAT-microinjected hamsters (1.02 ± 0.30) were not different (P=0.11) from those in vehicle/8-OH-DPAT-microinjected hamsters (1.34 ± 0.30), while those in NMDA/8-OH-DPAT-microinjected hamsters (0.67 ± 0.17) were smaller (P<0.05) than those in vehicle/8-OH-DPAT-microinjected hamsters (0.97 ± 0.10). DRN single microinjections of bicuculline, but not muscimol, NMDA, or MK-801 induced phase advances. Bicuculline also potentiated 8-OH-DPAT-induced phase advances (P<0.05). These finding suggest that the mechanism mediating DRN 5-HT(7) receptor induction of phase advances involves decreased glutamatergic neurotransmission, and furthermore, that inhibition of DRN GABAergic neurotransmission causes a phase advance., (Copyright © 2010 Elsevier B.V. All rights reserved.)

We present a memory model that explicitly constructs and stores the temporal information about when a stimulus was encountered in the past. The temporal information is constructed from a set of temporal context vectors adapted from the temporal context model (TCM). These vectors are leaky integrators that could be constructed from a population of persistently firing cells. An array of temporal context vectors with different decay rates calculates the Laplace transform of real time events. Simple bands of feedforward excitatory and inhibitory connections from these temporal context vectors enable another population of cells, timing cells. These timing cells approximately reconstruct the entire temporal history of past events. The temporal representation of events farther in the past is less accurate than for more recent events. This history-reconstruction procedure, which we refer to as timing from inverse Laplace transform (TILT), displays a scalar property with respect to the accuracy of reconstruction. When incorporated into a simple associative memory framework, we show that TILT predicts well-timed peak responses and the Weber law property, like that observed in interval timing tasks and classical conditioning experiments., (Copyright © 2010 Elsevier B.V. All rights reserved.)

CYP2B is a drug-metabolizing enzyme expressed in the liver and brain that metabolizes a variety of centrally acting drugs (e.g. propofol, bupropion and nicotine), endogenous neurochemicals (e.g. serotonin and testosterone) and toxins (e.g. chlorpyrifos). Human CYP2B6 is found at higher levels in the brains of smokers, and 7-day nicotine treatment induces rat brain CYP2B while not altering hepatic CYP2B. We characterized the time course of rat brain CYP2B induction by nicotine and determined if nicotinic acetylcholine receptors (nAChRs) mediated this induction. Rats were treated once daily with 1mg/kg nicotine base or saline s.c. for 1 or 7days and sacrificed from 30minutes to 7days after the last injection. One-day nicotine treatment did not induce brain CYP2B, whereas 7-day nicotine treatment significantly increased CYP2B expression for up to 24hours in the frontal cortex and brainstem; these levels returned to baseline by 7days post-treatment. CYP2B activity was also higher at 24hours in these regions. No change was seen in the cerebellar CYP2B levels or in vivo activity following nicotine treatment. Time of day of treatment and sacrifice altered the magnitude of brain CYP2B induction while chlorisondamine, an irreversible nAChR blocker, pre-treatment did not block CYP2B induction. Seven-day nicotine treatment resulted in an induction of rat brain CYP2B protein and in vivo activity for up to 24hours, which would suggest greater local drug metabolism by brain CYP2B. Humans or animals exposed to nicotine may have altered therapeutic drug response, brain levels of neurotransmitters and/or neurotoxicity., (Copyright 2010 Elsevier B.V. All rights reserved.)

The anatomy and physiology of the non-image forming visual system was investigated in a visually blind cone-rod homeobox gene (Crx) knock-out mouse (Crx(-)(/)(-)), which lacks the outer segments of the photoreceptors. We show that the suprachiasmatic nuclei (SCN) in the Crx(-/-) mouse exhibit morphology as in the wild type mouse. In addition, the SCN contain vasoactive intestinal peptide-, vasopressin-, and gastrin-releasing peptide-immunoreactive neurons as present in the wild type. Anterograde in vivo tracings from the retina of the Crx(-/-) and wild type mouse showed that the retinohypothalamic projection to the SCN and the central optic pathways were similar in both animals. Telemetric monitoring of the running activity and temperature revealed that both the Crx(-/-)and wild type mouse exhibited diurnal rhythms with a 24-h period, which could be phase changed by light. However, power spectral analysis revealed that both rhythms in the Crx(-/-) mouse were less robust than those in the wild type. The normal development of the SCN and the central visual pathways in the Crx(-/-) mouse suggests that a modulatory input from the photoreceptors in the peripheral retina to the retinal melanopsin neurons or the SCN may be necessary for a normal function of the non-image forming system of the mouse. However, a change in the SCN of the Crx(-/-) mouse might also explain the observed circadian differences between the knock out mouse and wild type mouse., (Copyright (c) 2010. Published by Elsevier B.V.)

Sensory input to different cortical areas differentially varies across the light-dark cycle and likely is responsible, in part, for activity-dependent changes in time-of-day differences in protein expression such as Fos. In this study we investigate time-of-day differences between dark (just before light onset) and light (just before dark onset) for the number of immunoreactive (IR) neurons that stained for tumor necrosis factor alpha (TNFalpha), interleukin-1 beta (IL1 beta), nerve growth factor (NGF), the neuronal nuclear protein (NeuN) and Fos in the rat somatosensory cortex (Sctx) and visual cortex (Vctx). Additionally, astrocyte IL1 beta-IR in the Sctx and Vctx was determined. TNFalpha and IL1 beta, as well as the immediate early gene protein Fos, were higher at the end of the dark phase (2300 h) compared to values obtained at the end of the light phase (1100 h) in the Sctx and Vctx. IL1 beta-IR in Sctx and Vctx astrocytes was higher at 2300 h than that observed at 1100 h. . In contrast, the number of NGF-IR neurons was higher in the Vctx than in the Sctx but did not differ in time. However, the density of the NGF-IR neurons in layer V was greater at 2300 h in the Sctx than at 1100 h. NeuN-IR was higher at 2300 h in the Sctx but was lower at this time in the Vctx compared to 1100 h. These data demonstrate that expressions of the molecules examined are dependent on activity, the sleep-wake cycle and brain location. These factors interact to modulate time-of-day expression., ((c) 2010 Elsevier B.V. All rights reserved.)

The bioflavonoid quercetin is widely found in plants and exerts a large number of biological activities such as anti-hypertensive and anti-inflammatory properties. However, the effect of quercetin on the sleep-wake cycle has not been investigated. In the present study, we investigated the effect of quercetin on sleep-wake regulation. Intraperitoneal administration of quercetin (200mg/kg) significantly increased non-rapid eye movement (non-REM) sleep during dark period in rats, while it significantly decreased REM sleep. The decrease in REM sleep induced by quercetin was blocked by intracerebroventricular (i.c.v.) injection of bicuculline, a GABA(A) receptor antagonist. In contrast, the increase in non-REM sleep induced by quercetin was not affected by i.c.v. injection of bicuculline. Therefore, the present results suggest that quercetin alters the sleep-wake cycle partly through activation of GABA(A) receptors., ((c) 2010 Elsevier B.V. All rights reserved.)

There is growing interest in sleep research and increasing demand for screening of circadian rhythms in genetically modified animals. This requires reliable sleep stage scoring programs. Present solutions suffer, however, from the lack of flexible adaptation to experimental conditions and unreliable selection of stage-discriminating variables. EEG was recorded in freely moving C57BL/6 mice and different sets of frequency variables were used for analysis. Parameters included conventional power spectral density functions as well as period-amplitude analysis. Manual staging was compared with the performance of two different supervised classifiers, linear discriminant analysis (LDA) and Classification Tree. Gamma activity was particularly high during REM (rapid eye movements) sleep and waking. Four out of 73 variables were most effective for sleep-wake stage separation: amplitudes of upper gamma-, delta- and upper theta-frequency bands and neck muscle EMG. Using small sets of training data, LDA produced better results than Classification Tree or a conventional threshold formula. Changing epoch duration (4 to 10s) had only minor effects on performance with 8 to 10s yielding the best results. Gamma and upper theta activity during REM sleep is particularly useful for sleep-wake stage separation. Linear discriminant analysis performs best in supervised automatic staging procedures. Reliable semi-automatic sleep scoring with LDA substantially reduces analysis time., (Copyright 2010 Elsevier B.V. All rights reserved.)

The aim of this work was to confirm previous findings suggesting that the eyes are required for night-time melatonin production in Nile tilapia and further characterise this divergent circadian organisation. To do so, melatonin levels were firstly measured in eyecups and plasma to determine circadian patterns of melatonin production. Secondly, the effect of partial ophthalmectomy on the suppression of melatonin production was determined in vivo as well as ex vivo pineal light/dark sensitivity. Finally, to investigate whether such findings could be related to post-surgery stress, melatonin analyses were performed in the subsequent 24 h and 7 days post-ophthalmectomy with cortisol levels assessed as an indicator of stress. Our results showed an inverse pattern of melatonin production in the eye cups of tilapia compared to blood circulating levels, suggesting different roles played by melatonin in these two tissues. Results then demonstrated that total or partial ophthalmectomy resulted in the suppression of night-time melatonin production. Furthermore, although pineals in culture were shown to be photosensitive, night-time melatonin levels were much lower than seen in other species. Finally, when performing sampling immediately or one week post-surgery, no difference in the melatonin profiles were observed. It is therefore unlikely that post-surgery stress would explain such suppression in melatonin production although all fish displayed high cortisol levels most probably due to social and handling stress. Taken together, these results provide further evidence of a new type of circadian organisation in a teleost species where the eyes are required to sustain night-time melatonin levels.

The suprachiasmatic nucleus (SCN) of the hypothalamus coordinates physiological and behavioral circadian rhythms such as activity, body temperature, and hormone secretion. Circadian rhythms coordinated by the SCN often show sex differences arising from both organizational and activational effects of gonadal hormones. In males, little is known about the organizational role of testosterone on the circadian regulation of core body temperature (CBT) in adulthood. To explore this, we castrated or sham-operated male rats on the day of birth, and at 4 months of age, implanted them with transmitters that measured CBT rhythms under a 12:12 light/dark cycle. This study revealed a significantly earlier rise in CBT during the light phase in neonatally castrated males. Subsequently, we found that treating neonatally castrated males with testosterone propionate (TP) in adulthood did not reverse the effect of neonatal castration, thus indicating an organizational role for testosterone. In contrast, a single injection of TP at the time of neonatal surgery, to mimic the postnatal surge of testosterone, coupled with TP treatment in adulthood, normalized the circadian rise in CBT. In a final study we examined CBT circadian rhythms in intact adult male and female rats and detected no differences in the rise of CBT during the light phase, although there was a greater overall elevation in female CBT. Together, results of these studies reveal an early organizational role of testosterone in males on the timing of the circadian rise of CBT, a difference that does not appear to reflect "defeminization".

Major components of energy homeostasis, including feeding behavior and glucose and lipid metabolism, are subject to circadian rhythms. Recent studies have suggested that dysfunctions of molecular clock genes are involved in the development of obesity and diabetes. To examine whether metabolic states per se alter the circadian clock in the central nervous system (CNS), we analyzed the daily mRNA expression profiles of core clock genes in the caudal brainstem nucleus of the solitary tract (NTS). In lean C57BL/6 mice, transcript levels of the core clock genes (Npas2, Bmal1, Per1, Per2 and Rev-erbalpha) clearly showed 24-h rhythmicity. On the other hand, the expression profiles of Bmal1 and Rev-erbalpha were attenuated in mice with high fat diet-induced obesity as well as genetically obese KK-A(y) and ob/ob mice. Clock expression levels were increased in mice with high fat diet-induced obesity and Cry1 expression levels were decreased in KK-A(y) and ob/ob mice. In addition, peroxisome proliferator-activated receptor alpha (PPARalpha), which reportedly increases the BMAL1 transcriptional level, was up-regulated in the NTS of these murine models of obesity and insulin resistance, suggesting involvement of PPARalpha in the attenuation of circadian rhythms in the NTS in obese states. Furthermore, a circadian expression profile of a downstream target of clock genes, the large conductance Ca(2+)-activated K(+)channel, was disturbed in the NTS of these murine obesity models. These perturbations might contribute to neuronal dysfunction in obese states. This is the first report showing that obesity perturbs the circadian expressions of core clock genes in the CNS.

Previous studies indicated that recovery of brain injury involves in circadian system and circadian system also modulates cardiovascular function. The present study was focused on the circadian characteristic of blood pressure (BP) and heart rate (HR) of patients with hypertensive intracerebral hemorrhage (HICH) after neurosurgical operation at the first 24-hour and its relationship to prognosis of HICH. This retrospective study was based on the analysis of circadian rhythm of postoperative patients with HICH who received no anti-hypertensive treatment before operation and during the first 24-hour after operation. Series data of BP and HR after operation were analyzed with cosinor method to determine whether circadian rhythms were present or absent. The patients were divided into two groups, including presence of circadian rhythm group and absence of circadian rhythm group. The basic clinical characteristics of two groups were analyzed with Student's t-test. The percentage of good prognosis in two groups was analyzed with Pearson's Chi-squared test. Statistical results indicated that the percentage of good prognosis was significantly different between the presence and absence group. More cases of good prognosis in presence group of Systolic Blood Pressure (SBP) was discovered than in absence group (p=0.032). The results of Diastolic Blood Pressure (DBP) and HR were similar as SBP was observed in presence group for DBP (p=0.002) and for HR (p=0.001), respectively. We conclude that the presence or absence of circadian rhythm after operation would be an early predictor of the postoperative prognosis from hypertensive intracerebral hemorrhage.

The thalamic paraventricular nucleus (PVT) receives afferents from numerous brain areas, including the hypothalamic suprachiasmatic nucleus (SCN), considered to be the major circadian pacemaker. The PVT also sends projections to the SCN, limbic system centers and some nuclei involved in the control of the Sleep-Wake cycle. In this study, we report the identification of a hitherto not reported direct retinal projection to the PVT of the rock cavy, a typical rodent species of the northeast region of Brazil. After unilateral intravitreal injections of cholera toxin subunit B (CTb), anterogradely transported CTb-immunoreactive fibers and presumptive terminals were seen in the PVT. Some possible functional correlates of the present data are briefly discussed, including the role of the PVT in the modulation of the circadian rhythms by considering the reciprocal connections between the PVT and the SCN. The present work is the first to show a direct retinal projection to the PVT of a rodent and may contribute to elucidate the anatomical substrate of the functionally demonstrated involvement of this midline thalamic nucleus in the modulation of the circadian timing system.

In mammals, circadian rhythms are driven by a pacemaker located in the suprachiasmatic nucleus (SCN), which is composed of multiple, single-cell oscillators. Isolated SCN tissue shows clear circadian oscillation in release of arginine vasopressin (AVP) in organotypic slice cultures. Previously, we reported that the oscillators in the dorsal SCN have shorter periods than those in the ventral part. Here, we examined whether a correlation between the period and the rostral-caudal co-ordination could exist. The rostral, central and caudal SCN were cultured separately and the periods of circadian rhythms of AVP release were measured. The rostral and caudal parts of the SCN showed shorter periods than the central SCN. Together with previous findings, it is suggested that the shorter period region originates from AVP containing areas, while the longer period region corresponds with vasoactive intestinal polypeptide (VIP) containing cells. In our VIP-immunoreactive slices, the application of VIP antagonists shortened the periods of the AVP-releasing rhythm. These data indicate that the oscillators in AVP cells have short periods and are entrained by VIP cells to form a single integrated rhythm.

Circadian timekeeping is a ubiquitous feature of all eukaryotes which allows for the imposition of a biologically appropriate temporal architecture on an animal's physiology, behavior and metabolism. There is growing evidence that in mammals the processes of circadian timing are under the influence of the immune system. Such a role for the neuroimmune regulation of the circadian clock has inferences for phenomena such as sickness behavior. Conversely, there is also accumulating evidence for a circadian influence on immune function, raising the likelihood that there is a bidirectional communication between the circadian and immune systems. In this review, we examine the evidence for these interactions, including circadian rhythmicity in models of disease and immune challenge, distribution of cytokines and their receptors in the suprachiasmatic nucleus of the hypothalamus, the site of the master circadian pacemaker, and the evidence for endogenous circadian timekeeping in immune cells.

The possible long-term effects of the recreational drug "ecstasy" (3,4-methylenedioxymethamphetamine, MDMA) on the function of 5-hydroxytryptamine-1B (5-HT(1B)) receptor in sleep and motor control were investigated using a selective 5-HT(1B) receptor agonist, 5-propoxy-3-(1,2,3,6-tetrahydro-4-pyrinzidyl)-1H-pyrrolo([3,2-b])pyridine hydrochloride (CP-94,253; 5 mg/kg). CP-94,253 or vehicle was administered to freely moving rats pre-treated with MDMA (15 mg/kg) or vehicle 6 months earlier, and polygraphic recording for 24 h and motor activity measurements were performed. Active wake (AW), passive wake (PW), light slow wave sleep (SWS-1), deep slow wave sleep (SWS-2), paradoxical sleep (PS), and diurnal rhythm were analyzed for the whole period. In additional, the EEG power spectrum was calculated for the second hour after the acute treatment for AW, PW, SWS-1, and SWS-2. 5-HT transporter (5-HTT) immunohistochemistry was measured in brain areas related to sleep and motor control 6 months after MDMA treatment. CP-94,253 increased AW and PW, decreased SWS-2 and PS, and altered parameters of diurnal rhythm in control animals. CP-94,253 decreased the EEG power spectra at higher frequencies. The effects of CP-94,253 on AW and diurnal rhythm were reduced or eliminated in MDMA-treated animals. MDMA treatment decreased 5-HTT fibre density in posterior hypothalamus, tuberomammillary nucleus, caudate putamen and ventrolateral striatum. These data suggest that long-term changes in 5-HT(1B) receptor function occur after serotonergic damage caused by a single dose of MDMA.