Circadian Synchronization of Cognitive Functions


Environmental cues

Entrainment pathways

Pacemarker or master clock

Output pathways

Effectors

Circadian rhythms

Light/dark cycle

Social and physical activities

Feeding

RHT (glutamate, PACAP)

Pineal gland-SCN (melatonin)

Intergeniculate leaflet-SCN (neuropeptide Y)

SCN

SCN-PVN

SCN-LC

SCN-MPO

SCN-ARC

SCN-DMH

SCN-DMV

SCN-MBH

SCN-SC

Pineal gland

Hippocampus

Brain cortex

HPA axis

Heart

Liver

Other

Melatonin secretion

Sleep-wake cycle

Body temperature

Endocrine cycles

Attention

Synaptic plasticity



The day/night cycle is the stronger environmental zeitgeber and light excites specialized melanopsin-containing ganglion cells in the retina. From there, the retinohypothalamic tract (RHT) transmits a “daytime” signal toward the master clock in the SCN, thus the RHT, via glutamate, constitutes the entrainment pathway in mammals, humans among them. The SCN comprises individual neuronal oscillators coupled into a neural network. First it was thought that the SCN was composed of identical resettable oscillators, however, more recent investigations have shown that circadian rhythmicity in the SCN is the product of a highly organized network of heterogeneous cells [4].

The SCN, located in the anterior hypothalamus, maintains a near-24-h rhythm of electrical activity, even in the absence of environmental cues. This circadian rhythm is generated by intrinsic molecular mechanisms in the SCN neurons. However, the circadian clock is modulated by a wide variety of influences, including glutamate and pituitary adenylate cyclase-activating peptide (PACAP) from the RHT, melatonin from the pineal gland, and neuropeptide Y from the intergeniculate (Table 11.1 and Fig. 11.1). By virtue of these and other inputs, the SCN responds to environmental cues such as light, social, and physical activities. In turn, the SCN controls or influences a wide variety of physiologic and behavioral functions, including attention, endocrine cycles, body temperature, melatonin secretion, and the sleep−wake cycle [5]. Thus, projections from the SCN toward the paraventricular nucleus (PVN), the locus coeruleus, the medial preoptic area (MPO), the arcuate nucleus (ARC), the dorsomedial hypothalamus (DMH), the mediobasal hypothalamus (MBH), the dorsal motor nucleus of the vagus (DMV), and the spinal cord translate oscillating neural signals from the master clock to more widespread and multiple neural and humoral signals that reach the rest of the tissues and organs in the body (Table 11.1 and Fig. 11.1). For example, neural circadian signals from the PVN reach the pineal gland and regulate the secretion of nocturnal melatonin. Melatonin secretion is inhibited by the SCN during the light phase but, in turn, the SCN contains melatonin receptors that inhibit SCN firing, thereby creating a negative feedback loop [6].

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Fig. 11.1
Schematic representation of some SCN input and output pathways (modified from Kwom and collaborators [13]. RHT retino hypothalamic tract, OB olfactory bulb, SCN suprachiasmatic nucleus, PVN paraventricular nucleus, MBH mediobasal hypothalamus, DMH dorsomedial hypothalamus, PG pineal gland, Arc arcuate nucleus, LC locus ceruleus, SC spinal cord, CNS central nervous system

In external 24-h light–dark cycles, the circadian system synchronizes daily rhythms in the body to the changing environment. However, in the absence of zeitgebers (i.e., in constant external conditions) for example, the rhythms are endogenously driven and show a free running pattern of about 24 h in constant darkness [7].

A vasopressinergic projection from the PVN also reaches the CA2 area in the hippocampus. In turn, CA2 forms disynaptic connections with the entorhinal cortex to influence dynamic memory processing. Thus, the pathway SCN-PVN-CA2-entorhinal cortex would explain a circadian control of cognitive functions. Additionally, dorsal CA2 neurons send bilateral projections to the medial and lateral septal nuclei, vertical and horizontal limbs of the diagonal band of Broca, and supramamillary nuclei (SUM). Novel connections from the PVN and to the SUM suggest important regulatory roles for CA2 in mediating social and emotional input for memory processing [8].


The Molecular Clock Machinery


In addition to the clock in the SCN, peripheral oscillators have their own cellular and molecular clock machinery. In mammals, it consists of a network of interlocking transcriptional-translational feedback loops that drive the rhythmic expression of core clock components as well as of clock-controlled genes [9]. The molecular clock components are transcription factors that constitute the mechanism for generation and maintenance of circadian rhythms within individual cells throughout the body. The heterodimeric basic helix-loop-helix-Per Arnt Sim transcription factor, Brain and Muscle Aryl hydrocarbon receptor nuclear translocator-Like 1:Circadian Locomotor Output Cycles Kaput (BMAL1:CLOCK) is the main participant in the clock’s positive feedback loop by binding to the E-box (CACGTG) cis-regulatory enhancer elements, in their target genes. Such genes include Period (Per1, Per2, and Per3) and Cryptochrome (Cry1 and Cry2), as well as clock-controlled genes. A negative feedback loop is achieved when Per and Cry proteins form heterocomplexes that translocate back to the nucleus and inhibit their own and other clock-controlled gene transcription. In addition to the primary feedback loops, an auxiliary regulatory loop is achieved by the nuclear receptor subfamily 1 group D member 2 (also known as REV-ERB) and the Retinoic acid related orphan receptor (ROR). Circadian transcription of these nuclear receptors is also driven by the BMAL1:CLOCK heterodimer. In the nucleus of neural cells, REV-ERBα competes with RORα for binding to the ROR-responsive element in the BMAL1 gene promoter. Whereas RORα activates transcription of Bmal1, REV-ERBα represses it. Consequently, the rhythmic expression of Bmal1 is achieved by both positive (RORα) and negative (REV-ERBα) regulation [9, 10].

If transcriptional activation were only followed by feedback repression, a molecular feedback loop would take just a few hours to run a cycle. However, epigenetic and post-translational modifications are also involved in the normal functioning of the circadian (~24 h) clockwork. Therefore, if not for the significant delay mediated by such modifications between transcriptional activation and repression, 24-h circadian periodicity would not be achieved [10]. For instance, studies on molecular circadian clock machinery in different species disclose the participation of several protein kinases in circadian regulation. Thus, mammalian casein kinase members (CK1δ and CK1ε) are considered as part of the cellular clock. This affirmation comes from the fact that a mutation in the CK1ε gene results in a shorter free-running period of hamsters [11]. Studies made in humans by Toh and collaborators have also showed that families with familial advanced sleep-phase syndrome have mutations in the CK1δ and CK1ε phosphorylation sites in the Per2 gene [12, 13].

Phosphorylation is also needed for the recruitment of ubiquitin ligases and the subsequent degradation of Per. Experiments where CK1δ or CK1ε are overexpressed show moderately shortened Per1 and Per2 proteins half-lives. Phosphorylation of Per creates binding sites for β-transducin repeat-containing protein, an F-box-containing E3 ubiquitin ligase. Another F-box protein, Fbxl3, is a Cry E3 ligase. Mutation in Fbxl3 results in impaired ubiquitination and subsequent degradation of Cry. Consequently, prolonged stability of the Cry proteins leads to an extended negative phase and period lengthening [13]. Furthermore, the cAMP-dependent protein kinase and mitogen-activated protein kinase (MAPK) pathways are also implicated in the cAMP response element (CRE) mediated induction of Per1. In addition to the CRE binding protein-mediated induction, the phosphorylation of CLOCK by Ca2+-dependent Protein kinase C would be involved in the phase resetting of the mammalian circadian clock [13].

Post-translational modifications of BMAL1 include sumoylation, acetylation, and phosphorylation. Sumoylation is a post-translational modification involved in various cellular processes, such as nuclear-cytosolic transport, transcriptional regulation, apoptosis, protein stability, response to stress, and progression through the cell cycle. Small ubiquitin-like modifier proteins are a family of small proteins that are covalently attached to and detached from other proteins in cells to modify their function [14]. BMAL1 is rhythmically sumoylated in vivo, and the interaction with CLOCK is necessary for proper sumoylation. Lee and colleagues showed that sumoylation promotes BMAL1 transactivation and ubiquitin-dependent degradation [15]. Additionally, BMAL1 acetylation and phosphorylation by CK2α, are essential for the maintenance of its circadian rhythmicity, nuclear accumulation, and circadian clock function [13].

Circadian clock work is also influenced by the cellular redox state. Studies from Rutter and colleagues have shown that DNA-binding activity of BMAL1:CLOCK and BMAL1:NPAS2 heterodimers is regulated by the redox state of nicotinamide adenine dinucleotide (NAD) cofactors in a purified system. The reduced forms of the redox cofactors, NAD(H) and NAD phosphate(H), strongly enhance DNA binding of the BMAL1:CLOCK and NPAS2:BMAL1 heterodimers to the E-boxes, whereas the oxidized forms inhibit it [16]. It is known that the cellular redox state is determined by the levels of several redox couples such as 2GSH/GSSG, NADH/NAD, and NADPH/NADP, which are the product of a coordinated balance in metabolic pathways and antioxidant systems. All the above observations raise the possibility that oxidative stress and unbalance of the cellular redox state observed, for example, in older individuals, might have an effect on the clock activity and circadian expression of putative target genes, such as brain-derived neurotrophic factor (BDNF), RC3, APP, or PSEN, by modulation of BMAL:CLOCK DNA-binding activity in memory-and-learning-related areas of the brain.

Following the core clockwork, circadian clock output is mediated by cAMP/MAPK/CREB, some of the same molecular signaling cascades that regulate memory formation [17].


Circadian Chronotype


Based on their individual disposition to sleep and wakefulness, humans can be categorized as early chronotype (EC), late chronotype (LC), or intermediate chronotype. While ECs prefer to wake up early in the morning and find it hard to remain awake beyond their usual bedtime, LCs go to bed late and have difficulties getting up in the early morning. Beyond sleep-wake timings, chronotypes show distinct patterns of cognitive performance, gene expression, endocrinology, and lifestyle [18].

A variable number tandem repeat polymorphism in the clock gene Per3 would be a genetic determinant of those individual differences because Per3(5/5) individuals are more likely to show morning preference, whereas homozygosity for the four-repeat allele, Per3(4/4), associates with evening preferences. The association between sleep timing and the circadian rhythms of melatonin and Per3 mRNA in leukocytes is stronger in Per3(5/5) than in Per3(4/4). Other differential characteristics include: electroencephalographic alpha activity in rapid eye movement sleep, theta/alpha activity during wakefulness and slow wave activity in nonrapid eye movement sleep, which are elevated in Per3(5/5). It has also been observed that sleep deprivation leads to a greater cognitive decline, and a greater reduction in functional magnetic resonance imaging-assessed brain responses to an executive task, in Per3(5/5) individuals [19].

Genetic variations in other clock genes are also related to different sleep and circadian phenotypes [19]. For example, variants of the human CLOCK gene have been associated with diurnal preference, sleep duration and modulation of differential sleep disturbance patterns in mood disorders. Worthy of mentioning is a non-circadian role for clock genes in sleep homeostasis. Many studies cited in a comprehensive review made by Maire and colleagues found that the expression of a number of clock genes at the cortical level is affected by the sleep−wake history and that the homeostatic sleep regulation is altered in mice that are mutant for one or more clock genes [20]. Intriguingly, circadian clock genes can also act on homeostatic markers in humans [21].



The Temporal Organization of Cognitive Functions at the Molecular, Biochemical, and Behavioral Levels and Their Clock-Mediated Regulation


Early findings by Holloway and Wansley demonstrated that memory performances for associative learning oscillate in a circadian manner across time, with high memory retention at multiples of 24 h following learning [22]. Later, Stephan and Kovacevic reported that SCN lesions impair hippocampus-dependent long-term memory in rodents [23]. Hoffmann and Balschun demonstrated that mice trained on an alternating T-maze produced fewer errors and faster rates of acquisition when training takes place during the dark-(active) phase [24]. Similarly, habituation to spatial novelty is more robust during the mouse’s endogenous active phase [25]. More recently, time-of-day effects on learning and memory have also been observed in human primates, non-human primates, and rats [2628]. For example, several forms of cognition such as working memory, associative learning, declarative memory, motor skill learning, and fear conditioning vary on a circadian basis in both humans and rodents [2933].

The molecular basis of those and other behavioral rhythms are constituted by differences between day and night in the expression of gene transcripts in the hippocampus, cerebral cortex, and cerebellum. Katoh-Semba and colleagues reported significant diurnal variations of the BDNF levels in those brain areas as well as of both BDNF and neurotrophin 3 in the visual cortex [34]. The authors found the highest protein levels occur during sleep in both the neocortex and cerebellum. As expected, BDNF protein peak follows mRNA maximum which occurs during wakefulness (the dark phase) in the same brain areas [35]. All those observations would indicate that neurons in the neocortex and cerebellum are actively working during sleep. That was also supported by reports showing that cortical neurons still work during sleep to restructure new memory representations and to facilitate fixation of memory [36, 37]. Thus, given BDNF is a memory-related molecule, it is likely to play roles in forming, rearranging, and fixing memory during sleep. Furthermore, the patterns of diurnal variations in BDNF levels are characteristic for individual brain regions, different from the SCN [34].

Golini and colleagues found that not only BDNF, but also neurogranin (RC3), the postsynaptic substrate of protein kinase C, display rhythmic expression patterns in the rat hippocampus. Maximal RC3 expression occurs at the end of the night preceding BDNF mRNA peak, as in the cellular events which occurs for postsynaptic activation [38]. As expected, BDNF and RC3 rhythms are in phase with the circadian clock, BMAL1 and Per1, protein levels as well as with the maximal antioxidant enzyme activity shown by Fonzo and colleagues [39]. In turn, the nocturnal peaks of catalase (CAT) and glutathione peroxidase (GPx) activity seen in the rat hippocampus would be in phase with the best time for performing learning and memory tests, as shown in young rats by Winocur and Hasher [27, 39].

All the above-mentioned observations allow us to build an illustrative phase map (Fig. 11.2) and to propose the existence of a temporally well-orchestrated RC3 and BDNF cycle underlying temporal patterns of synaptic plasticity in the hippocampus [38].

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Fig. 11.2
Temporal organization in the hippocampus. Schematic phase map of daily rhythmic parameters that interact harmonically to determine the best time for cognitive performance in the hippocampus. Graph shows calculated phases of abundance for cycling mRNA (squares), protein (circles), enzymatic activity (triangles) and lipoperoxides (oval) throughout a 24-h period, 12-h day (white panels) and 12-h night (grey panel). ZT zeitgeber time (with ZT0 when light is on), RORA retinoic acid related orphan receptor, CAT catalase, GPx glutathione peroxidase, LPO lipoperoxidation, RC3 neurogranin, BDNF brain-derived neurotrophic factor

Cognitive performance is under the combined influence of circadian processes and homeostatic sleep pressure throughout the day. Homeostatic sleep pressure can be considered a sleep promoting process that continuously accumulates with increasing time spent awake, concomitantly with a decrease in waking cognitive performance [20]. As homeostatic sleep pressure increases, activity in the suprachiasmatic area decreases, indicating a direct influence of the homeostatic and circadian interaction on the neural activity underlying human behavior [40].

There exist substantial interindividual differences in the way an individual reacts to an imbalance between circadian and homeostatic processes, a situation provoked by, for example, total or partial sleep deprivation or by performing night or rotating shift work [20]. As mentioned previously, EC individuals perform best in the morning (beginning of the activity period), whereas LC individuals are more alert in the evening (end of the activity phase). Chronotypes provide a unique way to study the effects of sleep−wake regulation on the cerebral mechanisms supporting cognition. Using functional magnetic resonance imaging in extreme chronotypes, Schmidt and collaborators found that maintaining attention in the evening is associated with higher activity in a region of the locus coeruleus and in the suprachiasmatic area, including the circadian master clock in the SCN, in LC individuals than in EC individuals [40].

Increasing evidence suggests a genetic contribution on the individual’s vulnerability to cognitively perform under sleep homeostatic challenges or at an adverse circadian phase. In addition to age and chronotype, other reported variables potentially contributing to cognitive vulnerability are gene polymorphisms such as the adenosine deaminase, adenosine receptor A2A, BDNF, catechol-O-methyltransferase, and Per3 genes [20, 41].

A variety of neuroanatomical, neurophysiological, molecular, and neurochemical mechanisms have been revealed. The neuroanatomical circuit mediating circadian regulation of arousal is a multisynaptic pathway between the SCN and the noradrenergic neurons of the locus coeruleus. The behavioral state of arousal and wakefulness is induced by stimulation of the frontal cortex by noradrenergic neurotransmission arising from the locus coeruleus [42]. Particularly, circadian influence on learning may be exerted via cyclic gamma-aminobutyric acid output from the SCN to target sites involved in learning such as the septum and the hippocampus [32].


Circadian Hormonal Regulation: Role of Glucocorticoids in the Temporal Regulation of Memory and Learning


Learning-dependent remodeling of synaptic connections is important in learning and memory. For example, motor learning induces the formation of persistent postsynaptic dendritic spines, and the survival of these spines is strongly correlated with behavioral performance after learning. Recent studies indicate that glucocorticoids (GC) have rapid effects on dendritic spine development and plasticity in the mouse somatosensory cortex.

GC refers to a class of multifunctional adrenal steroid hormones with activity on glucose metabolism. The main GC, cortisol in humans and corticosterone in rats and mice, are synthesized by the zona fasciculata cells in the adrenal cortex. GC secretion varies phasically with stressful environmental triggers and tonically with the circadian rhythm [43]. GC levels display a robust oscillating pattern, with a peak occurring at the onset of the daily activity phase; thus, early in the morning in humans, and the beginning of the night in rats and mice [44].

Evidence strongly supports the notion that the periodicity of GC involves the integrated activity of multiple regulatory mechanisms related to circadian timing system along with the classical hypothalamus/pituitary/adrenal (HPA) neuroendocrine regulation. In the case of the adrenal gland, the SCN activates rhythmic release of corticotrophin-releasing hormone from the PVN that evokes circadian adrenocorticotropin hormone (ACTH) release from hypophysial adrenocorticotrophs. In turn, ACTH regulates circadian corticoid release from the zona glomerulosa and the zona fasciculata of the adrenal cortex. In addition, neuronal signals generated by the SCN propagate through the autonomic nervous system to the adrenal cortex to contribute to the circadian regulation of GC production. The adrenal-intrinsic oscillator as well as the central pacemaker in the SCN plays a pivotal role in GC rhythmicity [44, 45].

GC influences numerous biological processes such as metabolic, cardiovascular, immune, and even higher brain functions; however, it also acts as a resetting signal for the ubiquitous peripheral clocks, suggesting its importance in harmonizing circadian physiology and behavior [46]. Glucocorticoids influence synaptic glutamate release and receptor trafficking through nontranscriptional mechanisms and rapidly modulate the function of inhibitory interneurons in the prefrontal cortex through nontranscriptional regulation of endocannabinoid signaling [43].

An interesting finding is that training increases spine formation when it concurs with the circadian GC peak. Elevated GC secretion during the circadian peak facilitates the formation of stable new spines after learning, and thus, it would enhance long-term memory retention [43].

Learning-related new spines are initially highly unstable: most new spines will be pruned within days after their formation, but a subset will be selectively stabilized over time, and most of those that survive will contain functional synapses. GC selectively stabilizes a subset of learning-related spines during the circadian trough while pruning a corresponding set of preexisting synapses. Disruption of the circadian trough during a critical period after learning interferes with this stabilization and pruning process. Thus, circadian GC peak is important for forming new spines after training, whereas trough is required for stabilizing a subset of new spines during a critical time after their formation. Liston and collaborators investigated nontranscriptional mechanisms of GC action. To do that, they obtained mouse cortical biopsies 20–25 min after direct cortical application of corticosterone and examined changes in protein expression [43]. Cofilin is a known regulator of actin filament dynamics. Lin11, Isl-1 and Mec-3 (LIM) protein-kinase 1 (LIMK-1), a serine/threonine kinase containing LIM and postsynaptic density protein 95/disc large/zonula occludens (PDZ) domains, is able to phosphorylate cofilin at SER 3 [47]. Liston’s group results showed rapid increases in the expression of phosphorylated forms of LIMK-1 and its substrate cofilin. These results correlate with phospho-glucocorticoid receptor (GR) expression levels, a marker of GR activity. They observed comparable effects after coadministration of corticosterone and actinomycin D, an interferent of DNA transcription, indicating that the effect of glucocorticoids on spine formation is likely mediated through a nontranscriptional LIMK1-cofilin pathway. These signaling mechanisms may generate new spines through direct effects on the dendritic cytoskeleton by modulating neuronal network activity, or by some combination of both mechanisms [43].


Factors that Could Disrupt the Normal Functioning of the Circadian System and Contribute to the Etiology of Cognitive Disorders


Cognitive disorders associated with circadian dysfunction can have their origin at every level of the circadian synchronization pathway. Thus, interferences in the input pathways to the SCN, uncoupling of autonomous oscillators in the SCN, disruptions in the output signaling from the SCN to other parts of the brain [42, 48], or alterations in local circadian clocks in learning and memory-related areas may constitute the circadian basis of cognitive disorders [38, 49].

Normal functioning of the circadian system guarantees sleep, wakefulness, and activity as well as peaks of neural and hormonal rhythms occur at an appropriate endogenous biological time. Thus, the circadian system benefits cognitive functions throughout the lifespan. Yet, when circadian rhythms are phase shifted and, for example, wakefulness occurs at inappropriate biological times because of environmental pressures (e.g., early school start times, long work hours that include work at night, shift work, jet lag) or because of circadian rhythm sleep disorders, the resulting misalignment between circadian and wakefulness-sleep physiology leads to impaired cognitive performance, learning, emotion, and safety [50].

Light reaches the ganglion photoreceptors in the retina from where the signal is transmitted throughout the RHT which releases neurotransmitters such as glutamate and the PACAP to the photic-receptor cells in the ventrolateral SCN. In certain cases, such as transmeridian flights, shift work, and night work, the light–dark cycle is badly perceived leading to rhythm desynchronization. It has been observed that chronic jet lag produces atrophy of the temporal cortex and neuronal degeneration in the human brain [51].

Rhythm desynchronization occurs when the clock is no longer in phase (harmony) with the environment, resulting in a phase shift (phase advance or phase delay) which can produce fatigue, sleep and mood disorders, impaired mental and physical performance, and severely compromise long-term health. Clock desynchronization is related to a loss of adaptation between the SCN and the environmental synchronizers, to an inability for the SCN to be entrained, or to a dysfunction of the master clock itself [52]. Circadian disruption is more severe during adaptation to advances in local time because the circadian clock takes much longer to phase advance than delay [53].

In in vivo experiments, Reddy and collaborators demonstrated that the mouse Period (mPer) circadian expression in the SCN responds faster than the mouse Cryptochrome (mCry) mRNA circadian rhythm to an advance in the lighting schedule. Rhythmic mCry1 expression advances more slowly, in parallel to the gradual resetting of the activity–rest cycle. On the contrary, the speed of mPer and mCry response is faster during a delay in local time. Per and Cry expressions complete the phase shift together by the second cycle, in parallel with the activity–rest cycle.[53] In the authors’ words, these results reveal the potential for dissociation of mPer and mCry expression within the central oscillator during circadian resetting and a differential molecular response of the clock during advance and delay resetting. Uncoupling of autonomous oscillators in the SCN and disruptions in the output signaling from the SCN to other parts of the brain have been described by Yang and coworkers in patients with bipolar disorder [48].

There is evidence of alterations in local circadian clocks which affect learning and memory in related brain areas. For example, in a model of hamsters made arrhythmic by an experimental lighting protocol, Ruby and collaborators report impaired spatial memory and long-term object recognition. Taking into account that both the novel object recognition as well as the spontaneous alternation in the T-maze test require normally functioning hippocampal or septal-hippocampal circuits, the authors propose that memory impairments caused by circadian arrhythmia might derive from changes in the excitability of these circuits or conceivably in others that comprise the medial temporal lobe [32].

Circadian rhythms in clock gene expression are observed in many brain regions including those with roles in motivational and emotional state, learning, hormone release, and feeding [54]. Meal time, which can be experimentally modulated by restricting feeding to a few hours within the individual’s rest phase, is a potent synchronizer for peripheral oscillators with no clear synchronizing influence on the SCN clock [55]. In particular, restricted feeding (RF) schedules, which limit food availability to a single meal each day, lead to the induction and entrainment of circadian rhythms and food-anticipatory activities in rodents. Food-anticipatory activities include increases in core body temperature, activity, and hormone release in the hours before the predictable mealtime. RF schedules and the accompanying food-anticipatory activities are also associated with shifts in the daily oscillation of clock gene expression in diverse brain areas involved in feeding, energy balance, learning and memory, and motivation [54]. Thus, for instance, RF-induced anticipatory activity rhythm is associated with a phase-shift, from night or subjective night to day hours, of the circadian mPer1 and mPer2 mRNA peaks, in the cerebral cortex and hippocampus of mice [56].

Analysis of clock mutant mice has highlighted the relevance of some, but not all, of the clock genes for food-entrainable clockwork. Npas2-mutant or Cry1- and Cry2-deficient mice show more or less altered responses to restricted feeding conditions. Moreover, a lack of food anticipation is specifically associated with a mutation of Per2, demonstrating the critical involvement of this gene in the anticipation of meal time [55].

The statement that feeding is a synchronizer as powerful as light/dark cycles relies on many empirical observations on laboratory rodents or from studies on consumers [57, 58]. Feeding can exert its entrainment activity on peripheral clocks either through temporal windows of food access (in or out of phase with the nocturnal or diurnal nature of the species including or not a fasting period) either through the meal nutrient composition. Examples of the latter include the effects of hipocaloric diets, intake of d-glucose, fasting, insulin injection, and feeding vitamin-free diets on the circadian regulation of clock and clock-controlled genes in peripheral oscillators [38, 39, 58, 59].

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Apr 20, 2017 | Posted by in PSYCHOLOGY | Comments Off on Circadian Synchronization of Cognitive Functions

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