Biological rhythms, higher brain function, and behavior: Gaps, opportunities, and challenges

May combine two claims.

Disruption of circadian clock genes impairs the sleep/wake cycle and social rhythms, which may be implicated in mental disorders.

“further, disruption of circadian clock genes impairs sleep/wake cycle and social rhythms which may be implicated in mental disorders.”

May combine two claims.

Projections from the suprachiasmatic nucleus to the locus coeruleus are important for contextual fear conditioning, circadian regulation of the sleep-wake cycle, and synaptic plasticity including long-term potentiation.

“contextual fear conditioning, circadian regulation of the sleep-wake cycle (Gonzales and Aston-Jones, 2006), and synaptic plasticity including long-term potentiation- (Chaudhury et al., 2005; Chaudhury and Colwell, 2002).”

• cites Gonzales and Aston-Jones, 2006Not checked yet

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• cites Chaudhury et al., 2005 sourceNot checked yet

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• cites Chaudhury and Colwell, 2002Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

In prenatal rats, activation of dopamine receptors resets the developing circadian pacemaker.

“whereas in prenatal rats, activation of dopamine receptors resets the developing circadian pacemaker (Shearman and Weaver 2001).”

• cites Shearman and Weaver 2001Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Alterations in neuropeptide Y receptors produce anxiety-like phenotypes.

“Alterations in neuroeptide Y receptors produce anxiety-like phenotypes (Karl et al 2006)”

• cites Karl et al 2006 sourceNot checked yet

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Circadian dysfunction associated with psychiatric illnesses likely represents uncoupling of autonomous oscillators in the suprachiasmatic nucleus or disruptions in the output from the suprachiasmatic nucleus to other parts of the brain.

“Circadian dysfunction associated with psychiatric illnesses likely represents uncoupling of autonomous oscillators in the SCN or disruptions in the output from the SCN to other parts of the brain (Yang et al., 2008).”

• cites Yang et al., 2008 sourceNot checked yet

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Traditionally, sleep disruption has been considered a symptom of several psychiatric disorders, including bipolar disorder, schizophrenia, major depression, seasonal affective disorder, as well as mood, anxiety, and substance use disorders.

“Traditionally, sleep disruption has been considered to be a symptom of several psychiatric disorders, including bipolar disorder, schizophrenia, major depression, SAD, as well as mood, anxiety, and substance use disorders (Benca, 1996).”

• cites Benca, 1996 sourceNot checked yet

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Mutant mice lacking the Clock analogue Npas2 display deficits in learning of cued and contextual fear paradigms, suggesting that Npas2 plays a role in the acquisition of specific types of memory.

“Mutant mice lacking the Clock analogue Npas2 display deficits in learning of cued and contextual fear paradigms, suggesting that Npas2 plays a role in the acquisition of specific types of memory (Garcia et al., 2001).”

• cites Garcia et al., 2001Not checked yet

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Classified as probably not a substantial claim.

It remains possible that disordered sleep reflects impaired biological clock function which provokes the development and maintenance of psychiatric disorders in susceptible individuals.

“However, it remains possible that disordered sleep reflects impaired biological clock function which provokes the development and maintenance of psychiatric disorders in susceptible individuals (Mansour et al., 2005).”

• cites Mansour et al., 2005Not checked yet

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Animals with mutated Clock gene exhibit mania-like behaviors that can be rescued by expressing a functional Clock protein in the dopamine-rich ventral tegmental area.

“For example, animals with mutated Clock gene exhibit mania- like behaviors that can be rescued by expressing a functional Clock protein in the dopamine-rich ventral tegmental area-VTA (Royball et al., 2007).”

• cites Royball et al., 2007Not checked yet

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Exposure to stress alters expression of vasoactive intestinal peptide mRNA and disrupts circadian rhythms.

“whereas exposure to stress alters expression of vasoactive intestinal peptide (VIP) mRNA and disrupts circadian rhythms (Handa et al., 2007).”

• cites Handa et al., 2007 sourceNot checked yet

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Loss of the SLEEPLESS protein reduced sleep by more than 80%, whereas reduced SLEEPLESS protein had little effect on baseline sleep but impaired rebound sleep.

“Loss of the SLEEPLESS protein reduced sleep by >80%, whereas reduced SLEEPLESS protein had little effect on baseline sleep, but impaired rebound sleep.”

• cites Koh et al., 2008 sourceNot checked yet

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Fibroblasts from bipolar patients and healthy individuals show reduced amplitudes and overall expression levels of some circadian genes, and decreased phosphorylation level of GSK3β, which may lead to dysregulation of downstream genes and might account for some pathological features of bipolar disorder.

“Their results suggest that reduced amplitudes and overall expression levels of some circadian genes, and the decreased phosphorylation level of GSK3β, may lead to dysregulation of downstream genes, which might account for some pathological features of bipolar disorder.”

• cites Yang et al., 2008 sourceNot checked yet

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Circadian cycles may be driven by metabolic cycles, supported by ubiquitous expression of oxidative-phosphorylation genes that oscillate in a circadian fashion in the SCN, circadian clock-driven periodic expression of many metabolic genes, and a strong parallel between metabolic cycles and circadian cycles.

“Additional evidence for the idea that circadian cycles may be driven by metabolic cycles includes the ubiquitous expression of oxidative-phosphorylation genes that oscillate in a circadian fashion in the SCN, the circadian clock-driven periodic expression of many metabolic genes, and the strong parallel between metabolic cycles and circadian cycles (Tu et al., 2005).”

• cites Tu et al., 2005Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

PGC-1α has been proposed as a link between the mammalian circadian clock and energy metabolism.

“Recently, the transcriptional coactivator PGC-1α has been proposed as a link between the mammalian circadian clock and energy metabolism (Liu et al., 2007).”

• cites Liu et al., 2007 sourceNot checked yet

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Norepinephrine is important in regulating vertebrate sleep, whereas octopamine appears important in regulating sleep and several other cognitive and affective responses in flies.

“Norpineine is important in regulating vertebrate sleep (Hunsley and Palmiter, 2004), whereas octopamine, an invertebrate homolog to norepinephrine (Roeder, 2005), appears important in regulating sleep, as well as several other cognitive and affective responses in flies.”

• cites Hunsley and Palmiter, 2004Not checked yet

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• cites Roeder, 2005 sourceNot checked yet

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In rats, prolonged light deprivation leads to loss of noradrenergic fibers in the frontal cortex, decreased amplitude of the sleep-wake rhythms, and delayed onset of activity periods.

“In rats, prolonged light deprivation leads to loss of noradrenergic fibers in the frontal cortex, decreased amplitude of the sleep-wake rhythms, and delayed onset of activity periods (Gonzalez and Aston- Jones, 2006).”

• cites Gonzalez and Aston-Jones, 2006Not checked yet

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Both the endogenous circadian timing system and exposure to ambient light influence cognition and affective state.

“Both the endogenous circadian timing system and exposure to ambient light are known to influence cognition and affective state (Chaudhury and Colwell, 2002; Chen et al., 2008; Gonzalez and Aston-Jones, 2008; Hampp et al., 2008; Ruby et al., 2008).”

• cites Chaudhury and Colwell, 2002Not checked yet

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• cites Chen et al., 2008 sourceNot checked yet

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• cites Gonzalez and Aston-Jones, 2008Not checked yet

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May combine two claims.

Decreases in noradrenergic activity, as well as serotonergic activity, are associated with depression.

“Decreases in noradrenergic activity, as well as serotonergic activity, are associated with depression.”

• AssumptionRests on an assumption: Decreases in noradrenergic activity, as well as serotonergic activity, are associated with depression.

May combine two claims.

Mood and affective disorders are associated with impairments in cognition, including deficits in attention and memory, which are exacerbated by aging.

“Mood and affective disorders are associated with impairments in cognition, including deficits in attention and memory, which are exacerbated by aging (Jorm, 2000; Kumar et al., 2006).”

• cites Jorm, 2000 sourceNot checked yet

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• cites Kumar et al., 2006 sourceNot checked yet

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The ability to learn and remember varies over the course of the day and has been shown under controlled conditions to exhibit bona fide circadian rhythms.

“The ability to learn and remember varies over the course of the day and has been shown under controlled conditions to exhibit bona fide circadian rhythms (Chaudhury and Colwell, 2002), i.e., ~24-h rhythms that are endogenously generated and can be entrained by the ambient light:dark cycle.”

• cites Chaudhury and Colwell, 2002Not checked yet

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Neurons in the suprachiasmatic nucleus project to the dorsomedial hypothalamus, which in turn projects to the locus coeruleus.

“As shown by neuroanatomical tract-tracing as well as lesion studies, the neurons in the SCN, which receives retinal input, project to the dorsomedial hypothalamus (DMH), which in turn projects to the LC (Aston-Jones et al., 2001; Deurveilher and Semba, 2005).”

• cites Aston-Jones et al., 2001 sourceNot checked yet

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• cites Deurveilher and Semba, 2005Not checked yet

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Long-term light deprivation induces apoptosis of locus coeruleus noradrenergic neurons and increases immobility in the forced swim test; treatment with the antidepressant desipramine alleviates both of these effects.

“In addition, long-term light deprivation induces apoptosis of LC noradrenergic neurons and increases immobility in the forced swim test, an indicator of depressive-like condition; treatment with the antidepressant, desipramine, alleviates both of these effects (Gonzalez and Aston-Jones, 2008).”

• cites Gonzalez and Aston-Jones, 2008Not checked yet

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May combine two claims.

Depression is characterized not only by feelings of sadness and worthlessness, but also by inertia, lethargy, and impaired cognition that is more prevalent in the elderly.

“Depression is characterized not only by feelings of sadness and worthlessness, but also by inertia, lethargy, and impaired cognition that is more prevalent in the elderly (Geda et al., 2006) (Jorm, 2000; Kumar et al., 2006).”

• cites Geda et al., 2006 sourceNot checked yet

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• cites Jorm, 2000 sourceNot checked yet

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• cites Kumar et al., 2006 sourceNot checked yet

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Lesions of the dorsomedial hypothalamus eliminate the circadian rhythm in locus coeruleus neuronal activity, whereas lesions of the locus coeruleus decrease the amplitude of circadian rhythms of slow-wave activity in the cortex.

“The functional importance of this circuit was demonstrated by the findings that lesions of the DMH eliminate the circadian rhythm in LC neuronal activity, whereas lesions of the LC decrease the amplitude of circadian rhythms of slow-wave activity in the cortex (Aston-Jones et al., 2001).”

• cites Aston-Jones et al., 2001 sourceNot checked yet

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Probably not a substantial claim: may not pass S4 (based). May combine two claims.

Circadian rhythms govern sleep-wake cycles and also rhythms in cognitive processes including subjective alertness, mathematical ability, and memory.

“Circadian rhythms not only govern sleep-wake cycles but also rhythms in cognitive processes including subjective alertness, mathematical ability and memory.”

May combine two claims.

During the phasic mode, locus coeruleus neuronal activity is characterized by a moderate baseline firing rate, large phasic responses, and transient increases in gain after task-relevant events, all of which favor task-focused behavior.

“During the phasic mode, the characteristics of LC neuronal activity include a moderate baseline firing rate, large phasic responses, and transient increases in gain after task-relevant events, all of which favor task-focused behavior.”

May combine two claims.

VIP-deficient mice exhibit lower levels of recall, but retain circadian rhythms of recall, even in the absence of circadian rhythms in wheel running behavior.

“Although the VIP-deficient mice exhibit lower levels of recall, they retain circadian rhythms of recall, even in the absence of circadian rhythms in wheel running behavior.”

• cites Chaudhury et al., 2008 sourceNot checked yet

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During the tonic mode, locus coeruleus neuronal activity is characterized by a higher baseline firing rate, diminished or absent phasic responses to task-relevant events, and indiscriminate increases in gain, including increased responsiveness to noise; these characteristics favor distractibility and exploration.

“In contrast, during the tonic mode, LC neuronal activity is characterized by a higher baseline firing rate, diminished or absent phasic responses to task-relevant events, and indiscriminate increases in gain, including increased responsiveness to noise. The characteristics of the tonic mode favor distractibility and exploration.”

May combine two claims.

Photoperiod regulates the circadian rhythm in pineal secretion of melatonin, which in turn regulates seasonal changes in reproduction, metabolism, and behavior.

“Photoperiod regulates the circadian rhythm in pineal secretion of melatonin, which in turn regulates seasonal changes in reproduction, metabolism, and behavior a (Goldman and Nelson, 1993).”

• cites Goldman and Nelson, 1993Not checked yet

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In humans, the incidence of depression and impairments in cognitive function, most notably spatial memory, are higher among the elderly.

“In humans, the incidence of depression and impairments in cognitive function, most notably spatial memory, are higher among the elderly (Geda et al, 2006; Jorm, 2000; Kumar et al., 2006).”

• cites Geda et al, 2006 sourceNot checked yet

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• cites Jorm, 2000 sourceNot checked yet

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• cites Kumar et al., 2006 sourceNot checked yet

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Classified as probably not a substantial claim. May combine two claims.

Reports that selective serotonin dennervation of the hamster suprachiasmatic nucleus mimics some aging effects led to the hypothesis that aging might be associated with decreased serotonergic neurotransmission in the suprachiasmatic nucleus.

“Reports that selective serotonin dennervation of the hamster SCN mimics some of these aging effects (Meyer-Bernstein and Morin, 1998) led to the hypothesis that aging might be associated with decreased serotonergic neurotransmission in the SCN.”

• cites Meyer-Bernstein and Morin, 1998Not checked yet

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Aging is associated with decrements in the circadian rhythms, including decreased amplitude, fragmentation or loss of rhythms, alterations in entrainment, and decreased sensitivity to phase resetting signals, including light and nonphotic signals.

“Interestingly, aging is also associated with decrements in the circadian rhythms, including decreased amplitude, fragmentation or loss of rhythms, alterations in entrainment, and decreased sensitivity to phase resetting signals, including light and nonphotic signals, e.g., benzodiazepines and serotonergic drugs [reviewed in(Hofman and Swaab, 2006) and (Duncan, 2007)].”

• cites Hofman and Swaab, 2006Not checked yet

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• cites Duncan, 2007 sourceNot checked yet

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These behaviors are influenced not only by acute short-day photoperiod exposure but also by prenatal melatonin exposure in utero, suggesting that photoperiodic exposure of the mother during gestation may organize the developing brain via exposure to the mother's melatonin rhythms, influencing subsequent adult affective responses.

“These behaviors are influenced not only by acute short-day photoperiod exposure but also by prenatal melatonin exposure in utero, suggesting that photoperiodic exposure of the mother during gestation may organize the developing brain via exposure to the mother’s melatonin rhythms , influencing subsequent adult affective responses (Workman et al., 2008).”

• cites Workman et al., 2008 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

The short-day photoperiod induction of anxiety- and depressive-like behaviors is associated with increased serotonin transport in the midbrain, consistent with the therapeutic use of selective serotonin re-uptake inhibitors to combat anxiety and depression in humans.

“It is also interesting to note that the short-day photoperiod induction of anxiety- and depressive-like behaviors is associated with increased serotonin transport in the midbrain, consistent with the therapeutic use of selective serotonin re-uptake inhibitors (SSRIs) to combat anxiety and depression in humans.”

May combine two claims.

In rodents such as white-footed mice, exposure to a short-day, winter-like photoperiod impairs spatial learning and alters hippocampal plasticity, such as dendritic spine density and decreased long-term potentiation in the CA1.

“In rodents, such as white-footed mice, exposure to a short-day, winter-like, photoperiod impairs spatial learning and alters hippocampal plasticity, such as dendritic spine density and decreased LTP in the CA1 (Pyter et al., 2005; Pyter et al., 2008) .”

• cites Pyter et al., 2005Not checked yet

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• cites Pyter et al., 2008 sourceNot checked yet

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Melatonin not only mediates seasonal changes, but also influences circadian rhythms and sleep.

“Melatonin not only mediates seasonal changes, but also affects influences circadian rhythms and sleep [see (Dubocovich, 2007), for review].”

• cites Dubocovich, 2007 sourceNot checked yet

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In the hamster suprachiasmatic nucleus, aging is accompanied by increases in both the serotonin terminal autoreceptors, 5-HT1B receptors, and the serotonin transporter binding sites, alterations that are likely to decrease suprachiasmatic nucleus extracellular serotonin levels.

“Indeed, in the hamster SCN, aging is accompanied by increases in both the serotonin terminal autoreceptors, 5-HT1B receptors, and the serotonin transporter (SERT) binding sites, alterations that are likely to decrease SCN extracellular serotonin levels (Duncan et al., 2000).”

• cites Duncan et al., 2000 sourceNot checked yet

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The relationship of LTP during waking to increased production of slow waves in sleep is likely relevant for depression, in that most effective antidepressants increase expression of plasticity-related genes much like sleep deprivation, although on a longer time course.

“The relationship of LTP during waking to increased production of slow waves in sleep is likely relevant for depression, in that most effective antidepressants increase expression of plasticity-related genes (reviewed in Duman, 2002; Payne et al., 2002) much like sleep deprivation (Cirelli et al., 2004), although on a longer time course.”

• cites Duman, 2002 sourceNot checked yet

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• cites Payne et al., 2002 sourceNot checked yet

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• cites Cirelli et al., 2004 sourceNot checked yet

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At the beginning of the sleep period, slow wave amplitude is high and the average slope of individual slow waves is steep, indicating high overall synaptic strength; at the end of the night, both slope and amplitude are decreased as synapses weaken.

“At the beginning of the sleep period, slow wave amplitude is high and the average slope of individual slow waves is steep, indicating high overall synaptic strength, but at the end of the night, both slope and amplitude are decreased, as synapses weaken.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Sleep is one of the most important behaviors influenced by the circadian system, and specific changes in sleep patterns, as well as circadian rhythms, have been described in a number of neuropsychiatric disorders, most notably mood disorders.

“Sleep is one of the most important behaviors influenced by the circadian system, and specific changes in sleep patterns, as well as circadian rhythms, have been described in a number of neuropsychiatric disorders, most notably mood disorders.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Sleep reverses the "costs" of being awake, which accrue from the build-up of synaptic strength in the brain through long-term potentiation and include increased energy utilization, increased neuropil density, increased need for cellular supplies, and saturation of the ability to learn.

“Tononi and Cirelli have proposed that sleep reverses the “costs” of being awake, which accrue from the build-up of synaptic strength in the brain through the process of long-term potentiation (LTP) and include increased energy utilization, increased neuropil density, increased need for cellular supplies and saturation of the ability to learn (Tononi and Cirelli, 2003).”

• cites Tononi and Cirelli, 2003 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Abnormalities in sleep homeostasis may somehow be related to depression.

“suggesting the possibility that abnormalities in sleep homeostasis may somehow be related to depression.”

• AssumptionRests on an assumption: Depression is characterized by decrements in slow wave sleep and slow wave activity.

May combine two claims.

Prolonged waking decreases the ability to induce further long-term potentiation in various models, which in turn should inhibit learning.

“Prolonged waking decreases the ability to induce further LTP in various models, which in turn should inhibit learning (Vyazovskiy et al., 2008);”

• cites Vyazovskiy et al., 2008 sourceNot checked yet

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An increase in synaptic potentiation may explain the antidepressant effects of acute sleep deprivation, and synaptic downscaling by slow waves during sleep may explain the rapid reversal of these antidepressant effects by even short bouts of recovery sleep.

“Thus an increase in synaptic potentiation may explain the antidepressant effects of acute sleep deprivation, and synaptic downscaling by slow waves during sleep the rapid reversal of these antidepressant effects by even short bouts of recovery sleep.”

Probably not a substantial claim: may not pass S4 (based).

Relationships between circadian rhythms and sleep may contribute to normal and abnormal behaviors.

“Recent work suggests that relationships between circadian rhythms and sleep may contribute to normal and abnormal behaviors.”

May combine two claims.

Aging alters serotonin neurotransmission in the dorsal raphe nucleus, which communicates indirectly with the suprachiasmatic nucleus as well as with many forebrain regions.

“Aging also alters serotonin neurotransmission in a midbrain region, the dorsal raphe nucleus (DRN), which communicates indirectly with the SCN as well as with many forebrain regions.”

May combine two claims.

The homeostatic sleep process is thought to regulate the amount of sleep obtained and is likely related to the function of sleep.

“The homeostatic sleep process is thought to regulate the amount of sleep obtained and is likely related to the function of sleep;”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Although circadian rhythms influence the timing of sleep and wakefulness across the day, a number of other factors regulate patterns of sleep, including developmental and environmental effects.

“Although circadian rhythms certainly influence the timing of sleep and wakefulness across the day, a number of other factors regulate patterns of sleep, including developmental and environmental effects.”

May combine two claims.

The most important determinant of sleep behavior is the homeostatic drive for sleep; the longer an organism is awake, the greater the pressure to sleep.

“Perhaps the most important determinant of sleep behavior, however, is the homeostatic drive for sleep; the longer an organism is awake, the greater the pressure to sleep.”

• AssumptionRests on an assumption: The most important determinant of sleep behavior is the homeostatic drive for sleep.

May combine two claims.

The age-related loss of 5-HT7 receptors in the dorsal raphe nucleus may represent down regulation caused by decreased serotonin transporter binding sites, which in turn may help to elucidate the reduced efficacy of selective serotonin re-uptake inhibitors in alleviating depression in the elderly.

“The age-related loss of 5-HT7 receptors in the DRN may represent down regulation caused by decreased SERT binding sites (Duncan and Hensler, 2002), which in turn may help to elucidate the reduced efficacy of SSRIs in alleviating depression in the elderly.”

• cites Duncan and Hensler, 2002Not checked yet

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Aging selectively decreases 5-HT7 receptors in the hamster dorsal raphe nucleus, strongly attenuating circadian phase shifts induced by microinjection of serotonergic agonists in this region.

“Aging selectively decreases 5- HT7 receptors in the hamster DRN, strongly attenuating circadian phase shifts induced by microinjection of serotonergic agonists in this region (Duncan et al., 1999; Duncan et al., 2004).”

• cites Duncan et al., 1999 sourceNot checked yet

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• cites Duncan et al., 2004 sourceNot checked yet

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Individuals with a variable-number tandem-repeat polymorphism of Per3 display elevated slow wave sleep and slow wave activity and more severe cognitive decrements in response to sleep deprivation than unaffected individuals.

“Individuals with a variable-number tandem-repeat polymorphism of Per3 display elevated slow wave sleep and slow wave activity and more severe cognitive decrements in response to sleep deprivation than unaffected individuals (Viola et al., 2007).”

• cites Viola et al., 2007 sourceNot checked yet

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Sleep and circadian rhythm abnormalities have been implicated in depression and bipolar disorder, attention-deficit disorder, and autism.

“Sleep and circadian rhythm abnormalities in children and adolescents may be risk factors for the development of psychiatric disorders, and have been implicated in depression and bipolar disorder (Harvey et al 2006), attention-deficit disorder (Owens 2008) and autism (Bourgeron 2007).”

• cites Harvey et al 2006 sourceNot checked yet

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• cites Owens 2008 sourceNot checked yet

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• cites Bourgeron 2007 sourceNot checked yet

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The consistency of sleep-waking patterns across species of adult mammals suggests similarities in the underlying neural control of sleep organization, which may include both homeostatic and circadian features.

“the consistency of these patterns across species of adult mammals suggest similarities in the underlying neural control of sleep organization, which may include both homeostatic and circadian features.”

May combine two claims.

Adult mammals, including rats, cats and humans, display brief waking bouts during the sleep period that show a power law distribution, whereas sleep bout durations are exponentially distributed.

“Adult mammals, including rats, cats and humans, display brief waking bouts during the sleep period that show a power law distribution, whereas sleep bout durations are exponentially distributed (Lo et al., 2004).”

• cites Lo et al., 2004Not checked yet

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In rats, the general organization of cycling between quiet and active sleep can be detected at least several days before postnatal day 11 and remains stable.

“Studies in rats have shown that although delta rhythm and other typical EEG features of quiet (NREM) and active (REM) sleep do not appear until postnatal day 11, the general organization of cycling between quiet and active sleep can be detected at least several days earlier, and remains stable (Seelke and Blumberg, 2008).”

• cites Seelke and Blumberg, 2008Not checked yet

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During adolescence, slow wave activity declines, possibly in relation to the synaptic pruning that occurs during this period of development.

“During adolescence, slow wave activity declines (Jenni and Carskadon, 2004), possibly in relation to the synaptic pruning that occurs during this period of development.”

• cites Jenni and Carskadon, 2004Not checked yet

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Circadian rhythms are likely expressed and functional earlier than previously thought, although their development may be shaped by early environmental influences.

“Circadian rhythms are likely expressed and functional earlier than previously thought, although their development may be shaped by early environmental influences.”

May combine two claims.

Circadian and/or seasonal rhythm abnormalities may be a core feature in some patients with mood disorders and provide an opportunity for identification of at-risk individuals and/or targets for therapeutic interventions.

“Circadian and/or seasonal rhythm abnormalities may be a core feature in some patients with mood disorders and provide an opportunity for identification of at-risk individuals and/or targets for therapeutic interventions.”

May combine two claims.

White-crowned sparrows decrease their overall sleep time by almost 2/3 during migratory restlessness in comparison to their winter, nonmigratory condition, without showing typical behavioral effects of sleep deprivation.

“Sleep EEG studies have shown that they decrease their overall sleep time by almost 2/3 during migratory restlessness in comparison to their winter, nonmigratory condition, without showing typical behavioral effects of sleep deprivation (Rattenborg et al., 2004).”

• cites Rattenborg et al., 2004 sourceNot checked yet

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Bouts of depression are more common during the fall and winter, and peaks of mania tend to occur in the spring and summer.

“Bouts of depression are more common during the fall and winter, and peaks of mania tend to occur in the spring and summer.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Those with greater tendency to delay circadian rhythms in adolescence may be more likely to become sleep restricted.

“Those with greater tendency to delay circadian rhythms in adolescence may be more likely to become sleep restricted.”

May combine two claims.

Over 90% of schizophrenic subjects show a dramatic reduction in sleep spindles, suggesting dysfunction in the reticular nucleus of the thalamus.

“For example, over 90% of schizophrenic subjects show a dramatic reduction in sleep spindles, suggesting dysfunction in the reticular nucleus of the thalamus (Ferrarelli et al., 2007).”

• cites Ferrarelli et al., 2007 sourceNot checked yet

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Classified as probably not a substantial claim.

If specific sleep EEG "fingerprints" for neuropsychiatric disorders can be determined, they may provide an opportunity to identify at-risk individuals.

“If specific sleep EEG “fingerprints” for neuropsychiatric disorders can be determined, they may provide an opportunity to identify at-risk individuals.”

May combine two claims.

Treatment with SSRIs restores the circadian rhythm and appears to be effective in controlling the episodes of nocturnal eating.

“Treatment with SSRIs restores the circadian rhythm and it appears to be effective in controlling the episodes of nocturnal eating (Miyaoka et al., 2003; O'Reardon et al., 2005; Stunkard et al., 2006).”

• cites Miyaoka et al., 2003Not checked yet

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• cites O'Reardon et al., 2005 sourceNot checked yet

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• cites Stunkard et al., 2006 sourceNot checked yet

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Clock mutant mice show weight gain, particularly on a high fat diet, and changes in the expression of feeding-related hormones and peptides in the body.

“This includes weight gain, particularly on a high fat diet, and changes in the expression of feeding-related hormones and peptides in the body.”

• cites Naylor et al., 2000 sourceNot checked yet

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• cites Turek et al., 2005Not checked yet

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Mice that have a mutation in the Clock gene spend less time in all phases of sleep, and have a number of symptoms indicative of metabolic disorder.

“In addition, mice that have a mutation in the Clock gene spend less time in all phases of sleep, and have a number of symptoms indicative of metabolic disorder (Naylor et al., 2000; Turek et al., 2005).”

• cites Naylor et al., 2000 sourceNot checked yet

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• cites Turek et al., 2005Not checked yet

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Glutamate receptor 6 (GluR6) knock-out mice are hyperactive, have an increased response to amphetamine, have low anxiety-related behaviors, and have lower depression-like behavior.

“Indeed, Glutamate receptor 6 (GluR6) knock-out mice are hyperactive, have an increased response to amphetamine, have low anxiety-related behaviors, and have lower depression-like behavior (Shaltiel et al., 2008).”

• cites Shaltiel et al., 2008 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The Clock gene is one of the central components of the circadian machinery.

“This includes the identification of the Clock gene which is one of the central components of the circadian machinery (King et al., 1997).”

• cites King et al., 1997 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Lithium treatment reduced GluR6 knock-out mice hyperactivity, increased anxiety, and reduced aggressive behavior.

“Lithium treatment was able to reduce their hyperactivity, increase anxiety, and reduce their aggressive behavior.”

• cites Shaltiel et al., 2008 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Such interventions suggest possible relationships with 5-HT transporter changes, supported by SPECT studies.

“Such interventions suggest possible relationships with 5-HT transporter changes, supported by SPECT studies (Lundgren et al., 2008).”

• cites Lundgren et al., 2008 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

The manic-like profile of Clock mutant mice includes hyperactivity, lowered depression-like behavior, greater risk taking behavior, an increase in the preference for sucrose and cocaine, and an increase in goal-directed behavior resulting in intracranial self-stimulation.

“This includes hyperactivity, lowered depression-like behavior, greater risk taking behavior, an increase in the preference for sucrose and cocaine, and an increase in goal-directed behavior resulting in intracranial self-stimulation.”

• cites McClung et al., 2005 sourceNot checked yet

  Not checked in the free run.

• cites Roybal et al., 2007 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Feeding mice a high fat diet alters the circadian period and attenuates the diurnal pattern of feeding behavior.

“In concert with these findings, simply feeding mice a high fat diet alters the circadian period and attenuates the diurnal pattern of feeding behavior (Kohsaka et al., 2007).”

• cites Kohsaka et al., 2007 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Recent reports suggest that sleep problems, mood problems and obesity are "interacting epidemics".

“Indeed recent reports suggest that sleep problems, mood problems and obesity are “interacting epidemics” (Laposky et al., 2008).”

• cites Laposky et al., 2008 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based).

Cultured human fibroblasts derived from biopsies express sustained circadian rhythms similar to cultured SCN neurons from rodents.

“For instance, cultured human fibroblasts derived from biopsies express sustained circadian rhythms similar to cultured SCN neurons from rodents.”

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

Treatments for bipolar disorder that combine pharmacotherapy with interpersonal and social rhythm therapy demonstrate that social rhythm stabilization speeds recovery from acute bipolar depression and delays the recurrence of both manic and depressive episodes.

“Treatments for bipolar disorder that combine pharmacotherapy with interpersonal and social rhythm therapy demonstrate that social rhythm stabilization speeds recovery from acute bipolar depression and delays the recurrence of both manic and depressive episodes.”

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

The circadian genes appear to be involved in the regulation of mood, sleep, and metabolism, perhaps through their functions outside of the SCN.

“Furthermore, the circadian genes appear to be involved in the regulation of mood, sleep, and metabolism, perhaps through their functions outside of the SCN.”

Classified as probably not a substantial claim.

Disruptions in social zeitgebers produce disturbances in circadian rhythms that may increase vulnerability to mood disorders.

“Studies investigating how disruptions in social zeitgebers produce disturbances in the circadian rhythms that may increase vulnerability to mood disorders warrant more integrative and systems level approaches.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

GSK3-β gene polymorphisms influence responses to lithium treatment.

“while GSK3-β gene polymorphisms influence responses to lithium treatment.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Patients with bipolar and sleep disorders may also benefit from proper rhythm alignment.

“Patients with bipolar and sleep disorders may also benefit from proper rhythm alignment.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Casein kinase 1 epsilon/delta may be an interesting target for drug design for rhythm modifications.

“Recent studies find that casein kinase 1 epsilon/delta may be an interesting target for drug design for rhythm modifications.”

Classified as probably not a substantial claim. May combine two claims.

The ability of circadian oscillators in the SCN to produce sustained and synchronous cellular rhythmicity in both central and peripheral tissues and to produce efficient integration of molecular with behavioral rhythms throughout the body indicates the importance of using systems level and integrative approaches.

“The ability of circadian oscillators in the SCN to produce sustained and synchronous cellular rhyhtmicity in both central and peripheral tissues and to produce efficient integration of molecular with behavioral rhythms throughout the body indicates the importance of using systems level and integrative approaches to elucidate the neural bases underlying the role of circadian oscillators in learning”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

A single nucleotide polymorphism (SNP) in the 3' flanking region of the Clock gene influences diurnal preference in healthy human subjects.

“a single nucleotide polymorphism-SNP in the 3’ flanking region of the Clock gene influences diurnal preference in healthy human subjects”

May combine two claims.

The proper shifting of rhythms in individual SAD patients is necessary for therapeutic effects, suggesting a real circadian basis for SAD.

“A recent study reported that the proper shifting of rhythms in individual SAD patients is necessary for therapeutic effects suggesting a real circadian basis for SAD (Lewy et al., 2006).”

• cites Lewy et al., 2006 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Long-term changes in neural circuits are implicated in affective disorders.

“long term changes in neural circuits that are implicated in affective disorders”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). The quote only partly states this claim.

The interplay between the circadian clock and serotonin transporters appears to play a role in the positive effects of light exposure in bipolar patients.

“as well as positive effects of light exposure in bipolar patients.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Studies on the interaction between the CLOCK protein and the VTA dopaminergic neurons provide an excellent model for studying mania-like phenotypes.

“Studies on the interaction between the CLOCK protein and the VTA dopaminergic neurons provide an excellent model for studying mania-like phenotypes.”

Probably not a substantial claim: may not pass S4 (based).

Casein kinase 1ε/δ phosphorylates the Period and Cryptochrome proteins, leading to control of circadian timing.

“Casein kinase 1ε/δ phosphorylates the Period and Cryptochrome proteins, leading to control of circadian timing.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The interplay between the circadian clock and serotonin transporters appears to play a role in the positive effects of total sleep deprivation in depressed individuals.

“the interplay between the circadian clock and serotonin transporters appears to play a role in positive effects of total sleep deprivation in depressed individuals”

Probably not a substantial claim: may not pass S4 (based).

Bipolar and depressed patients show apparent sensitivity to light.

“To elucidate the mechanisms of the apparent sensitivity to light in bipolar and depressed patients, it would be necessary to carry out multi-level interdisciplinary research studies investigating clock gene polymorphisms associated with affective disorders.”