|The SCN and other hypothalamic nuclei sync circadian rythms,
like waking and sleeping, to a 24 hour light-dark cycle
ImageSource: Horacio de la Iglesia, fac.org
Located in the hypothalamus is the suprachiasmatic nucleus (SCN): the body’s master clock, which, among other things, governs one’s sleep-wake cycle, secretion of cortisol and core body temperature. It also modulates behavioural states like arousal and feeding. To accomplish this, the SCN projects to other hypothalamic nuclei and communicates and coordinates with many oscillators in peripheral tissue. The lateral hypothalamus and paraventricular nucleus serve as important regions of influence. They communicate with the SCN and other rhythmic systems like the HPA-axis and can elicit motivated behaviours. The activity of neuropeptides in hypothalamic nuclei, namely orexin/hypocretin, is emerging as an important strategy by which the brain maintains energy homeostasis.
While the SCN relies predominantly on photic entrainment, peripheral clocks must be entrained by nonphotic cues. Importantly among them is one’s feeding schedule, which can have dramatic effects on one’s liver, pancreas and other organs. Thus, food-entrainable oscillators (FEOs) are important mechanisms of homeostasis. The discovery of FEOs elucidates the fact that the circadian regulation of hormone secretion and behaviour is reciprocal.
That is: while endogenous oscillators influence behaviour, so too can these oscillators be affected by behaviours
like feeding, sleep duration and stress.
Misalignment in the integration of the SCN and peripheral clocks is associated with a variety of metabolic and affective disorders.
With obesity, major depressive disorder and other pathologies on the rise, it is crucial to understand how one’s temporal habits may
be affecting one’s physiology and, subsequently, one’s health.
Table of Contents
1.1 Orexin/hypocretin in arousal and stimulation of feeding
|Expression of Hrct/OX neurons in the LH, perifornical n. and posterior hypothalamus|
|Rat hypothalamus: (top) WT, with adrenal gland removed,
activity rescued with DEX.
Orexins, also termed hypocretins, are peptide neuromodulators which bind GPCRs. There are two varieties: Orexin A (also called hcrt1) and Orexin B (hrct2), both synthesized exclusively in the lateral hypothalamus (LH) from prepro- Hrct/OX . Beyond the LH, Hrct/OX neurons have extensions in the perifornical nucleus and the posterior hypothalamus. There are two Hrct/OX receptors: receptor 1 binds mostly A type Hrct/OXs while receptor 2 binds both A and B types.
Hrct/OX neurons project, among other places, to the paraventricular nucleus (PVN) of the hypothalamus and the arcuate nucleus (AN). The PVN is involved in the initiation of feeding; as such, patients with lesions to the PVN exhibit anorexia. The Hrct/OX system is involved in appetite and food intake and may be a site of neuroendocrine disruptions associated with obesity.
1.1a Interactions with the hypothalamic-pituitary-adrenal-axis (HPA)
It is well known that the HPA-axis is implicated in obesity and anatomical evidence suggests interaction between the HPA-axis and Hrct/OX neurons. Corticotropin-releasing hormone (CRH) is released from the PVN. Relatedly; CRH neurons in the amygdala project to the LH. As such, Hrct/OX’s functional interaction with glucocorticoids has been investigated.
It has been demonstrated that the removal of the adrenal gland in rats, and subsequent disruption in the release of corticosterone, results in a 50% drop in the expression of prepro-Hrct/OX mRNA in the LH, with reductions of the synthesized peptide in the perifornical nucleus and posterior hypothalamus as well. Hrct/OX activity could be rescued, with mRNA expression returning to normal, with administration of dexamethasone (DEX), a synthetic glucocorticoid.
As the HPA-axis regulates itself by a system of negative feedback, a deficit in corticosterone would result in an increased release of CRH. As such, researchers speculate that in may be the increased expression of CRH in the PVN that is causing a decrease in Hrct/OX expression in the LH. Experiments, finding that administering CRH antagonists causes an increase in Hrct/OX-related activity, support this theory.
The Hrct/OX has been most extensively studied in its relation to arousal states and sleep. To this end, it has projects to the locus coerleus, the raphe nucleus, the basal forebrain, the pedunculopontine nucleus and the tuberomamillary nucleus. Hrct/OX neurons serve a stimulating role: they are active during waking and inactive during REM and slow wave sleep. Similarly, a rise in Hrct/OX levels can be induced by sleep deprivation and injecting Orexin A will increase one’s wakefulness.
Narcolepsy is associated with abnormalities in sleep/wake cycling, including sudden episodes of REM sleep interrupting waking and hyper-somnolence throughout the day. Patients also often suffer periods of clinical depression. Recently, it was discovered that
narcolepsy arises from a mutation in Hrct/OX receptor 2, such that it will not bind Orexins. Hrct/OX receptor 1 knock-out mice also exhibit symptoms,
albeit more mild, of narcolepsy.
Hrct/OX's involvement with both feeding and sleeping behaviours suggests that it has an important role in controlling energy homeostasis in the body.
1.2 Interaction between the SCN and peripheral oscillators
|The body's "master" clock|
|The SCN is entrained predominantly by photic cues.
The SCN, the body’s “master” circadian clock is predominantly entrained by photic cues. In certain insects, like Drosophila, circadian clocks in peripheral tissue are also known to be entrained by light-dark signals. However, this is not the case in mammals. As such, peripheral clocks are sensitive to a variety of non-photic entrainment cues. Equally, to maintain synchrony between master and peripheral clocks, the SCN and circadian oscillators require tighter internal interaction. Peripheral clocks in organs, the organs having been removed from an animal, will maintain cycling for several days, but this will eventually dampen. This is due, in part, to a loss of interaction and synchrony with the SCN.
While peripheral oscillators seem intuitively useful, they do not exist for the expected purpose of the efficiency in resource consumption. Rather, they act to temporally coordinate metabolic reactions, such that chemically incompatible reactions do not antagonize each other by proceeding simultaneously.
The mechanism by which the SCN communicates with peripheral oscillators is thought to be indirect in nature. That is: rather than secreting hormones with the express purpose of entrainment, the SCN likely controls clocks in peripheral tissue via the rest-activity cycle, which, among other things, would dictate the time of meals.
1.2a Feeding time and entrainment
Feeding time seems to be the predominant entrainment factor for peripheral clocks: feeding nocturnal lab animals during daylight will invert circadian gene expression in a number of visceral organs, but has no direct effect on the cycling of the SCN. These observations have lead to terming body sites influenced by feeding time food-entrainable-oscillators (FEOs).
The exact mechanism through which food interacts with FEOs is not known, although a few candidates have been eliminated. Glucocorticoids, while they are importantly involved in feeding and likely interact with the Hrct/OX system, cannot be the mechanism, as rats deficient in glucocorticoids are immediately responsive to food-induced phase-shifts. Thus, glucocorticoids may actually be a relay for the SCN in controlling peripheral oscillators and dampening desynchronization, which may result from usual feeding times.
|The SCN's control over peripheral clocks is largely indirect|
As the gastrointestinal tract is dense with endocrine cells, it may be peptide hormones which originate from digestion which interact with FEOs and can induce phase-shifting. MAP kinases, as well as CREB likely underlie temporal changes in circadian gene expression. Thus, digestive peptides which signal cascade reactions causing the phosphorylation of CREB may serve as relay between food and FEOs. Two such peptides are CKK and gastrin, which, signaling through the CKK-B/gastrin receptor, cause the downstream phosphorylation of CREB. Ingested macromolecules themselves, like glucose, and metabolites resultant from cellular respiration may also perform a similar function.
1.3 Effects of sleep deprivation
It is a well-documented phenomenon that sleep deprivation induces an increase in food intake. In fact, it has been shown that even a single night of sleep deprivation or sleep restriction (4.5 hours) will increase circulating levels of ghrelin in the body, as well as feelings of hunger.
It has been speculated that this increase in food consumption may serve to reverse an energy deficit from extended waking. The Hrct/OX system, in addition to projecting to the PVN, sends axons to the arcuate nucleus, where it makes direct contact with NPY secretory neurons. This suggests that the behaviour may instead be due to prolonged stimulation of the Hrct/OX neurons in the LH.
A 2009 experiment, using rats as a model, subjected them to either: a discrete period of sleep deprivation (several days) or a longer period of sleep restriction (three weeks) and monitored their feeding behaviours as well as expression of Hrct/OX. The latter was done by measuring prepro-orexin mRNA in the LH, as well as levels of NPY. A marked increase in food intake was noted after 72 hours of sleep deprivation and this was preceded first by an increase in prepro-orexin mRNA, followed by an increase in NPY.
2.1 Desynchronization and relation to pathology
As the SCN is entrained by photic cues while peripheral clocks are otherwise entrained, by cues much more subject to temporal habits, there is the possibility for internal desynchrony (ID). ID, as shown in rats, can result from activity during hours normally spent sleeping, thus, it can be induced by shift work. ID causes neuroendocrine dysregulation and is associated with a number of cancers, obesity and type II diabetes.
2.1a Depression and Hrct/OX
|Unusual temporal patterns can generate internal desynchrony|
|Desynchronization may be related to the development of disease.|
Depression, in addition to symptoms of low mood, anhedonia, etc., is also often associated with disruptions in sleep schedule. Both narcoleptics and those suffering from a major depressive episode show an increase in REM sleep. Studies, using mice with depressive-like sleep patterns, found that these sleep disruptions were associated with 18% fewer Hrct/OX A cells in the LH as compared to mice with normal sleep patterns. Interestingly, most antidepressants have a suppressive effect on REM sleep. Equally Hrct/OX neurons are speculated to interact with the HPA-axis and their expression may be reduced with high levels of CRH. Thus, it is possible that Hrct/OX neurons are a site of influence for ADs or that their activity is modulated indirectly by ADs interacting with the HPA-axis.
2.1b Night-Eating Syndrome (NES) and obesity
Those with NES suffer insomnia and, perhaps as a result or actually underlying their sleep disruption, consume approximately 25% of their daily energy intake after eating dinner. Additionally, they will often skip breakfast. Those affected by NES often exhibit symptoms of depression and the syndrome is more common among individuals with affective disorders in general, but especially schizophrenia and bulimia nervosa. While it is not always associated with weight gain, NES is more often observed in overweight individuals. Weight gain may arise for a number of reasons: more time to eat during the evenings, increased feelings of hunger associated with sleep deprivation, less physical activity during the day due to fatigue. Weight loss
seems to be an effective way to treat NES, suggesting that obesity-associated neuroendocrine dysregulation may underlie some of the
NES may serve as an important model for examining the role of feeding time on FEOs and the ways in which associated peripheral tissue
oscillators are affected. Moreover, how ID is associated with pathology.
|Dualist thinking may land you
with neuroendocrine dysregulation!
|Circadian rhythms and behaviour influence
each other reciprocally.