Generating circadian rhythms (central + peripheral)

Question 1

Kawamura

Answer 1

1979, inserted fine electrode in rate brain to measure the electrical activity of multiple neurons. fount hat neurons within the SCN exhibited circadian rhythms of electrical activity (high in the day), whilst neurons just outside the SCN showed the opposite.
When the SCN was isolated, the rhythm in the SCN continued but that in neighbouring cells was abolished

Question 2

Welsch

Answer 2

1995, single-cell recordings from dispersed SCN neurons (using multielectrode arrays) showed that these isolated cells exhibited a range of autonomous periods (22-30hrs), thus indicating that the clock is a product of subcellular mechanisms.
Argued that intracellular couple acts to mutually couple the entire population to a narrow period range (though cell:cell interactions)

Question 3

Ko

Answer 3

2010, Found that although BMAL1 KO mice SCN neurons lack cell autonomous oscillatory potential, SCN explants express highly variable stochastic oscillations. Thus, coupling pathwas can propagate rhythms that reflect feed-forward coupling mechanisms, and rhythmicity can arise as a network property

Question 4

Konopka and Benzer

Answer 4

1971, first described the genetic material responsible for circadian rhythms in flies

Question 5

Lucas (cell essay)

Answer 5

2003, evidence that the intrinsic excitability of these cells is melanopsin-dependent

Question 6

Panda (cell essay)

Answer 6

2002, melanopsin is critical for photoentrainment

Question 7

Jagannath

Answer 7

2013, found evidence for/discovered the entrainment pathway.
In vitro evidence: using immortalised mouse embryonic fibroblast cell lines, found that serum shock lead to the nuclear localisation of dephosphorylated CRTC1, and upregulation os Per1 and Sik1
In vivo evidence: using knock-down of Sik1 via siRNA injections into the 3rd ventricle adjacent to the SCN. Found this resulted in enhanced behavioural responses to light (increased phase shifts and rapid re-entrainment after experiencing jet-lag).

Question 8

Schibler

Answer 8

1998, cultured rat-1 fibroblasts of H35 hepatoma cells and treated them with high concentrations of serum (acts as an entraining stimulus to induce rhythmic expression of various genes). Found that up to 3 consecutive days of oscillations of genes whose transcription oscillated in living animals could be recorded (with period approx 22.5hrs)

Question 9

Yoo

Answer 9

2004, using a clock gene reporter mouse (Period2:Luciferase), showed that peripheral tissues are capable of self-sustained oscillations for over 20 cycles in isolation.
SCN lesion did not abolish peripheral tissue rhythms, but did cause desynchrony in the rhythms among tissues

Question 10

Liu

Answer 10

2007, using a Period2:Luciferase reporter mouse line, studied Per or Cry loss-of-funciton mutations. These caused subtle changes at the behavioural level, and in SCN explants (coupling of the cells could rescue cell-autonomous defects).
However, it caused strong loss-of-rhythm phenotype in peripheral tissue, due to a lack of coupling.
Thus, mutations can differentially affect SCN/peripheral tissue

Question 11

Kornmann

Answer 11

2007, overexpression of Rev-erb(alpha) in the mouse liver to cause genetic disruption of the circadian clock specifically in hepatic cells.
Liver mRNA microanalysis showed arrhythmicity of most hepatic transcripts, indicating that they rely on the intact clock for rhythmic transcription.
However, a subset of genes (including Per2) still cycled robustly (though not in liver explants), indicating that these genes might be responding to rhythmic system cues generated by SCN-driven behaviour rhythms in vivo.

Question 12

Cailotto

Answer 12

2009, found that autonomic innervation of the liver was essential to transmit light information from the SCN. Thus, the ANS is an imporant gateway for the SCN to cause immediate peripheral physiology resetting after phase-shift inducing light exposure

Question 13

Balsobre

Answer 13

2000, foudn that dexamethasone (a glucocorticoid analog) could shift peripheral tissue phase in vivo

Question 14

Reddy

Answer 14

2007, found evidence that glucocorticoids can synchronise the circadian expression of much of the oscillatory components of the liver transcriptome in SCN-lesioned mice by activating the nuclear receptor HNF4(alpha)

Question 15

Vollmers

Answer 15

2009, found that many liver transcripts of Cry1/2 null mice showed rhythms when the mice were fed in regular 24hr rhythms

Question 16

Saini

Answer 16

2013, carried out an in vivo transduction of mouse hepatocytes with adenovirus-BMAL1-Luciferase. Found that feeding rhythms entrained the liver.
Found that oscillations synchronised my rapidly to feeding rhythms in SCN-lesioned mice than in intact-SCN mice

Question 17

Jones

Answer 17

1999, studies 3 kindreds with profound sleep-wake phase advance and short melatonin and temperature rhythm periods, leading to the discovery of familian short phase syndrome (FASPS)

Question 18

Toh

Answer 18

2001, reported a strong localisation fo the FASPS gene to the same locus as hPer2 (near the telomere of chromosome 2q).
Sequence analysis showed it resulted in a mutation in the CKlepsilon binding region of hPER2, thus making it less readily degraded, thus resulting in phase advance

Question 19

Thorpy

Answer 19

1998, foundt hat over 50% of teens with DSPS had depression

Question 20

Cho

Answer 20

2001, 2002, found learning and memory deficits and reduced temporal lobe volume in chronically jet-lagged flight attendants

Question 21

Van Cauter

Answer 21

2004, carried out a study on healthy 30yr old men in which they slept 4hrs a night for 2 nights, or 10hrs a night for 2 nights.
Short sleep was associated with reduced leptin levels, and increased grehlin levels, hunger and appetite

Question 22

Hirotsu

Answer 22

2015, showed that stress is involved in the underlying relationship between sleep and metabolism, though the activation of the HPA axis.
Sleep disorders are associated with changes in the HPA axis, which can lead to neuroendocrine dysregulation