Rhythm/Sleep Endophenotypes in Human CNS Disease and in Mouse Models.

<p>Rhythm/Sleep Endophenotypes in Human CNS Disease and in Mouse Models.</p

The Mammalian Molecular Circadian Oscillator.

<p>The molecular circadian oscillator incorporates numerous transcriptional and posttranslational elements. Disruptions in many of the individual circadian elements in mice can lead to behavioural disturbances that mirror endophenotypes in human neurological and psychiatric disorders. Moreover, some studies have established circadian gene polymorphisms in psychiatric conditions and mutations in behavioural syndromes (see text for details). The central component of the figure depicts the core mammalian circadian feedback loop. CLOCK(or NPAS2):BMAL1 heterodimers drive the transcription of multiple genes (<i>Cry1/2</i>, <i>Per1-3</i>, <i>Rev-Erba/b</i>, <i>Rora/b/c</i>, multiple CCGs) through E-box elements. Nuclear accumulation of CRY and PER proteins can inhibit CLOCK:BMAL1-mediated transcription by directly interacting with the complex (black bar–ended arrow). As PER and CRY levels fall, the negative repression is lifted and CLOCK:BMAL1-driven transcription re-occurs. In an additional stabilising loop, REV-ERB and ROR proteins co-regulate the transcription of <i>Bmal1</i> by competing for RREs in its promoter sequence. Rhythmic output of the clock is achieved through E-box elements in CCG which can impact a range of cell processes and physiology. The stability and subcellular localisation of circadian proteins is highly regulated by kinases and phosphatases (inset box). Although not entirely understood, the phosphorylation state of circadian proteins can affect their cellular localisation and/or stability. Mutations affecting the stability of Per proteins can accelerate the molecular clock in humans, leading to the inherited syndrome familial advanced sleep phase syndrome (FASPS).</p

The corticosterone response to the forced swim test.

<p>A significant increase in plasma corticosterone level was seen following the forced swim (F = 160, P<0.0001) but there was no effect of genotype on either corticosterone level at baseline or in response to stress. (Data shown is mean ± SEM).</p

Evidence of association between SNPs in <i>FBXL3</i> and bipolar disorder in three independent samples

<p>(WTCCC <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038263#pone.0038263-TheWellcomeTrustCaseControl1" target="_blank">[30]</a>, Sklar et al <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038263#pone.0038263-Sklar1" target="_blank">[31]</a> and Cichon et al <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038263#pone.0038263-Cichon1" target="_blank">[32]</a>).</p

Immobility in the forced swim test is attenuated in after hours mice.

<p>Results from the forced swim test indicate no significant difference in immobility in trial 1 but the increase in immobility observed in trial 2 was not seen in <i>Afh/Afh</i> mice. (Data shown is mean ± SEM). **, <i>P</i><0.01 results from posthoc t-tests comparing immobility in trial 1 <i>vs.</i> trial 2 in <i>Afh/Afh. Afh</i>/+ and +/+ mice.</p

Unadjusted SNP p-values for SNPs in FBXL3 reaching significance p<0.05 in at least one study.

<p>Unadjusted SNP p-values for SNPs in FBXL3 reaching significance p<0.05 in at least one study.</p

Anxiety-like behaviour is lower in after hours mice.

<p>In the open field test (A-D) <i>Afh</i>/<i>Afh</i> mice entered the central zone more frequently and spent more time there but did not differ in activity measures of speed and distance in the outer zone. In the light-dark box (E–H) <i>Afh</i>/<i>Afh</i> mice entered the light compartment more often and spent more time there and had increased speed in the dark compartment but did not differ in distance travelled in the dark compartment. In the elevated plus maze (I-L), <i>Afh</i>/<i>Afh</i> mice spent more time in the open arms but did not differ in their frequency of entry or closed arm activity measures. (Data shown is mean ± SEM). **<i>P</i><0.01, *<i>P</i><0.05, ^#<i>P</i> = 0.06; effects of genotype in posthoc t-tests (<i>Afh</i>/<i>Afh vs. Afh</i>/+ and +/+<i>)</i>.</p

The effect of after hours genotype on exploratory and anxiety-like behaviour in the holeboard.

<p>Results from the holeboard test indicate no difference in exploratory behaviours (A–B) or overall activity (C–D). <i>Afh</i>/<i>Afh</i> mice spent more time in the centre (E) but did not differ in their number of entries (F). (Data shown is mean ± SEM). **, <i>P</i><0.01 effects of genotype in posthoc t-tests (<i>Afh</i>/<i>Afh vs. Afh</i>/+ and +/+<i>)</i>.</p

The arousal-promoting and sleep-promoting effects of nocturnal light exposure in mice depend upon different neural pathways.

<p>In response to blue light, M1 pRGC projections to the SCN result in activation of the adrenal gland via the ANS. This alertness promoting pathway is associated with corticosterone release and increased waking. This pathway is strongly activated by blue light due to the spectral sensitivity of melanopsin which peaks ~480 nm. Loss of melanopsin results in reduced activation of this pathway, resulting in enhanced sleep induction. Additional arousal-promoting pathways undoubtedly contribute to this response. By contrast, green light results in activation of the sleep-promoting VLPO pathway, most likely via non-M1 melanopsin pRGCs that are more dependent upon rod and cone input. As melanopsin plays a critical role in rod and cone adaptation, under bright light conditions, loss of melanopsin results in attenuated sleep induction via this pathway. Moreover, the resultant saturation of rod and cone pathways also results in a loss of chromatic responses.</p

Wavelength-dependent effects on light on sleep induction and sleep duration.

<p>(<b>A</b>) Mice exposed to different wavelengths (405 nm violet, 470 nm blue, or 530 nm green) for 1 hr at ZT14 exhibited differences in sleep onset and sleep duration. (<b>B</b>) Sleep induction is delayed in response to blue light exposure. One-way ANOVA for wavelength, F_(2.23) = 18.791, <i>p</i> ≤ 0.001. Posthoc Tukey violet versus blue <i>p</i> = 0.003, violet versus green <i>p</i> = 0.041, blue versus green <i>p</i> ≤ 0.001. (<b>C</b>) Total sleep duration during the 1 h light pulse is reduced in response to blue light. Data plotted as mean percentage ± SEM (<i>n</i> = 8–10/group). Horizontal black-white-black bar illustrates the light pulse condition from ZT14 until ZT15. One-way ANOVA for wavelength, F_(2.23) = 4.391, <i>p</i> = 0.024. Posthoc Tukey violet versus blue <i>p</i> = 0.046, violet versus green <i>p</i> = 0.517, blue versus green <i>p</i> = 0.008. Statistical differences indicated by *** <i>p</i> ≤ 0.001, ** <i>p</i> ≤ 0.01, * <i>p</i> ≤ 0.05, NS = not significant. The data used to make this figure can be found in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1002482#pbio.1002482.s001" target="_blank">S1 Data</a>.</p