Is SCN the master mammalian clock? Flashcards
What two studies showed that SCN may be the master clock? Why did they not prove it?
In 1972, lesions of the rat SCN were reported to abolish circadian rhythms of behavioral (wheel running/locomotor and drinking) (Stephan and Zucker, 1972) and endocrine (corticosterone) (Moore and Eichler, 1972) activity.
However, whilst these two studies indicated that the SCN was important for circadian rhythms throughout the body, they didn’t necessarily show that the SCN was the central clock. For instance, it was possible that the SCN could contain the central clock OR that it connected the central clock to motor centres controlling the rhythmic behaviour.
Welsh et al., 1995
In 1995, individual dissociated SCN neurons were shown to oscillate independently with different circadian periods in vitro (Welsh et al., 1995), demonstrating that a circadian clock was localized within individual cells rather than arising as an emergent property of an SCN network.
Which study gave the definitive proof that the SCN was the master clock?
The definitive proof that the SCN is the master clock for an animal’s behavior came when Michael Menaker and colleagues transplanted SCN from tau mutant hamsters into SCN-lesioned wild-type hosts. The behavior of the host invariably ran with the free-running period of the donor SCN graft (Ralph et al., 1990). This showed that the SCN was the master clock as it was necessary and sufficient to orchestrate timings of circadian rhythms in the rest of the body.
Ralph et al., 1988
He dicovered a tau mutant hamster. The heterozygous mutant had a 22-hour clock whereas the homozygous mutant had a 20 hour clock (ran 4 hours earlier everyday).
Is the master clock- peripheral clock arrangement clear in mammals?
In mammals, the SCN is seen as the master clock as it receives direct input from the retina via the retino‐hypothalamic tract (Berson et al., 2002), meaning that the rhythm in the SCN can be entrained by an external zeitgeber: the rhythmic chnage of light and dark.
Furthermore, the neurons within the SCN have shown to be coupled. As an ensemble they produce electrical and molecular circadian rhythms of a robustness not seen in isolated neurons and other types of cells (peripheral clocks) (Li et al., 2007). This robust circdian rhythm is then thought to subsquently synchronise peripheral clocks with each other, and thus align the entire circadian system to the external light‐dark cycle, supporting the idea of a top-down control of the master SCN.
However, this model of a strictly SCN‐centric/master circadian control has been challenged.Timing signals other than light, such as rhythmically timed food intake, can potently reset peripheral clocks directly without affecting clock rhythms in the SCN (Damiola et al., 2000).
Furthemore, Ishida et al., (2005) showed that light exposure can acutely activate clock gene expression and glucocorticoid release in the adrenal gland via sympathetic innervation by the splanchnic nerve, and this effect appears to be independent of photic responses at the level of the SCN (Keissling et al., 2014)
What is the limatation of SCN lesion studies?
A significant limitation of lesions is that they not only ablate the structure in question, but also interrupt the associated neuronal networks. Since the SCN is also part of such a network, it is necessary that classical SCN surgical experiments are complemented by alternative approaches such as SCN‐specific deletion of clock genes that preserves the neuronal circuit.
Do peripheral clocks in mammals exist. What is the difference between peripheral clocks and the SCN?
Numeruous circadian clocks have been shown to exist outside the SCN in peripheral tissues such as the liver, heart, lung and muscle. The presence of mammalian peripheral clocks has been demonstrated by measuring circadian gene expression in cultured fibroblasts or tissue explants.
Unlike the central pacemaker in the SCN, these peripheral oscillators are not directly entrained by light. Instead, output signals from the SCN or other external stimuli, such as feeding, can control the circadian rhythmicity of the peripheral local clocks.
Although the peripheral oscillators share the same basic molecular components with the central pacemaker, the peripheral clocks are thought to be less self-sustainable while the master pacemaker is indispensible for rhythm generation in peripheral clocks. Indeed, circadian rhythms in peripheral clocks of liver, lung and skeletal muscle are damped in two to seven days, whereas the SCN exhibits robust rhythmicity up to 30 days in vitro (Yamazaki et al., 2000). These findings strongly support the hierarchical organization of circadian oscillators, where the self-sustainable SCN clock entrains other easily dampened peripheral oscillators. However, Yoo et al., (2004) showed that the explants of peripheral tissues, such as liver and lung, could also sustain the circadian rhythmicity of PER2 expression for more than 20 days.
Why is the master SCN- peripheral clock not at all clear cut in other species?
However, unlike mammals, Drosophila peripheral cellular circadian clocks can be directly entrained by light, meaning that environmental cycles can be directly coordinated with cellular physiology in the absence of specialised clock centres (Plautz et al. 1997). This decentralization of the clock organisation is also observed in other clock models such as zebrafish (Whitmore et al. 1998, 2000).
What did Whitmore et al., 1998, 2000 find?
What did (Carr and Whitmore, 2005) which adds to this?
He found that in zebrafish, clock gene expression in numerous tissues, such as the brain, eye, pineal gland, kidney and heart oscillated in levels on a L-D cycle, but remained contanst on a D-D cycle. In addition when the kidney and heart cell cultures were placed in a reverse L-D cycle, he found that the peaks and troughs of Clock expression was also then reversed. This showed that light directly influenced the circadian oscillation in peripheral tissues, and set the phase of the clock, indicating the decentralisation of the clock system in zebrafish.
Carr and Whitmore (2005) showed that with single-celled imaging, individual cells do continue to oscillate in darkness, but have widely distributed circadian phases. They also showed that a single 15 min light pulse reset desynchronous cellular oscillations to a common phase.
What did Plautz et al., 1997/1998 find?
Transgenic Drosophila that expressed the per:luciferase construct were used to monitor the circadian clock in peripheral tissues. The peripheral tissues were found to have rhythmic bioluminescence (rhthymic per gene expression), and the rhythms could be reset by light and phase-shifted. These results showed that individual cells in Drosophila are capable of supporting their own independent clocks.
Dibner et al., (2010)
Dibner et al., (2010) showed that peripheral tissues and cells seem to possess self-sustainable circadian clocks that can generate overt rhythms in the absence of the central pacemaker. Thus it can be said that the SCN is a master synchronizer rather than a driver for persistent circadian rhythmicity in the peripheral tissues.
